биологии и медицины

Эпигенетика

Под редакцией С.Д. Эллиса,

Т. Дженювейна, Д. Рейнберга

Перевод с английского
под редакцией д.б.н. А.Л. Юдина

ТЕХНОСФЕРА
Москва
2013
УДК 575
ББК 28.04
Э71
Э71 Эпигенетика
Под ред. С.Д. Эллиса, Т. Дженювейна, Д. Рейнберга
Москва: Техносфера, 2013. – 496 c. ISBN 978-5-94836-257-1

Книга ярко и наглядно повествует о новой науке общебиологического значения – эпигенетике,

а также об ее отдельных областях. В издании представлено детальное описание разных эпигенети-
ческих сигналов и механизмов их реализации, а также собственно феномен, история и концепции
эпигенетики, ее отдельные механизмы и пути реализации эпигенетических сигналов в клетке.
Авторы различных глав данной книги – ведущие в мире специалисты в области эпигенетики,
являющиеся, как правило, и основоположниками ее отдельных областей.
Издание будет полезно широкому кругу читателей, интересующихся коренными проблемами
живого мира, сущности жизни и молекулярных механизмов ее проявления.
УДК 575
ББК 28.04

Originally published in English as Epigenetics edited by C. David Allis, Thomas Jenuwein,

Danny Reinberg and associate editor Marie-Laure Caparros, © 2007 Cold Spring Harbor
Laboratory Press, Cold Spring Harbor, New York, USA
© 2013, ЗАО «РИЦ «Техносфера», перевод на русский язык, оригинал-макет,
оформление
Официальный русский перевод английского издания © 2007 Cold Spring Harbor
Laboratory Press. Перевод издан и распространяется с разрешения Cold Spring
Harbor Laboratory Press, владельца всех прав, уполномоченного выдавать
лицензии, издавать и продавать их

ISBN 978-5-94836-257-1
ISBN 978-087969724-2 (англ.)
ÎÃËÀÂËÅÍÈÅ

Ïðåäèñëîâèå ê ðóññêîìó èçäàíèþ ............................................................................................................................. 12

Ãëàâà 1
Ýïèãåíåòèêà: îò ÿâëåíèÿ ê îáëàñòè íàóêè ................................................................................................................ 13
Daniel E. Gottschling
1. Ââåäåíèå .................................................................................................................................................................... 13
2. Èñòîðèÿ ýïèãåíåòèêè íà ñèìïîçèóìàõ Êîëä Ñïðèíã Õàðáîð ................................................................................. 14
3. 69-é ñèìïîçèóì ......................................................................................................................................................... 19
3.1. Ãèïîòåçà ãèñòîíîâîãî êîäà ................................................................................................................................ 19
3.2. Äèíàìè÷åñêèé «ìîë÷àùèé» õðîìàòèí ............................................................................................................. 20
3.3. ßäåðíàÿ îðãàíèçàöèÿ ........................................................................................................................................ 20
3.4. Ïðèîíû .............................................................................................................................................................. 21
3.5. Íîâîå ÿâëåíèå ................................................................................................................................................... 21
4. Çàêëþ÷èòåëüíûå ñîîáðàæåíèÿ ................................................................................................................................. 21
Áëàãîäàðíîñòè ............................................................................................................................................................... 22
Ëèòåðàòóðà ..................................................................................................................................................................... 22
Ãëàâà 2
Êðàòêàÿ èñòîðèÿ ýïèãåíåòèêè .................................................................................................................................... 26
Gary Felsenfeld
1. Ââåäåíèå .................................................................................................................................................................... 26
2. Êëþ÷è îò ãåíåòèêè è áèîëîãèè ðàçâèòèÿ ................................................................................................................. 27
3. Âî âñåõ ñîìàòè÷åñêèõ êëåòêàõ îðãàíèçìà ÄÍÊ îäèíàêîâà ..................................................................................... 27
4. Ðîëü ìåòèëèðîâàíèÿ ÄÍÊ ........................................................................................................................................ 28
5. Ðîëü õðîìàòèíà .......................................................................................................................................................... 28
6. Âñå ìåõàíèçìû âçàèìîñâÿçàíû ................................................................................................................................. 30
Ëèòåðàòóðà ..................................................................................................................................................................... 31
Ãëàâà 3
Îáùèé îáçîð è îñíîâíûå ïîíÿòèÿ ............................................................................................................................. 33
C. David Allis, Thomas Jenuwein è Danny Reinberg
Îáùåå ðåçþìå ............................................................................................................................................................... 33
1. Ãåíåòèêà vs. ýïèãåíåòèêà ........................................................................................................................................... 34
2. Ìîäåëüíûå ñèñòåìû äëÿ èçó÷åíèÿ ýïèãåíåòèêè ..................................................................................................... 36
3. Îïðåäåëåíèå ýïèãåíåòèêè ........................................................................................................................................ 38
4. Õðîìàòèíîâàÿ ìàòðèöà ............................................................................................................................................. 39
5. Áîëåå âûñîêèå óðîâíè îðãàíèçàöèè õðîìàòèíà ...................................................................................................... 40
6. Ðàçëè÷èå ìåæäó ýóõðîìàòèíîì è ãåòåðîõðîìàòèíîì............................................................................................... 44
7. Ìîäèôèêàöèè ãèñòîíîâ è ãèñòîíîâûé êîä.............................................................................................................. 46
8. Êîìïëåêñû, îñóùåñòâëÿþùèå ðåìîäåëèíã õðîìàòèíà, è âàðèàíòû ãèñòîíîâ ....................................................... 49
9. Ìåòèëèðîâàíèå ÄÍÊ ................................................................................................................................................ 50
10. ÐÍÊè è ñàéëåíñèíã ãåíîâ, íàïðàâëÿåìûé ÐÍÊ .................................................................................................... 51
11. Îò îäíîêëåòî÷íûõ ñèñòåì ê ìíîãîêëåòî÷íûì ....................................................................................................... 53
12. Polycomb è Trithorax ................................................................................................................................................. 55
13. Èíàêòèâàöèÿ Õ-õðîìîñîìû è ôàêóëüòàòèâíûé ãåòåðîõðîìàòèí .......................................................................... 57
14. Ðåïðîãðàììèðîâàíèå êëåòî÷íîé ñóäüáû ................................................................................................................ 58
15. Ðàê ............................................................................................................................................................................ 60
16.  ÷åì æå â äåéñòâèòåëüíîñòè çàêëþ÷àåòñÿ ýïèãåíåòè÷åñêèé êîíòðîëü? .............................................................. 62
17. Îñíîâíûå âîïðîñû â ýïèãåíåòè÷åñêèõ èññëåäîâàíèÿõ ......................................................................................... 64
Ëèòåðàòóðà ..................................................................................................................................................................... 65
Ãëàâà 4
Ýïèãåíåòèêà äðîææåé Saccharomyces cerevisiae ..................................................................................................... 71
Michael Grunstein è Susan M. Gasser
Îáùåå ðåçþìå ............................................................................................................................................................... 71
1. Ãåíåòè÷åñêèå è ìîëåêóëÿðíûå ìåòîäû èññëåäîâàíèÿ äðîææåé ............................................................................. 72
2. Æèçíåííûé öèêë äðîææåé ....................................................................................................................................... 73
4 Îãëàâëåíèå

3. Ãåòåðîõðîìàòèí ó äðîææåé íàõîäèòñÿ â «ìîë÷àùèõ» ëîêóñàõ òèïîâ ñïàðèâàíèÿ HM è òåëîìåðàõ....................... 74

4. Ãåòåðîõðîìàòèí îòëè÷àåòñÿ ðåïðåññèâíîé ñòðóêòóðîé, êîòîðàÿ ðàñïðîñòðàíÿåòñÿ íà âåñü ìîë÷àùèé äîìåí ..... 75
5. Îòäåëüíûå ýòàïû ñáîðêè ãåòåðîõðîìàòèíà .............................................................................................................. 77
5.1. HM ãåòåðîõðîìàòèí ........................................................................................................................................... 77
5.2. Òåëîìåðíûé ãåòåðîõðîìàòèí ............................................................................................................................ 78
6. Äåàöåòèëèðîâàíèå ãèñòîíîâ áåëêîì Sir2 îáåñïå÷èâàåò ñàéòû ñâÿçûâàíèÿ
äëÿ ðàñïðîñòðàíåíèÿ SIR-êîìïëåêñîâ ........................................................................................................................ 78
7. Sir2 äåàöåòèëèðóåò ãèñòîí H4 ïî 16-ìó îñòàòêó ëèçèíà........................................................................................... 79
8. Àöåòèëèðîâàíèå ãèñòîíîâ â ýóõðîìàòèíå îãðàíè÷èâàåò ðàñïðîñòðàíåíèå SIR-êîìïëåêñîâ ................................ 80
9. Îáðàçîâàíèå òåëîìåðíûõ ïåòåëü ............................................................................................................................. 80
10. Íàðóøåíèå íåïðåðûâíîñòè ðåïðåññèè åñòåñòâåííûõ ñóáòåëîìåðíûõ ýëåìåíòîâ òåëîìåðíûìè ïåòëÿìè ......... 81
11. Âçàèìîäåéñòâèå òåëîìåð in trans è ïåðèíóêëåàðíîå ïðèêðåïëåíèå ãåòåðîõðîìàòèíà ......................................... 81
12. Íàñëåäîâàíèå ýïèãåíåòè÷åñêèõ ñîñòîÿíèé ............................................................................................................ 82
13. Ñòàðåíèå è Sir2 ñâÿçàíû íåñòàáèëüíîñòüþ ïîâòîðîâ ðÄÍÊ ................................................................................. 83
14. Ðåçþìå...................................................................................................................................................................... 84
Ëèòåðàòóðà ..................................................................................................................................................................... 84
Ãëàâà 5
Ýôôåêò ïîëîæåíèÿ ìîçàè÷íîãî òèïà,ôîðìèðîâàíèå ãåòåðîõðîìàòèíà è ñàéëåíñèíã ãåíîâ ó Drosophila ........ 87
Sarah C.R. Elgin è Gunter Reuter
Îáùåå ðåçþìå ............................................................................................................................................................... 87
1. Ãåíû, îêàçûâàþùèåñÿ â íåíîðìàëüíîì ñîñåäñòâå ñ ãåòåðîõðîìàòèíîì, îáíàðóæèâàþò ìîçàè÷íûé ôåíîòèï .... 88
2. Ñêðèíèíã ñóïðåññîðîâ è ýíõàíñåðîâ PEV ïîçâîëèë èäåíòèôèöèðîâàòü õðîìîñîìíûå áåëêè
è ìîäèôèêàòîðû õðîìîñîìíûõ áåëêîâ ........................................................................................................................ 90
3. Èììóíîôëóîðåñöåíòíîå îêðàøèâàíèå ïîëèòåííûõ õðîìîñîì ïîçâîëèëî èäåíòèôèöèðîâàòü áåëêè,
ñïåöèôè÷åñêè àññîöèèðîâàííûå ñ ãåòåðîõðîìàòèíîì ............................................................................................... 93
4. Ìîäèôèêàöèÿ ãèñòîíîâ èãðàåò êëþ÷åâóþ ðîëü â ñàéëåíñèíãå ãåòåðîõðîìàòèíà .................................................. 95
5. Õðîìîñîìíûå áåëêè îáðàçóþò âçàèìîçàâèñèìûå êîìïëåêñû äëÿ ïîääåðæàíèÿ è ðàñïðîñòðàíåíèÿ
ãåòåðîõðîìàòèíîâîé ñòðóêòóðû .................................................................................................................................... 96
6. Êàê ôîðìèðîâàíèå ãåòåðîõðîìàòèíà «íàöåëèâàåòñÿ» ó Drosophila? ........................................................................ 97
7. Íå âåñü ãåòåðîõðîìàòèí èäåíòè÷åí ........................................................................................................................ 100
8. PEV, ôîðìèðîâàíèå ãåòåðîõðîìàòèíà è ñàéëåíñèíã ãåíîâ ó ðàçëè÷íûõ îðãàíèçìîâ .......................................... 101
9. Ïîäâåäåíèå èòîãîâ: ìû íå çíàåì î ãåòåðîõðîìàòèíå î÷åíü ìíîãîå ......................................................................... 102
Áëàãîäàðíîñòè ............................................................................................................................................................. 102
Ëèòåðàòóðà ................................................................................................................................................................... 103
Ãëàâà 6
Ãðèáû êàê ìîäåëüíûå îðãàíèçìû äëÿ ýïèãåíåòè÷åñêèõ èññëåäîâàíèé:
Schizosaccharomyces pombe è Neurospora crassa...................................................................................................... 106
Robin C. Allshire è Eric U. Selker
Îáùåå ðåçþìå ............................................................................................................................................................. 107
1. Schizosaccharomyces pombe: îðãàíèçì ....................................................................................................................... 107
1.1. Ñàéëåíñèíã õðîìàòèíà ó S. pombe îòëè÷àåòñÿ îò òàêîâîãî ó S. cerevisiae....................................................... 108
1.2. Ãåíû, ïîìåùåííûå â öåíòðîìåðû äðîáÿíêîâûõ äðîææåé, ñàéëåíñèðîâàíû ............................................... 108
1.3. Öåíòðîìåðû äðîáÿíêîâûõ äðîææåé ñîñòîÿò èç ðàçíûõ ãåòåðîõðîìàòèíîâûõ
è öåíòðàëüíûõ êèíåòîõîðíûõ äîìåíîâ................................................................................................................. 109
1.4. Öåíòðîìåðíûå âíåøíèå ïîâòîðû áåç ïîñòîðîííåé ïîìîùè äåëàþò âîçìîæíîé
ñáîðêó «ìîë÷àùåãî» õðîìàòèíà............................................................................................................................. 111
1.5. ÐÍÊ-èíòåðôåðåíöèÿ íàïðàâëÿåò ñáîðêó «ìîë÷àùåãî» õðîìàòèíà .............................................................. 112
1.6. Òðàíñêðèïöèÿ öåíòðîìåðíûõ ïîâòîðîâ ÐÍÊ-ïîëèìåðàçîé II ñâÿçûâàåò RNAi
ñ ìîäèôèêàöèÿìè õðîìàòèíà ................................................................................................................................ 113
1.7. «Ìîë÷àùèé» õðîìàòèí â öåíòðîìåðàõ íåîáõîäèì äëÿ îïîñðåäîâàíèÿ êîãåçèè
ñåñòðèíñêèõ öåíòðîìåð è íîðìàëüíîé ñåãðåãàöèè õðîìîñîì ............................................................................. 113
1.8. Ýïèãåíåòè÷åñêîå íàñëåäîâàíèå ôóíêöèîíàëüíîãî ñîñòîÿíèÿ öåíòðîìåðû ................................................ 114
1.9. Ðàçëè÷íûå ìåõàíèçìû ñàéëåíñèíãà ó ãðèáîâ ................................................................................................ 115
2. Neurospora crassa: èñòîðèÿ è îñîáåííîñòè îðãàíèçìà............................................................................................. 116
2.1. Ìåòèëèðîâàíèå ÄÍÊ ó Neurospora.................................................................................................................. 117
2.2. RIP — ñèñòåìà çàùèòû ãåíîìà, èìåþùàÿ êàê ãåíåòè÷åñêèå, òàê è ýïèãåíåòè÷åñêèå àñïåêòû ................... 119
2.3. Èññëåäîâàíèÿ ðåëèêòîâ RIP ïîçâîëèëî ïðîíèêíóòü â êîíòðîëü ìåòèëèðîâàíèÿ ÄÍÊ .............................. 120
2.4. «Ïîäàâëåíèå» (quelling) ................................................................................................................................... 121
2.5. Ìåéîòè÷åñêèé ñàéëåíñèíã, îñóùåñòâëÿåìûé íåñïàðåííîé ÄÍÊ (MSUD) ................................................. 122
 Îãëàâëåíèå 5

2.6. Âåðîÿòíûå ôóíêöèè è ïðàêòè÷åñêîå èñïîëüçîâàíèå RIP, «ïîäàâëåíèÿ» è MSUD ...................................... 123
3. Çàêëþ÷èòåëüíûå çàìå÷àíèÿ .................................................................................................................................... 124
Áëàãîäàðíîñòè ............................................................................................................................................................. 125
Ëèòåðàòóðà ................................................................................................................................................................... 125
Ãëàâà 7
Ýïèãåíåòèêà èíôóçîðèé............................................................................................................................................ 129
Eric Meyer è Douglas L. Chalker
Îáùåå ðåçþìå ............................................................................................................................................................. 130
1. Èíôóçîðèè: îäèíî÷íûå êëåòêè ñ äâóìÿ ðàçíûìè ãåíîìàìè ................................................................................ 131
2. Êîíúþãàöèÿ: ðåöèïðîêíîå îïëîäîòâîðåíèå îáíàðóæèâàåò íåìåíäåëåâñêóþ íàñëåäñòâåííîñòü ....................... 131
3. Öèòîïëàçìàòè÷åñêàÿ íàñëåäñòâåííîñòü ó èíôóçîðèé ........................................................................................... 132
4. Êîðòèêàëüíîå ïàòòåðíèðîâàíèå: ñëó÷àé ñòðóêòóðíîé íàñëåäñòâåííîñòè ............................................................ 133
5. Ìàêðîíóêëåóñû è ìèêðîíóêëåóñû: ìîäåëü àêòèâíîãî è «ìîë÷àùåãî» õðîìàòèíà ............................................... 135
5.1. Ðàçäåëåíèå ìèêðî- è ìàêðîíóêëåàðíûõ ãèñòîíîâ âûÿâëÿåò ðàçëè÷íóþ ðîëü âàðèàíòîâ ãèñòîíîâ............. 135
5.2. Ìîäèôèêàöèè õðîìàòèíà êîððåëèðóþò ñ ñîñòîÿíèÿìè àêòèâíîñòè ............................................................ 135
6. Â õîäå ðàçâèòèÿ ìàêðîíóêëåóñà ïðîèñõîäÿò îáùåãåíîìíûå ïåðåñòðîéêè ........................................................... 136
6.1. Âíóòðåííèå äåëåöèè ÄÍÊ: òî÷íûå (âíóòðèãåííûå IES) è íåòî÷íûå (ìåæãåííûå ïîâòîðû)
ñîáûòèÿ................................................................................................................................................................... 137
6.2. Ôðàãìåíòàöèÿ õðîìîñîì ................................................................................................................................. 138
7. Ìåõàíèçìû ïåðåñòðîåê ãåíîìà ............................................................................................................................... 138
8. Çàâèñÿùèé îò ãîìîëîãèè ñàéëåíñèíã ãåíîâ ó èíôóçîðèé ..................................................................................... 139
8.1. Ñàéëåíñèíã, èíäóöèðóåìûé òðàíñãåíàìè ...................................................................................................... 139
8.2. Ñàéëåíñèíã èíäóöèðóåòñÿ äâóíèòåâîé ÐÍÊ .................................................................................................. 139
9. Ïåðåñòðîéêè ãåíîìà íàïðàâëÿþòñÿ çàâèñÿùèìè îò ãîìîëîãèè ìåõàíèçìàìè .................................................... 140
9.1. Ýêñïåðèìåíòàëüíàÿ èíäóêöèÿ ñïåöèôè÷åñêèõ äåëåöèé â ðàçâèâàþùåìñÿ ìàêðîíóêëåóñå........................ 140
10. Ïàòòåðíû ïåðåñòðîåê îïðåäåëÿþòñÿ, âåðîÿòíî, ïóòåì ñðàâíåíèÿ ãåíîìîâ çàðîäûøåâîé ëèíèè
è ñîìàòè÷åñêîãî .......................................................................................................................................................... 141
10.1. Ïàðàäèãìà d48: ýïèãåíåòè÷åñêîå íàñëåäîâàíèå àëüòåðíàòèâíûõ ïåðåñòðîåê ............................................ 141
10.2. Ýïèãåíåòè÷åñêîå íàñëåäîâàíèå ýêñïåðèìåíòàëüíî èíäóöèðîâàííûõ äåëåöèé ......................................... 141
10.3. «Ñïîíòàííàÿ» ýëèìèíàöèÿ ÷óæåðîäíûõ ïîñëåäîâàòåëüíîñòåé, èíòðîäóöèðîâàííûõ
â ìèêðîíóêëåàðíûé ãåíîì..................................................................................................................................... 142
10.4. Ýêñïåðèìåíòàëüíîå «ñïàñåíèå» íàñëåäóåìûõ ìàêðîíóêëåàðíûõ äåëåöèé................................................. 142
10.5. Ýêñïåðèìåíòàëüíîå ïîäàâëåíèå ýëèìèíàöèè IES â ðàçâèâàþùåìñÿ ìàêðîíóêëåóñå ............................... 143
11. Trans-íóêëåàðíîå ñðàâíåíèå öåëûõ ãåíîìîâ, îïîñðåäîâàííîå ÐÍÊ-èíòåðôåðåíöèåé ..................................... 144
11.1. Ñâÿçü êîðîòêèõ ÐÍÊ ñ ýëèìèíàöèåé ÄÍÊ .................................................................................................. 145
11.2. Òðàíñïîðò ÐÍÊ èç ìàòåðèíñêîãî â çèãîòè÷åñêèå ìàêðîíóêëåóñû ó Paramecium ........................................ 145
12. Çàêëþ÷åíèå: ýëèìèíàöèÿ ÄÍÊ êàê ìåõàíèçì çàùèòû ãåíîìà ........................................................................... 146
13. Áóäóùèé âêëàä èññëåäîâàíèé íà èíôóçîðèÿõ â ýïèãåíåòèêó.............................................................................. 149
Ëèòåðàòóðà ................................................................................................................................................................... 149
Ãëàâà 8
RNAi è ñáîðêà ãåòåðîõðîìàòèíà .............................................................................................................................. 153
Robert Martiensser è Danesh Moazed
Îáùåå ðåçþìå ............................................................................................................................................................. 153
1. Îáçîð RNAi-ïóòè..................................................................................................................................................... 154
2. Ðàííèå äàííûå, ïîçâîëÿþùèå ïðåäïîëàãàòü, ÷òî ÐÍÊ ÿâëÿåòñÿ ïîñðåäíèêîì
â òðàíñêðèïöèîííîì ñàéëåíñèíãå ............................................................................................................................. 156
3. RNAi è ñáîðêà ãåòåðîõðîìàòèíà ó S. pombe ............................................................................................................ 156
4. Ìàëûå ÐÍÊ èíèöèèðóþò ñáîðêó ãåòåðîõðîìàòèíà â ñâÿçè ñ ýôôåêòîðíûì êîìïëåêñîì RNAi ........................ 158
5. Ñèíòåç dsRNA è îáðàçîâàíèå siRNA ...................................................................................................................... 159
6. Ìîäåëè ðàñïîçíàâàíèÿ ÐÍÊ-ÐÍÊ versus ÐÍÊ-ÄÍÊ ............................................................................................ 160
7. Êàê RNAi ðåêðóòèðóåò ýíçèìû, ìîäèôèöèðóþùèå õðîìàòèí? ............................................................................ 161
8. Ìîäèôèêàöèè õðîìàòèíà è ÄÍÊ ó Arabidopsis, îïîñðåäîâàííûå RNAi ............................................................... 162
9. Êîíñåðâàòèçì ìîäèôèêàöèé õðîìàòèíà, îïîñðåäîâàííûõ RNAi, ó æèâîòíûõ ................................................... 164
10. Çàêëþ÷èòåëüíûå çàìå÷àíèÿ .................................................................................................................................. 165
Ëèòåðàòóðà ................................................................................................................................................................... 165
Ãëàâà 9
Ýïèãåíåòè÷åñêàÿ ðåãóëÿöèÿ ó ðàñòåíèé .................................................................................................................. 169
Marjori Matzke è Mittelsten Scheid
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Îáùåå ðåçþìå ............................................................................................................................................................. 169

1. Ïðåèìóùåñòâà èñïîëüçîâàíèÿ ðàñòåíèé â ýïèãåíåòè÷åñêèõ èññëåäîâàíèÿõ ...................................................... 170
1.1. Ñõîäñòâî ðàñòåíèé è æèâîòíûõ ïî îðãàíèçàöèè (ýïè)ãåíîìà ....................................................................... 170
1.2. Ðàñòåíèÿ ïðåäîñòàâëÿþò äîïîëíèòåëüíûå íàïðàâëåíèÿ ýïèãåíåòè÷åñêèõ èññëåäîâàíèé ........................... 170
1.3. Ðàñòåíèÿ ëó÷øå âûíîñÿò íåêîòîðûå ìåòîäîëîãè÷åñêèå ìàíèïóëÿöèè,
êîòîðûå î÷åíü òðóäíî ïðèìåíèìû ê ìëåêîïèòàþùèì ....................................................................................... 173
1.4. Èññëåäîâàíèå ðàñòåíèé âíåñëî ñàìûé çíà÷èìûé âêëàä â ýïèãåíåòèêó ...................................................... 177
2. Ìîëåêóëÿðíûå êîìïîíåíòû õðîìàòèíà ó ðàñòåíèé .............................................................................................. 177
2.1. Ðåãóëÿòîðû ìåòèëèðîâàíèÿ ÄÍÊ ó ðàñòåíèé................................................................................................. 177
2.2. Ôåðìåíòû ìîäèôèêàöèè ãèñòîíîâ................................................................................................................. 179
2.3. Äðóãèå áåëêè õðîìàòèíà ................................................................................................................................. 180
3. Ìîëåêóëÿðíûå êîìïîíåíòû ïóòåé îïîñðåäîâàííîãî ÐÍÊi ñàéëåíñèíãà ........................................................... 182
3.1. Âûðàáîòêà ÐÍÊi-çàâèñèìîãî ñàéëåíñèíãà ó ðàñòåíèé ................................................................................. 182
3.2. Ïóòü 1: ñâÿçàííîå ñ òðàíñãåíàìè ïîñòòðàíñêðèïöèîííîå è èíäóöèðîâàííîå âèðóñàìè
çàìàë÷èâàíèå ãåíîâ (PTGS/VICS) ........................................................................................................................ 182
3.3. Ïóòü 2: ðåãóëÿöèÿ ðàçâèòèÿ ðàñòåíèé miÐÍÊ è òðàíñ-äåéñòâóþùèìè siÐÍÊ ............................................. 184
3.4. Ïóòü 3: ñâÿçàííûé ñ òðàíñãåíàìè òðàíñêðèïöèîííûé ñàéëåíñèíã,
íàïðàâëÿåìîå ÐÍÊ ìåòèëèðîâàíèå ÄÍÊ è îáðàçîâàíèå ãåòåðîõðîìàòèíà ....................................................... 186
4. Ýïèãåíåòè÷åñêàÿ ðåãóëÿöèÿ áåç ó÷àñòèÿ ÐÍÊ ...................................................................................................... 187
5. Ïåðñïåêòèâû ........................................................................................................................................................... 187
Ëèòåðàòóðà ................................................................................................................................................................... 188
WWW èñòî÷íèêè ................................................................................................................................................... 190
Ãëàâà 10
Ìîäèôèêàöèè õðîìàòèíà è ìåõàíèçì èõ äåéñòâèÿ............................................................................................... 191
Tony Kouzarides è Shelley L. Berger
Îáùåå ðåçþìå ............................................................................................................................................................. 191
1. Ãèñòîíû è àöåòèëèðîâàíèå èãðàþò ðåãóëÿòîðíóþ ðîëü â òðàíñêðèïöèè ............................................................. 192
2. Àöåòèëèðîâàíèå è äåàöåòèëèðîâàíèå .................................................................................................................... 193
3. Ôîñôîðèëèðîâàíèå ................................................................................................................................................. 195
4. Ìåòèëèðîâàíèå ....................................................................................................................................................... 196
4.1. Ìåòèëèðîâàíèå ëèçèíîâ ................................................................................................................................. 196
4.2. Äåìåòèëèðîâàíèå ëèçèíîâ .............................................................................................................................. 200
4.3. Ìåòèëèðîâàíèå àðãèíèíîâ ............................................................................................................................. 201
5. Äåèìèíèðîâàíèå ..................................................................................................................................................... 202
6. Óáèêâèòèëèðîâàíèå/äåóáèêâèòèëèðîâàíèå è ñóìîèëèðîâàíèå ........................................................................... 202
7. Òåìû â ìîäèôèêàöèÿõ ............................................................................................................................................. 203
7.1. Ãèñòîíîâûé êîä................................................................................................................................................ 203
7.2. Ïàòòåðíû ìîäèôèêàöèé ................................................................................................................................. 203
7.3. Èçìåíåíèÿ â ñòðóêòóðå õðîìàòèíà, ñâÿçàííûå ñ àêòèâàöèåé òðàíñêðèïöèè è ýëîíãàöèåé ........................ 204
8. Çàêëþ÷èòåëüíûå çàìå÷àíèÿ .................................................................................................................................... 205
Ëèòåðàòóðà ................................................................................................................................................................... 205
Ãëàâà 11
Òðàíñêðèïöèîííûé ñàéëåíñèíã, îñóùåñòâëÿåìûé áåëêàìè ãðóïïû Polycomb ................................................... 210
Ueli Grossniklaus è Renato Paro
Îáùåå ðåçþìå ............................................................................................................................................................. 211
1. Ââåäåíèå .................................................................................................................................................................. 211
1.1. Êîíöåïöèÿ êëåòî÷íîé ïàìÿòè ........................................................................................................................ 211
1.2. Ãåíåòè÷åñêàÿ èäåíòèôèêàöèÿ ãðóïïû Polycomb ............................................................................................. 212
2. Óñòàíîâêà ìåòîê ñàéëåíñèíãà íà õðîìàòèí ............................................................................................................ 214
2.1. Êîìïîíåíòû PRC2 è åãî ýâîëþöèîííûé êîíñåðâàòèçì ............................................................................... 214
2.2. Ìîäèôèöèðóþùàÿ õðîìàòèí àêòèâíîñòü PRC2 ............................................................................................ 216
2.3. Äèíàìè÷åñêàÿ ôóíêöèÿ PRC2 â ðàçâèòèè...................................................................................................... 218
3. Ïîääåðæàíèå òðàíñêðèïöèîííîãî ñàéëåíñèíãà.................................................................................................... 219
3.1. Êîìïîíåíòû PRC1 .......................................................................................................................................... 219
3.2. «Íàöåëèâàíèå» PRC1 íà ñàéëåíñèðîâàííûå ãåíû......................................................................................... 220
3.3. Óñòàíîâëåíèå ðåïðåññèâíûõ ôóíêöèé ñ ïîìîùüþ PRC1.............................................................................. 222
3.4. Ïðåäîòâðàùåíèå íàñëåäóåìîé ðåïðåññèè àíòèñàéëåíñèíãîì ...................................................................... 222
4. Ðåïðåññèÿ PcG â ðàçâèòèè ìëåêîïèòàþùèõ .......................................................................................................... 223
4.1. Îò ðåïðåññèè ãåíà ê ðåïðåññèè õðîìîñîìû ................................................................................................... 223
 Îãëàâëåíèå 7

4.2. Ïîñëåäñòâèÿ àáåððàíòíîé àêòèâàöèè òðàíñêðèïöèè .................................................................................... 224

4.3. Ïîääåðæàíèå ñóäüáû ñòâîëîâîé êëåòêè ......................................................................................................... 225
5. Çàêëþ÷åíèå è ïåðñïåêòèâû .................................................................................................................................... 226
Ëèòåðàòóðà ................................................................................................................................................................... 226
Ãëàâà 12
Ðåãóëÿöèÿ òðàíñêðèïöèè áåëêàìè ãðóïïû Trithorax ............................................................................................. 230
Robert E. Kingston è John W. Tamkun
Îáùåå ðåçþìå ............................................................................................................................................................. 230
1. Ââåäåíèå .................................................................................................................................................................. 231
1.1. Èäåíòèôèêàöèÿ ãåíîâ, ó÷àñòâóþùèõ â ïîääåðæàíèè äåòåðìèíèðîâàííîãî ñîñòîÿíèÿ ............................. 232
1.2. Áåëêè trxG ó äðóãèõ îðãàíèçìîâ ..................................................................................................................... 233
1.3. Áåëêè trxG èãðàþò ðàçíûå ðîëè â ýóêàðèîòè÷åñêîé òðàíñêðèïöèè ............................................................. 235
2. Ñâÿçè ìåæäó áåëêàìè trxG è õðîìàòèíîì .............................................................................................................. 236
2.1. Áåëêè trxG, ó÷àñòâóþùèå â ÀÒÔ-çàâèñèìîì ðåìîäåëèðîâàíèè õðîìàòèíà ................................................ 236
2.2. Áåëêè trxG, êîâàëåíòíî ìîäèôèöèðóþùèå íóêëåîñîìíûå ãèñòîíû............................................................ 240
3. Ñâÿçè ìåæäó áåëêàìè trxG è îáùåé òðàíñêðèïöèîííîé ìàøèíåðèåé ................................................................ 242
4. Áèîõèìè÷åñêèå ôóíêöèè äðóãèõ áåëêîâ trxG ........................................................................................................ 242
5. Ôóíêöèîíàëüíûå âçàèìîäåéñòâèÿ ìåæäó áåëêàìè trxG ....................................................................................... 242
6. Áåëêè trxG: àêòèâàòîðû èëè àíòèðåïðåññîðû? ...................................................................................................... 243
7. Âûâîäû è ïåðñïåêòèâû ........................................................................................................................................... 243
Ëèòåðàòóðà ................................................................................................................................................................... 245
Ãëàâà 13
Âàðèàíòû ãèñòîíîâ è ýïèãåíåòèêà........................................................................................................................... 247
Steven Henikoff è Mitchell Smith
Îáùåå ðåçþìå ............................................................................................................................................................. 247
1. Ó âñåõ îðãàíèçìîâ ÄÍÊ óïàêîâûâàåòñÿ àðõèòåêòóðíûìè áåëêàìè ...................................................................... 248
2. Ýóêàðèîòè÷åñêèå êîðîâûå ãèñòîíû ðàçâèëèñü èç ãèñòîíîâ àðõåé ........................................................................ 249
3. Îñíîâíàÿ ìàññà ãèñòîíîâ îòêëàäûâàåòñÿ ïîñëå ðåïëèêàöèè ÄÍÊ....................................................................... 250
4. Âàðèàíòû ãèñòîíîâ îòêëàäûâàþòñÿ íà ïðîòÿæåíèè âñåãî êëåòî÷íîãî öèêëà ...................................................... 251
5. Öåíòðîìåðû èäåíòèôèöèðóþòñÿ ñïåöèàëüíûì âàðèàíòîì Í3 ............................................................................ 252
6. Çàìåùåíèå ãèñòîíîâûì âàðèàíòîì Í3.3 îáíàðóæèâàåòñÿ â àêòèâíîì õðîìàòèíå .............................................. 254
7. Ôîñôîðèëèðîâàíèå Í2ÀÕ ôóíêöèîíèðóåò â ðåïàðàöèè äâóíèòåâûõ ðàçðûâîâ ÄÍÊ ......................................... 255
8. H2AZ èãðàåò ðîëü â ðåãóëèðîâàíèè òðàíñêðèïöèè ............................................................................................... 257
9. Áåëêîâûå êîìïëåêñû äëÿ îòêëàäêè è çàìåùåíèÿ âàðèàíòîâ Í2À ........................................................................ 258
10. Äðóãèå âàðèàíòû Í2À äèôôåðåíöèðóþò õðîìàòèí, íî èõ ôóíêöèè âñå åùå íåèçâåñòíû ................................. 259
11. Ýâîëþöèÿ ìíîãèõ ãèñòîíîâ áûëà íàïðàâëåíà íà áîëåå ïëîòíóþ óïàêîâêó ÄÍÊ .............................................. 259
12. Çàêëþ÷åíèå è ïåðñïåêòèâû èññëåäîâàíèé ........................................................................................................... 260
Ëèòåðàòóðà ................................................................................................................................................................... 261
Ãëàâà 14
Ýïèãåíåòè÷åñêàÿ ðåãóëÿöèÿ õðîìîñîìíîãî íàñëåäîâàíèÿ ................................................................................... 263
Gary H. Karen è R. Scott Hawley
Îáùåå ðåçþìå ............................................................................................................................................................. 264
1. Ââåäåíèå .................................................................................................................................................................. 264
1.1. Êàê îñóùåñòâëÿåòñÿ õðîìîñîìíàÿ íàñëåäñòâåííîñòü? .................................................................................. 264
1.2. Êàêèå ýëåìåíòû òðåáóþòñÿ äëÿ õðîìîñîìíîé íàñëåäñòâåííîñòè? ............................................................... 264
2. Ýïèãåíåòè÷åñêàÿ ðåãóëÿöèÿ ðåïëèêàöèè ÄÍÊ, ðåïàðàöèè è òåëîìåð ................................................................. 266
2.1. Èíèöèàöèÿ ðåïëèêàöèè ÄÍÊ êîíòðîëèðóåòñÿ ýïèãåíåòè÷åñêèìè ìåõàíèçìàìè ...................................... 266
2.2. Ðåïàðàöèÿ ÄÍÊ âêëþ÷àåò ýïèãåíåòè÷åñêèå èçìåíåíèÿ â ñòðóêòóðå õðîìàòèíà ......................................... 267
2.3. Ýïèãåíåòè÷åñêèé êîíòðîëü ñòðóêòóðû è ôóíêöèè òåëîìåð .......................................................................... 268
3. Ýïèãåíåòè÷åñêàÿ ðåãóëÿöèÿ èäåíòè÷íîñòè è ôóíêöèè öåíòðîìåð ...................................................................... 269
3.1. Ñòðóêòóðà è ôóíêöèÿ öåíòðîìåðû ó ðàçíûõ ýóêàðèîò .................................................................................. 270
3.2. Öåíòðîìåðíûå ïîñëåäîâàòåëüíîñòè íå ÿâëÿþòñÿ íåîáõîäèìûìè èëè äîñòàòî÷íûìè
äëÿ ôîðìèðîâàíèÿ è ôóíêöèîíèðîâàíèÿ êèíåòîõîðà ......................................................................................... 271
3.3. Íåîáû÷íûé ñîñòàâ öåíòðîìåðíîãî õðîìàòèíà .............................................................................................. 272
3.4. Ìîäåëè ñòðóêòóðû , ôóíêöèè è âîñïðîèçâåäåíèÿ öåíòðîìåðû .................................................................... 275
3.5. Ýïèãåíåòèêà è ýâîëþöèÿ öåíòðîìåð .............................................................................................................. 276
4. Ãåòåðîõðîìàòèí è ìåéîòè÷åñêîå ñïàðèâàíèå / ðàñõîæäåíèå ................................................................................ 277
4.1. Îáíàðóæåíèå ñàéòà ãåòåðîõðîìàòèíîâîãî ñïàðèâàíèÿ ó ñàìöîâ Drosophila ................................................. 278
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4.2. Ñïàðèâàíèå ãåòåðîõðîìàòèíà îáëåã÷àåò ðàñõîæäåíèå ó ñàìîê Drosophila .................................................... 279

4.3. Ðîëü öåíòðîìåðû â îáëåã÷åíèè àõèàçìàòè÷åñêîé ñåãðåãàöèè ó ïî÷êóþùèõñÿ äðîææåé ............................ 279
4.4. Àññîöèèðîâàííûé ñ ãåòåðîõðîìàòèíîì ëîêóñ Ph1 ó êóêóðóçû è åãî ðîëü â îïîñðåäîâàíèè
ãîìîëîãè÷íîãî versus íåãîìîëîãè÷íîãî ñïàðèâàíèÿ ............................................................................................ 280
5. Ãåòåðîõðîìàòèí è ìåéîòè÷åñêèé äðàéâ .................................................................................................................. 280
5.1. Íàðóøèòåëü ñåãðåãàöèè (Segregation Distorter) ó ñàìöîâ Drosophila .............................................................. 280
5.2. Óòåðÿ îòöîâñêîé õðîìîñîìû ó Sciara è êàðòèðîâàíèå ðåàãèðóþùåãî ýëåìåíòà ........................................... 281
5.3. Óòåðÿ îòöîâñêèõ õðîìîñîì ó Nasonia .............................................................................................................. 281
5.4. Âçäóòèå 10 ó êóêóðóçû — ðîëü ïîñëåäîâàòåëüíîñòåé, ñîîòâåòñòâóþùèõ ãåòåðîõðîìàòèíîâûì
«âçäóòèÿì», â îáëåã÷åíèè ðàñõîæäåíèÿ õðîìîñîì â ìåéîçå I .............................................................................. 282
6. Ñàéëåíñèíã ãåíîâ íåñïàðåííûìè ÄÍÊ â ìåéîçå .................................................................................................. 282
6.1. Ìåéîòè÷åñêèé ñàéëåíñèíã íåñïàðåííîé ÄÍÊ â ìåéîçå ó Neurospora .......................................................... 282
6.2. Ñàéëåíñèíã àñèíàïñíûõ õðîìîñîì ó ìûøè................................................................................................... 283
6.3. Äèñôóíêöèÿ ïîëîâîé õðîìîñîìû ó Drosophila ............................................................................................... 283
7. Ïåðñïåêòèâû è âûâîäû ........................................................................................................................................... 283
Ëèòåðàòóðà ................................................................................................................................................................... 284
Ãëàâà 15
Ýïèãåíåòè÷åñêàÿ ðåãóëÿöèÿ Õ-õðîìîñîì ó C. elegans ........................................................................................... 287
Susan Strome è William G. Kelly
Îáùåå ðåçþìå ............................................................................................................................................................. 287
1. Äèñáàëàíñ ïîëîâûõ õðîìîñîì ó C. elegans .............................................................................................................. 288
2. DDC ïîõîæ íà êîìïëåêñ êîíäåíñèíà .................................................................................................................... 288
3. Îöåíêà îòíîøåíèÿ Õ:À ........................................................................................................................................... 290
4. Ðåêðóòèðîâàíèå è ðàñïðîñòðàíåíèå DCC .............................................................................................................. 292
5. Ýôôåêòû DCC: äàóí-ðåãóëÿöèÿ ñöåïëåííûõ ñ Õ ãåíîâ è àóòîñîìíîãî ãåíà her-1 ............................................... 292
6. Ðåãóëèðîâàíèå Õ-õðîìîñîì â çàðîäûøåâîì ïóòè.................................................................................................. 293
7. Ðàçâèòèå çàðîäûøåâîãî ïóòè è ñàéëåíñèíã Õ-õðîìîñîìû.................................................................................... 293
8. Åäèíñòâåííàÿ Õ-õðîìîñîìà ó ñàìöîâ îáíàðóæèâàåò ìåòêè ãåòåðîõðîìàòèíà ..................................................... 294
9. Âëèÿíèå MSUD íà ïàòòåðíû ýêñïðåññèè ãåíîâ â çàðîäûøåâîì ïóòè.................................................................. 296
10. Ðåãóëÿöèÿ ñàéëåíñèíãà Õ-õðîìîñîìû ìîäèôèêàòîðàìè ãèñòîíîâ MES............................................................ 296
11. Õ-õðîìîñîìà ñïåðìèÿ èìïðèíòèðîâàíà .............................................................................................................. 298
12. Çàêëþ÷èòåëüíûå çàìå÷àíèÿ .................................................................................................................................. 299
Ëèòåðàòóðà ................................................................................................................................................................... 300
Ãëàâà 16
Êîìïåíñàöèÿ äîçû ó Drosophila ............................................................................................................................... 302
John C. Lucchesi è Mitzi I. Kuroda
Îáùåå ðåçþìå ............................................................................................................................................................. 302
1. ßâëåíèå êîìïåíñàöèè äîçû áûëî îòêðûòî ó Drosophila ......................................................................................... 303
2. Êîìïåíñàöèÿ äîçû ñâÿçàíà ñ ìîäèôèêàöèÿìè õðîìàòèíà ................................................................................... 303
3. Ðåãóëèðîâàíèå êîìïåíñàöèè äîçû íà÷èíàåòñÿ ñ èçìåðåíèÿ îòíîøåíèÿ Õ:àóòîñîìû ......................................... 306
4. Íåêîäèðóþùèå ÐÍÊ roX îáëåã÷àþò ñáîðêó è «íàöåëèâàíèå» êîìïëåêñà MSL íà Õ-õðîìîñîìó ....................... 307
5. Áàëàíñèðîâêà ìåæäó àíòàãîíèñòè÷åñêèìè àêòèâíîñòÿìè ðåìîäåëèíãà õðîìàòèíà ............................................ 309
6. Ïåðñïåêòèâû............................................................................................................................................................ 310
Ëèòåðàòóðà ................................................................................................................................................................... 311
Ãëàâà 17
Êîìïåíñàöèÿ äîçû ó ìëåêîïèòàþùèõ ..................................................................................................................... 313
Neil Brockdorff è Bryan M. Turner
Îáùåå ðåçþìå ............................................................................................................................................................. 314
1. Ââåäåíèå .................................................................................................................................................................. 314
1.1. Ïðåèìóùåñòâà ïîëîâîãî âîñïðîèçâåäåíèÿ .................................................................................................... 314
1.2. Ñïîñîáû îïðåäåëåíèÿ ïîëà ............................................................................................................................ 315
1.3. Õðîìîñîìíûå ñïîñîáû äåòåðìèíàöèè ïîëà ñîçäàþò íåîáõîäèìîñòü â êîìïåíñàöèè äîçû ....................... 316
1.4. Èäåíòèôèêàöèÿ íåàêòèâíîé Õ-õðîìîñîìû ó ñàìîê ìëåêîïèòàþùèõ ......................................................... 316
2. Êëþ÷åâûå êîíöåïöèè ............................................................................................................................................. 316
2.1. Èíàêòèâàöèÿ Õ ðåãóëèðóåòñÿ â õîäå ðàçâèòèÿ................................................................................................ 316
2.2. Ñàéëåíñèíã õðîìîñîìû âêëþ÷àåò ìíîæåñòâåííûå óðîâíè ýïèãåíåòè÷åñêîé ìîäèôèêàöèè ..................... 317
2.3. Íåêîòîðûå ãåíû èçáåãàþò Õ-èíàêòèâàöèè ................................................................................................... 317
2.4. Õ-èíàêòèâàöèÿ ðåãóëèðóåòñÿ ãëàâíûì ëîêóñîì-ïåðåêëþ÷àòåëåì — öåíòðîì Õ-èíàêòèâàöèè .................. 317
 Îãëàâëåíèå 9

3. Èíèöèàöèÿ Õ-èíàêòèâàöèè.................................................................................................................................... 317

3.1. Èìïðèíòèðîâàííàÿ versus ñëó÷àéíàÿ Õ-èíàêòèâàöèÿ ................................................................................... 317
3.2. Ðåãóëÿöèÿ èìïðèíòèðîâàííîé Õ-èíàêòèâàöèè ............................................................................................ 318
3.3. Ðåãóëÿöèÿ ñëó÷àéíîé Õ-èíàêòèâàöèè — ñ÷åò ................................................................................................ 319
3.4. Ðåãóëÿöèÿ ñëó÷àéíîé Õ-èíàêòèâàöèè — âûáîð .............................................................................................. 321
3.5. Ñïîñîáû ïåðåêëþ÷åíèÿ èíàêòèâàöèè â ðàííåì ýìáðèîãåíåçå .................................................................... 322
4. Âîñïðîèçâåäåíèå è ïîääåðæàíèå íåàêòèâíîãî ñîñòîÿíèÿ .................................................................................... 322
4.1. Xist-ÐÍÊ, ñàéëåíñèíã ãåíîâ è ñáîðêà ãåòåðîõðîìàòèíà ................................................................................ 322
4.2. Ãåòåðîõðîìàòèíîâàÿ ñòðóêòóðà íåàêòèâíîé Õ-õðîìîñîìû ........................................................................... 323
4.3. Ýíçèìîëîãèÿ ìîäèôèêàöèé ãèñòîíîâ íà Xi................................................................................................... 325
4.4. Ïîñëåäîâàòåëüíîñòü ñîáûòèé, ïðèâîäÿùèõ ê Õ-èíàêòèâàöèè; ES-êëåòêè êàê ìîäåëüíàÿ ñèñòåìà ........... 326
4.5. Ðàñïðîñòðàíåíèå «ìîë÷àùåãî» õðîìàòèíà ..................................................................................................... 327
4.6. Óõîä îò èíàêòèâàöèè Õ-õðîìîñîìû ............................................................................................................... 327
4.7. Õ-èíàêòèâàöèÿ ó ñóì÷àòûõ ìëåêîïèòàþùèõ ................................................................................................. 328
5. Ðåàêòèâàöèÿ è ðåïðîãðàììèðîâàíèå Õ-õðîìîñîìû .............................................................................................. 328
5.1. Ñòàáèëüíîñòü Õ-èíàêòèâàöèè â ñîìàòè÷åñêèõ êëåòêàõ................................................................................. 328
5.2. Ðåàêòèâàöèÿ Õ-õðîìîñîìû â íîðìàëüíîì ðàçâèòèè ..................................................................................... 329
5.3. Ðåàêòèâàöèÿ Õ-õðîìîñîìû â õîäå ýêñïåðèìåíòàëüíîãî ðåïðîãðàììèðîâàíèÿ ........................................... 329
5.4. Óðîêè èç îïûòîâ ñ èíäóöèáåëüíûìè òðàíñãåíàìè Xist ................................................................................. 329
6. Ðåçþìå è íàïðàâëåíèÿ áóäóùèõ èññëåäîâàíèé ..................................................................................................... 330
Ëèòåðàòóðà ................................................................................................................................................................... 330
Ãëàâà 18
Ìåòèëèðîâàíèå ÄÍÊ ó ìëåêîïèòàþùèõ................................................................................................................ 333
En Li è Adrian Bird
Îáùåå ðåçþìå ............................................................................................................................................................. 334
1. Ìåõàíèçì êëåòî÷íîé ïàìÿòè .................................................................................................................................. 334
1.1. Ãèïîòåçà............................................................................................................................................................ 334
1.2. Äàííûå î íàñëåäóåìûõ ïàòòåðíàõ ìåòèëèðîâàíèÿ......................................................................................... 334
1.3. Ïîääåðæèâàþùàÿ ÄÍÊ-ìåòèëòðàíñôåðàçà ìëåêîïèòàþùèõ ....................................................................... 335
2. Ïðîèñõîæäåíèå ïàòòåðíîâ ìåòèëèðîâàíèÿ ÄÍÊ .................................................................................................. 335
2.1. De novo ìåòèëèðîâàíèå ÄÍÊ ó ðàííèõ ýìáðèîíîâ ....................................................................................... 335
2.2. Îòêðûòèå de novo ìåòèëòðàíñôåðàç ............................................................................................................... 336
2.3. Îñòðîâêè CpG è ïàòòåðíû ìåòèëèðîâàíèÿ ÄÍÊ .......................................................................................... 336
2.4. Äèíàìè÷åñêèå èçìåíåíèÿ â ïàòòåðíàõ ìåòèëèðîâàíèÿ ÄÍÊ â õîäå ðàçâèòèÿ ............................................. 337
2.5. Àêòèâíîå äåìåòèëèðîâàíèå çèãîòè÷åñêîãî îòöîâñêîãî ãåíîìà .................................................................... 338
2.6. ×òî çàùèùàåò îñòðîâêè CpG îò ìåòèëèðîâàíèÿ ÄÍÊ? ................................................................................ 339
2.7. Ïåðåêëþ÷àåòñÿ ëè ìåòèëèðîâàíèå ÄÍÊ ñòðóêòóðîé õðîìàòèíà? ................................................................. 339
2.8. Ðîëü SWI/SNF-ïîäîáíûõ áåëêîâ ðåìîäåëèíãà õðîìàòèíà ........................................................................... 340
3. Ðåãóëÿöèÿ ýêñïðåññèè ãåíîâ ìåòèëèðîâàíèåì ÄÍÊ ............................................................................................. 340
3.1. Ðàííèå äàííûå................................................................................................................................................. 340
3.2. Èíòåðôåðåíöèÿ ñî ñâÿçûâàíèåì òðàíñêðèïöèîííîãî ôàêòîðà.................................................................... 340
3.3. Ïðèòÿæåíèå áåëêîâ, ñâÿçûâàþùèõñÿ ñ ìåòèë-CpG ...................................................................................... 341
3.4. MeCP2 è ñèíäðîì Ðåòòà .................................................................................................................................. 342
3.5. MBD2 îïîñðåäóåò çàâèñÿùóþ îò ìåòèëèðîâàíèÿ ðåïðåññèþ òðàíñêðèïöèè............................................... 343
4. Ìåòèëèðîâàíèå ÄÍÊ, ìóòàöèè è ñòàáèëüíîñòü õðîìîñîì ................................................................................... 343
4.1. Ìåòèëèðîâàíèå ÄÍÊ è ìóòàöèè .................................................................................................................... 343
4.2. Ìåòèëèðîâàíèå ÄÍÊ è íåñòàáèëüíîñòü õðîìîñîì........................................................................................ 344
5. Áóäóùèå íàïðàâëåíèÿ èññëåäîâàíèé ..................................................................................................................... 344
5.1. Ôàêòîðû âíåøíåé ñðåäû, èíäóöèðóþùèå ýïèãåíåòè÷åñêèå èçìåíåíèÿ ..................................................... 345
5.2. Ýïèãåíåòè÷åñêàÿ íåñòàáèëüíîñòü è êîìïëåêñíûå çàáîëåâàíèÿ ................................................................... 345
5.3. Ìîäóëÿöèÿ îáðàòèìûõ ýïèãåíåòè÷åñêèõ ñîñòîÿíèé ..................................................................................... 345
Ëèòåðàòóðà ................................................................................................................................................................... 346
Ãëàâà 19
Ãåíîìíûé èìïðèíòèíã ó ìëåêîïèòàþùèõ ............................................................................................................... 349
Denise P. Barlow è Marisa S. Bartolomei
Îáùåå ðåçþìå ............................................................................................................................................................. 349
1. Èñòîðè÷åñêèé îáçîð ................................................................................................................................................ 350
2. Ãåíîìíûé èìïðèíòèíã — ýïèãåíåòè÷åñêàÿ ñèñòåìà ðåãóëÿöèè ãåíîâ ................................................................. 353
3. Êëþ÷åâûå îòêðûòèÿ â îáëàñòè ãåíîìíîãî èìïðèíòèíãà ...................................................................................... 355
10 Îãëàâëåíèå

3.1. Èìïðèíòèðîâàííûå ãåíû êîíòðîëèðóþò ýìáðèîíàëüíûé è íåîíàòàëüíûé ðîñò........................................ 355

3.2. Ôóíêöèÿ ãåíîìíîãî èìïðèíòèíãà ó ìëåêîïèòàþùèõ................................................................................... 355
3.3. Èìïðèíòèðîâàííûå ãåíû ñîáðàíû â êëàñòåðû è êîíòðîëèðóþòñÿ èìïðèíòíûìè
êîíòðîëüíûìè ýëåìåíòàìè .................................................................................................................................. 357
3.4. Êëàñòåðû èìïðèíòèðîâàííûõ ãåíîâ ñîäåðæàò ïî ìåíüøåé ìåðå îäíó ncRNA............................................ 359
3.5. Ðîëü ìåòèëèðîâàíèÿ ÄÍÊ â ãåíîìíîì èìïðèíòèíãå ................................................................................... 360
3.6. Äâà òèïà cis-äåéñòâóþùåãî ñàéëåíñèíãà, èäåíòèôèöèðîâàííîãî
â êëàñòåðàõ èìïðèíòèðîâàííûõ ãåíîâ .................................................................................................................. 362
4. Ãåíîìíûé èìïðèíòèíã — ìîäåëü ýïèãåíåòè÷åñêîé ðåãóëÿöèè ó ìëåêîïèòàþùèõ ............................................. 364
5. Íàïðàâëåíèÿ áóäóùèõ èññëåäîâàíèé ..................................................................................................................... 365
Áëàãîäàðíîñòè ............................................................................................................................................................. 365
Ëèòåðàòóðà ................................................................................................................................................................... 365
WWW-ðåñóðñû ........................................................................................................................................................ 367
Ãëàâà 20
Çàðîäûøåâàÿ ëèíèÿ è ïëþðèïîòåíòíûå ñòâîëîâûå êëåòêè ................................................................................. 368
M. Azim Surani è Wolf Reik
Îáùåå ðåçþìå ............................................................................................................................................................. 369
1. Ââåäåíèå. Æèçíü ìëåêîïèòàþùèõ: ãåíåòè÷åñêàÿ è ýïèãåíåòè÷åñêàÿ íåïðåðûâíîñòü ....................................... 369
2. Ãåíåòè÷åñêèå è ýïèãåíåòè÷åñêèå ìåõàíèçìû, ðåãóëèðóþùèå ñïåöèôèêàöèþ
ïîëîâûõ êëåòîê (îò ðàííåãî ýìáðèîíà ê ïîëîâûì êëåòêàì) ..................................................................................... 372
2.1. Ïðèíöèïû ðàçâèòèÿ ïîëîâûõ êëåòîê â ðàçëè÷íûõ ãðóïïàõ æèâîòíûõ......................................................... 372
2.2. Ðàííåå ðàçâèòèå ëèíèè ïîëîâûõ êëåòîê ó ìëåêîïèòàþùèõ.......................................................................... 372
2.3. Ðîëü Blimp 1 â cïåöèôèêàöèè PGC ................................................................................................................ 374
2.4. Ðåïðåññèÿ cîìàòè÷åñêîé ïðîãðàììû â ïîëîâûõ êëåòêàõ – ÿâëåíèå, ýâîëþöèîííî êîíñåðâàòèâíîå......... 374
2.5. Ðåãóëÿöèÿ ýïèãåíåòè÷åñêîé ïðîãðàììû ó ìûøåé ïîñëå ñïåöèôèêàöèè PGC ........................................... 375
2.6. Ëèíèÿ ïîëîâûõ êëåòîê è ñòâîëîâûå êëåòêè – îáðàòèìûé ôåíîòèï ............................................................. 376
2.7. Ðàçâèòèå ïîëîâûõ êëåòîê èç ïëþðèïîòåíòíûõ ES-êëåòîê ............................................................................ 376
2.8. Îò ïðèìîðäèàëüíûõ ïîëîâûõ êëåòîê ê ãàìåòàì ............................................................................................ 376
3. Îò îîöèòîâ ê ðàííåìó ýìáðèîíó ............................................................................................................................ 377
3. 1. Ìàòåðèíñêàÿ íàñëåäñòâåííîñòü è ïîòåíöèàëüíîå àñèììåòðè÷åñêîå ðàñïðåäåëåíèå?................................ 377
3.2. Ýïèãåíåòè÷åñêèå ñîáûòèÿ ïðè îïëîäîòâîðåíèè ........................................................................................... 378
3.3. Îò çèãîòû ê áëàñòîöèñòå ................................................................................................................................. 379
4. Îò ïëþðèïîòåíòíûõ êëåòîê ê ñîìàòè÷åñêèì êëåòêàì è îáðàòíî ê ïîëîâûì êëåòêàì ......................................... 379
4.1. Ïîëó÷åíèå ïëþðèïîòåíòíûõ ñòâîëîâûõ êëåòîê ............................................................................................ 379
4.2. Ýïèãåíåòè÷åñêèå ñâîéñòâà ïëþðèïîòåíòíûõ ñòâîëîâûõ êëåòîê .................................................................. 380
4.3. Ñïîñîáíîñòü ñòâîëîâûõ êëåòîê ê ðåïðîãðàììèðîâàíèþ ............................................................................. 381
5. Ïåðñïåêòèâû............................................................................................................................................................ 382
Áëàãîäàðíîñòè ............................................................................................................................................................. 383
Ëèòåðàòóðà ................................................................................................................................................................... 383
Ãëàâà 21
Ýïèãåíåòè÷åñêîå ðåãóëèðîâàíèå ëèìôîöèòîïîýçà ................................................................................................ 387
Meinrad Busslinger è Alexander Tarakhovsky
Îáùåå ðåçþìå ............................................................................................................................................................. 387
1. Ââåäåíèå .................................................................................................................................................................. 388
2. Êîììèòèðîâàíèå ëèíèé â ðàííåì ëèìôîïîýçå ..................................................................................................... 390
2.1. Âíåêëåòî÷íûå ñèãíàëû ................................................................................................................................... 390
2.2. Òðàíñêðèïöèîííûå ôàêòîðû ......................................................................................................................... 390
2.3. Ýïèãåíåòè÷åñêèé êîíòðîëü ýêñïðåññèè ãåíîâ ............................................................................................... 392
3. Ýïèãåíåòè÷åñêèé êîíòðîëü ðàçíîîáðàçèÿ ðåöåïòîðîâ àíòèãåíîâ ........................................................................ 392
3.1. Ðåãóëÿöèÿ ïåðåñòðîåê ãåíîâ ðåöåïòîðîâ àíòèãåíîâ â ïðîöåññå ðàçâèòèÿ .................................................... 392
3.2. Ñóáúÿäåðíîå ïåðåìåùåíèå ãåíîâ èììóíîãëîáóëèíîâ .................................................................................. 395
3.3. Ñîêðàùåíèå ëîêóñà ãåíîâ èììóíîãëîáóëèíà ................................................................................................ 395
3.4. Êîíòðîëü àëëåëüíîãî èñêëþ÷åíèÿ â ëîêóñàõ IgH è Igκ ..........................................................................................396
4. Êîíå÷íàÿ äèôôåðåíöèðîâêà çðåëûõ Â-êëåòîê ...................................................................................................... 398
4.1. Äèôôåðåíöèðîâêà ïëàçìàòè÷åñêèõ êëåòîê.................................................................................................... 398
4.2. Ïëàñòè÷íîñòü çðåëûõ Â-êëåòîê â ïðîöåññå ðàçâèòèÿ .................................................................................... 400
5. Çàêëþ÷èòåëüíûå çàìå÷àíèÿ ................................................................................................................................... 401
Ëèòåðàòóðà ................................................................................................................................................................... 401
 Îãëàâëåíèå 11

Ãëàâà 22
Òðàíñïëàíòàöèÿ ÿäåð è ðåïðîãðàììèðîâàíèå ãåíîìà ............................................................................................ 405
Rudolf Jaenisch è John Gurdon
Îáùåå ðåçþìå ............................................................................................................................................................. 405
1. Èñòîðèÿ.................................................................................................................................................................... 406
2. Ïðîöåäóðû ïåðåñàäêè ÿäåð ..................................................................................................................................... 406
2.1. Àìôèáèè .......................................................................................................................................................... 406
2.2. Ìëåêîïèòàþùèå ............................................................................................................................................. 406
3. Ôåíîòèï êëîíèðîâàííûõ æèâîòíûõ ...................................................................................................................... 409
3.1. Àìôèáèè .......................................................................................................................................................... 409
3.2. Ìëåêîïèòàþùèå ............................................................................................................................................. 410
3.3. Ïîëó÷åíèå êëîíèðîâàííûõ ìëåêîïèòàþùèõ èç òåðìèíàëüíî äèôôåðåíöèðîâàííûõ êëåòîê ................... 411
4. Èçìåíåíèÿ, ñâÿçàííûå ñ ðåïðîãðàììèðîâàíèåì ÿäðà .......................................................................................... 414
4.1. Àìôèáèè .......................................................................................................................................................... 414
4.2. Ìëåêîïèòàþùèå ............................................................................................................................................. 416
5. Ýïèãåíåòè÷åñêàÿ ïàìÿòü ......................................................................................................................................... 417
6. Çíà÷åíèå ÿäåðíîé òðàíñïëàíòàöèè äëÿ ìåäèöèíû................................................................................................ 418
6.1. Ðåïðîäóêòèâíîå êëîíèðîâàíèå ...................................................................................................................... 419
6.2. Ïðèìåíåíèå ÿäåðíîé òðàíñïëàíòàöèè â òåðàïèè.......................................................................................... 420
6.3. Ðåïðîäóêòèâíîå versus òåðàïåâòè÷åñêîå êëîíèðîâàíèå: â ÷åì ðàçíèöà? ...................................................... 421
Ëèòåðàòóðà ................................................................................................................................................................... 421
Ãëàâà 23
Ýïèãåíåòèêà è áîëåçíè ÷åëîâåêà ............................................................................................................................. 424
Huda Y. Zoghbi è Arthur L. Beaudet
Îáùåå ðåçþìå ............................................................................................................................................................. 424
1. Ââåäåíèå .................................................................................................................................................................. 425
2. Èññëåäîâàíèÿ áîëåçíåé ÷åëîâåêà âñêðûâàþò ðîëü ýïèãåíåòèêè â áèîëîãèè ....................................................... 426
3. Çàáîëåâàíèÿ ÷åëîâåêà ............................................................................................................................................. 427
3.1. Íàðóøåíèÿ ãåíîìíîãî èìïðèíòèíãà ............................................................................................................. 427
3.2. Íàðóøåíèÿ, âëèÿþùèå íà ñòðóêòóðó õðîìàòèíà â trans-êîíôèãóðàöèè ....................................................... 431
3.3. Ðàññòðîéñòâà, âëèÿþùèå íà ñòðóêòóðó õðîìàòèíà â cis-êîíôèãóðàöèè ....................................................... 435
3.4. Âçàèìîäåéñòâèå ýïèãåíåòèêè è îêðóæàþùåé ñðåäû ..................................................................................... 438
4. Ãëÿäÿ â áóäóùåå........................................................................................................................................................ 439
Áëàãîäàðíîñòè ............................................................................................................................................................. 439
Ëèòåðàòóðà ................................................................................................................................................................... 439
Ãëàâà 24
Ýïèãåíåòè÷åñêèå äåòåðìèíàíòû ïðè ðàêîâûõ çàáîëåâàíèÿõ ............................................................................... 445
Stephen B. Baylin è Peter A. Jones
Îáùåå ðåçþìå ............................................................................................................................................................. 445
1. Áèîëîãè÷åñêàÿ îñíîâà ðàêîâûõ çàáîëåâàíèé ......................................................................................................... 446
2. Çíà÷åíèå õðîìàòèíà äëÿ ðàêîâûõ çàáîëåâàíèé ..................................................................................................... 447
3. Ðîëü ìåòèëèðîâàíèÿ ÄÍÊ ïðè ðàêîâûõ çàáîëåâàíèÿõ .......................................................................................... 448
4. Ãèïåðìåòèëèðîâàííûå ïðîìîòîðû ãåíîâ ïðè ðàêîâûõ çàáîëåâàíèÿõ .................................................................. 449
4.1. Ãåíû, ó÷àñòâóþùèå â ïðîöåññå ....................................................................................................................... 449
4.2. Ïîèñê íîâûõ ãåíîâ, ýïèãåíåòè÷åñêè ñàéëåíñèðîâàííûõ ïðè ðàêå .............................................................. 451
4.3. Îïðåäåëåíèå ôóíêöèîíàëüíîé âàæíîñòè ãåíîâ, ãèïåðìåòèëèðîâàííûõ ïðè ðàêîâûõ çàáîëåâàíèÿõ ........ 452
5. Ýïèãåíåòè÷åñêèé ñàéëåíñèíã ãåíîâ è åãî ðîëü â ýâîëþöèè ðàêà – çíà÷åíèå
äëÿ ðàííèõ ñòàäèé ðàçâèòèÿ îïóõîëè ......................................................................................................................... 452
6. Ìîëåêóëÿðíàÿ àíàòîìèÿ ýïèãåíåòè÷åñêè ñàéëåíñèðîâàííûõ ðàêîâûõ ãåíîâ ..................................................... 455
7. Ðåçþìå ãëàâíûõ ðåçóëüòàòîâ èññëåäîâàíèé ïî îñìûñëåíèþ ýïèãåíåòè÷åñêîãî ñàéëåíñèíãà ãåíîâ ïðè ðàêå .. 458
8. Âûÿâëåíèå ðàêà ïîñðåäñòâîì ìåòèëèðîâàíèÿ ÄÍÊ .............................................................................................. 459
9. Ýïèãåíåòè÷åñêàÿ òåðàïèÿ ....................................................................................................................................... 459
Ëèòåðàòóðà ................................................................................................................................................................... 461
Ïðèëîæåíèå 1
WWW-ðåñóðñû ........................................................................................................................................................... 465
Ïðèëîæåíèå 2
Ìîäèôèêàöèè ãèñòîíîâ è ëèòåðàòóðà..................................................................................................................... 468
ÏÐÅÄÈÑËÎÂÈÅ Ê ÐÓÑÑÊÎÌÓ ÈÇÄÀÍÈÞ
Ãëóáîêîóâàæàåìûé ÷èòàòåëü !
Ïåðåä Âàìè ðóññêîÿçû÷íîå èçäàíèå ïåðâîé â ìèðå îáñòîÿ-
òåëüíîé íàó÷íîé êíèãè îá ýïèãåíåòèêå. Ïîä ýïèãåíåòèêîé
îáû÷íî ïîíèìàþò îáëàñòü çíàíèé î ñîâîêóïíîñòè ñâîéñòâ
îðãàíèçìà, êîòîðûå íå ïðÿìî, à îïîñðåäîâàííî çàêîäèðî-
âàíû â ãåíîìå è, ïî îïðåäåëåíèþ, äîëæíû ïåðåäàâàòüñÿ ïî
íàñëåäñòâó. Ïî ñóòè äåëà â ïåðâóþ î÷åðåäü ýòà íàóêà èìååò
äåëî ñ ìåõàíèçìàìè, êîíòðîëèðóþùèìè ýêñïðåññèþ ãåíîâ
è êëåòî÷íóþ äèôôåðåíöèðîâêó. Ó îðãàíèçìîâ ñóùåñòâóþò
ìîùíûå ðåãóëÿòîðíûå ýëåìåíòû (â ñàìîì ãåíîìå è äàæå
öåëûå ñèñòåìû â êëåòêàõ), êîòîðûå êîíòðîëèðóþò ðàáîòó
ãåíîâ, â òîì ÷èñëå è â çàâèñèìîñòè îò ðàçíûõ âíóòðåííèõ
è âíåøíèõ ñèãíàëîâ áèîëîãè÷åñêîé è àáèîòè÷åñêîé ïðè-
ðîäû. Ýòè ñèãíàëû íàêëàäûâàþòñÿ íà ãåíåòèêó è ÷àñòî
ïî-ñâîåìó ðåøàþò êîðåííîé âîïðîñ – áûòü èëè íå áûòü?
Äåéñòâèòåëüíî, äàæå ñàìàÿ îòëè÷íàÿ ãåíåòèêà ìîæåò âîâñå
è íå ðåàëèçîâàòüñÿ, åñëè ýïèãåíåòèêà íåáëàãîïîëó÷íà. Ïî
îáðàçíîìó âûðàæåíèþ Íîáåëåâñêîãî ëàóðåàòà Ï. Ìåäàâàðà
«ãåíåòèêà ïîëàãàåò, à ýïèãåíåòèêà ðàñïîëàãàåò».
Äîëãîå âðåìÿ ýïèãåíåòèêó ìíîãèå íå ïðèçíàâàëè ñî-
âñåì, à ÷àñòî ñòûäëèâî èëè äàæå íàìåðåííî óìàë÷èâàëè
î íåé. Â îñíîâíîì, ýòî ïðîèñõîäèëî ïîòîìó, ÷òî çíàíèÿ î
ïðèðîäå ýïèãåíåòè÷åñêèõ ñèãíàëîâ è ïóòÿõ èõ ðåàëèçàöèè â
îðãàíèçìå áûëè î÷åíü ðàñïëûâ÷àòûìè. Ñåãîäíÿ ñòàëî ÿñíî,
÷òî îäíèì èç òàêèõ ýïèãåíåòè÷åñêèõ ñèãíàëîâ â êëåòêå ÿâ-
ëÿåòñÿ ýíçèìàòè÷åñêàÿ ìîäèôèêàöèÿ (ìåòèëèðîâàíèå) ñà-
ìîé ãåíåòè÷åñêîé ìàòðèöû, òî åñòü ìåòèëèðîâàíèå ÄÍÊ.
Ñ ðàñêðûòèåì è îïèñàíèåì èñêëþ÷èòåëüíîé ðîëè ìåòèëè-
ðîâàíèÿ ÄÍÊ â æèçíè îðãàíèçìîâ, ïî ñóòè äåëà, âïåðâûå
ïî-íàñòîÿùåìó ïðîèçîøëè ñòàíîâëåíèå è ìàòåðèàëèçàöèÿ
ýïèãåíåòèêè êàê íàóêè. Èìåííî â Ðîññèè áûëè îòêðûòû
òêàíåâàÿ è âîçðàñòíàÿ ñïåöèôè÷íîñòü ìåòèëèðîâàíèÿ ÄÍÊ
ó ýóêàðèîòè÷åñêèõ îðãàíèçìîâ, â òîì ÷èñëå ó æèâîòíûõ è
âûñøèõ ðàñòåíèé, è áûëî âïåðâûå îáîñíîâàííî çàÿâëåíî,
÷òî ýòà ýíçèìàòè÷åñêàÿ ìîäèôèêàöèÿ ãåíîìà ìîæåò áûòü
îäíèì èç ìåõàíèçìîâ ðåãóëÿöèè ýêñïðåññèè ãåíîâ è êëå-
òî÷íîé äèôôåðåíöèðîâêè. Çäåñü æå áûëè ïîëó÷åíû ïåðâûå
äàííûå î òîì, ÷òî ìåòèëèðîâàíèå ÄÍÊ êîíòðîëèðóåòñÿ ãîð-
ìîíàëüíî, à èñêàæåíèå ìåòèëèðîâàíèÿ ÄÍÊ – ïóòü ê ðàêó.
Íàáîð è ïðèðîäà ýïèãåíåòè÷åñêèõ ñèãíàëîâ â êëåòêå
âåñüìà ðàçíîîáðàçíû, òàêèõ ñèãíàëîâ ìíîãî è ñåãîäíÿ îíè
ðàçäåëÿþòñÿ, ïî êðàéíåé ìåðå, íà íåñêîëüêî ãðóïï – ìåòè-
ëèðîâàíèå è äåìåòèëèðîâàíèå ÄÍÊ, «ãèñòîíîâûé êîä» (ýí-
çèìàòè÷åñêàÿ ìîäèôèêàöèÿ ãèñòîíîâ – àöåòèëèðîâàíèå,
ìåòèëèðîâàíèå, óáèêâèòèíèðîâàíèå, ôîñôîðèëèðîâàíèå
è äðóãèå), òðàíñêðèïöèîííîå è òðàíñëÿöèîííîå çàìàë÷è-
âàíèå ãåíîâ ìàëûìè ÐÍÊ, ïîçèöèîíèðîâàíèå ýëåìåíòîâ
õðîìàòèíà. Ëþáîïûòíî, ÷òî ìíîãèå èç ýòèõ ïðîöåññîâ ïå-
ðåïëåòåíû ìåæäó ñîáîé è âçàèìîçàâèñèìû. Ýòî âî ìíîãîì
îáåñïå÷èâàåò è ãàðàíòèðóåò íàäåæíîñòü ýïèãåíåòè÷åñêîãî
êîíòðîëÿ çà èçáèðàòåëüíûì ôóíêöèîíèðîâàíèåì ãåíîâ.
Äåòàëüíîå îïèñàíèå ðàçíûõ ýïèãåíåòè÷åñêèõ ñèãíàëîâ è
ìåõàíèçìîâ èõ ðåàëèçàöèè ìîæíî íàéòè â ñîîòâåòñòâóþùèõ
ãëàâàõ ýòîé ëþáîïûòíîé êíèãè. Â íåé äåòàëüíî îïèñàíû
ñîáñòâåííî ôåíîìåí, èñòîðèÿ è êîíöåïöèè ýïèãåíåòèêè,
åå îòäåëüíûå ìåõàíèçìû è ïóòè ðåàëèçàöèè ýïèãåíåòè-
÷åñêèõ ñèãíàëîâ â êëåòêå. Îñîáîå ìåñòî çàíèìàþò ãëàâû,
îïèñûâàþùèå ðîëü ìàëûõ ÐÍÊ â çàìàë÷èâàíèè ãåíîâ, ðå-
ìîäåëèðîâàíèå õðîìàòèíà, åãî ðàçíûå ýíçèìàòè÷åcêèå ìî-
äèôèêàöèè, òðàíñêðèïöèîííîå çàìàë÷èâàíèå ãåíîâ áåëêà-
ìè ãðóïï ïîëèêîìá è òðèòîðàêñ, èíàêòèâàöèþ Õ õðîìîñîì
è ïîëîâóþ äèôôåðåíöèðîâêó ó íåìàòîä è ìëåêîïèòàþùèõ,
ìåõàíèçìû äîçîâîé êîìïåíñàöèè ãåíîâ ó äðîçîôèëû è ìëå-
êîïèòàþùèõ, ìåòèëèðîâàíèå ÄÍÊ è ìåõàíèçìû ãåíîìíîãî
èìïðèíòèíãà ó ìëåêîïèòàþùèõ, ýïèãåíåòè÷åñêèå ìåõàíèç-
ìû äèôôåðåíöèðîâêè ñòâîëîâûõ êëåòîê, ýïèãåíåòè÷åñêèé
êîíòðîëü çà ëèìôîïîýçîì, ïåðåñàäêó ÿäåð è ðåïðîãðàììè-
ðîâàíèå ÿäðà, ýïèãåíåòèêó ðàêà, ýïèãåíåòè÷åñêèå áîëåçíè
÷åëîâåêà. Ïî îòäåëüíîñòè â ñîîòâåòñòâóþùèõ ãëàâàõ äî-
âîëüíî äåòàëüíî ðàññìàòðèâàåòñÿ òàê íàçûâàåìàÿ ÷àñòíàÿ
ýïèãåíåòèêà ðàçíûõ ãðóïï îðãàíèçìîâ: äðîææåé è äðóãèõ
ãðèáîâ, íàñåêîìûõ (äðîçîôèëà), ðåñíèò÷àòûõ ïðîñòåéøèõ
(Ciliata), âûñøèõ ðàñòåíèé.
Êàæäàÿ èç ãëàâ ýòîé êíèãè íàïèñàíà êðóïíûìè, âåäó-
ùèìè â ìèðå ñïåöèàëèñòàìè â ýïèãåíåòèêå, êîòîðûå, êàê
ïðàâèëî, ÿâëÿþòñÿ è îñíîâîïîëîæíèêàìè åå îòäåëüíûõ îá-
ëàñòåé. Ê ñîæàëåíèþ, ðàáîòû íàøèõ ñîîòå÷åñòâåííèêîâ,
âíåñøèõ äîñòîéíûé âêëàä â ñòàíîâëåíèå è ðàçâèòèå ýïèãåíå-
òèêè, îñòàëèñü ïðàêòè÷åñêè áåç âíèìàíèÿ. Æàëü òàêæå, ÷òî â
ýòîé êíèãå íå ïðèíÿëè ó÷àñòèå è òàêèå âñåìèðíî èçâåñòíûå
ðîäîíà÷àëüíèêè ýïèãåíåòèêè, êàê Ðîáèí Õîëëèäåé, Àðòóð
Ðèããñ, Âàëüòåð Äåðôëåð è äðóãèå. Ýòà ìíîãîîáåùàþùàÿ îá-
ëàñòü çíàíèé ðàçâèâàåòñÿ î÷åíü áûñòðî è áóðíî, è óæå ñåãîä-
íÿ ýòà êíèãà ìîãëà áû áûòü èçðÿäíî äîïîëíåíà ïðèíöèïè-
àëüíî íîâûìè è âàæíûìè íàó÷íûìè ñâåäåíèÿìè.
Êíèãà äàåò î÷åíü õîðîøåå è îáøèðíîå ïðåäñòàâëåíèå
îá ýïèãåíåòèêå â öåëîì, åå îòäåëüíûõ îáëàñòÿõ è ìîëåêó-
ëÿðíûõ ìåõàíèçìàõ.
Íàóêà ýïèãåíåòèêà óæå óñïåëà îñíîâàòåëüíî ïðîðàñòè
â òåõíîëîãèè. Â îäíîì èç ïîñëåäíèõ áþëëåòåíåé (Technol-
ogy Review) Ìàññà÷óññåòñêîãî òåõíîëîãè÷åñêîãî èíñòèòóòà
(ÑØÀ) ýïèãåíåòèêà íàçâàíà ñðåäè äåñÿòè âàæíåéøèõ òåõ-
íîëîãèé, êîòîðûå â áëèæàéøåå âðåìÿ ìîãóò èçìåíèòü ìèð
è îêàçàòü íàèáîëüøåå âëèÿíèå íà ÷åëîâå÷åñòâî. È ýòî äåé-
ñòâèòåëüíî òàê. Ñ íåé áåçóñëîâíî ñâÿçàí ïðîãðåññ áèîëîãèè,
ìåäèöèíû, ñåëüñêîãî õîçÿéñòâà è ðàçíûõ áèîòåõíîëîãèé.
Ðàçóìååòñÿ, ýòà êíèãà, ÿðêî è íàãëÿäíî ïîâåñòâóþùàÿ î
íîâîé íàóêå íàøåãî âåêà îáùåáèîëîãè÷åñêîãî çíà÷åíèÿ –
ýïèãåíåòèêå, î÷åíü ïîëåçíà äëÿ øèðîêîãî êðóãà ÷èòàòåëåé,
èíòåðåñóþùèõñÿ êîðåííûìè è îñòðûìè ñîâðåìåííûìè ïðî-
áëåìàìè æèâîãî, ñóùíîñòè æèçíè è ìîëåêóëÿðíûõ ìåõàíèçìîâ
åå ïðîÿâëåíèé. Ïîýòîìó ïîÿâëåíèå ýòîé êíèãè â Ðîññèè ñëåäó-
åò âñÿ÷åñêè ïðèâåòñòâîâàòü, îíà íå òîëüêî ïðîáóäèò èíòåðåñ ê
ýïèãåíåòèêå, ðàñøèðèò è óãëóáèò íàøè çíàíèÿ, íî è ïîñëóæèò
ðàçâèòèþ ýòîé âàæíîé íàó÷íîé äèñöèïëèíû â ñòðàíå.
Êíèãà ïåðåâåäåíà íà ðóññêèé ÿçûê è èçäàíà ïî èíèöèà-
òèâå èçâåñòíîãî ðîññèéñêîãî ó÷åíîãî – Íèêîëàÿ Âèêòîðî-
âè÷à Òîìèëèíà. Ïåðåâîä ñäåëàí ê.á.í. Â.Â. Àøàïêèíûì
(ãëàâà 4), ÷ë.-êîð. ÐÀÍ Á.Ô. Âàíþøèíûì (ãëàâà 9), ê.á.í.
Þ.È. Ïîäëèïàåâîé (ãëàâû 21, 23 è 24), ê.á.í. È.È. Ôðèä-
ëÿíñêîé (ãëàâà 20) è ä.á.í. À.Ë.Þäèíûì.
×ëåí-êîððåñïîíäåíò ÐÀÍ
Á.Ô. Âàíþøèí
ÃËÀÂÀ I
ÝÏÈÃÅÍÅÒÈÊÀ: ÎÒ ßÂËÅÍÈß Ê ÎÁËÀÑÒÈ ÍÀÓÊÈ
Daniel E. Gottschling
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
Ñîäåðæàíèå:
1. Ââåäåíèå
2. Èñòîðèÿ ýïèãåíåòèêè íà ñèìïîçèóìàõ Êîëä
Ñïðèíã Õàðáîð
3. 69-é ñèìïîçèóì
3.1. Ãèïîòåçà ãèñòîíîâîãî êîäà
3.2. Äèíàìè÷åñêèé «ìîë÷àùèé» õðîìàòèí
1. Ââåäåíèå
Ñîñòîÿâøèéñÿ ëåòîì 2004 ãîäà 69-é ñèìïîçèóì (Cold
Spring Harbor Symposium on Quantitative Biology) áûë ïî-
ñâÿùåí òåìå «Ýïèãåíåòèêà» è ìíîãèå àâòîðû ýòîé êíèãè
áûëè â ÷èñëå åãî ó÷àñòíèêîâ. Êàê íàáëþäàòåëü íà ýòîì
ñèìïîçèóìå ÿ çíàë, ÷òî ýòî äîëæíà áûëà áûòü èíòåðåñ-
íàÿ âñòðå÷à. Ñîâåùàíèå íà÷àëîñü äîñòàòî÷íî ïðîñòî — ñ
ïîïûòîê îïðåäåëåíèÿ ýïèãåíåòèêè. Ïîñëå íåäåëüíûõ
ðàñïðîñîâ ó÷àñòíèêîâ íà ýòó òåìó ñòàëî ÿñíî, ÷òî çàäàâàòü
òàêîé âîïðîñ — âñå ðàâíî ÷òî ïðîñèòü êîãî-òî îïðåäåëèòü,
÷òî òàêîå «ñåìåéíûå öåííîñòè»: êàæäûé çíàåò, ÷òî ýòî
òàêîå, íî äëÿ êàæäîãî ýòî èìååò ðàçíûé ñìûñë. Êàê îáú-
ÿñíèë Äýâèä Õåéã [David Haig], îò÷àñòè ïðè÷èíó òàêîãî
øèðîêîãî ñïåêòðà ìíåíèé ìîæíî ïîíÿòü èñõîäÿ èç ýòè-
ìîëîãèè ñëîâà «ýïèãåíåòèêà»: ýòî ñëîâî èìååò äâîéíîå
ïðîèñõîæäåíèå â áèîëîãè÷åñêîé ëèòåðàòóðå ïðîøëîãî
âåêà, è çíà÷åíèå ýòîãî òåðìèíà ïðîäîëæàåò ýâîëþöèî-
íèðîâàòü. Óîääèíãòîí [Waddington] ïåðâûì èçîáðåë ýòîò
òåðìèí äëÿ îáîçíà÷åíèÿ èññëåäîâàíèé «êàóçàëüíûõ ìåõà-
íèçìîâ», ïîñðåäñòâîì êîòîðûõ «ãåíû ãåíîòèïà îñóùåñò-
âëÿþò ôåíîòèïè÷åñêèå ýôôåêòû» (ñì. Haig, 2004). Ïîçæå
Íýííè [Nanney] èñïîëüçîâàë ýòîò òåðìèí äëÿ îáúÿñíåíèÿ
ñâîèõ ïðåäñòàâëåíèé î òîì, êàê êëåòêè ñ îäíèì è òåì æå
ãåíîòèïîì ìîãóò èìåòü ðàçíûå ôåíîòèïû, ñîõðàíÿþùèåñÿ
íà ïðîòÿæåíèè ìíîãèõ ïîêîëåíèé.
ß îïðåäåëÿþ ýïèãåíåòè÷åñêîå ÿâëåíèå êàê èçìåíå-
íèå â ôåíîòèïå, êîòîðîå ÿâëÿåòñÿ íàñëåäóåìûì, íî íå
ñâÿçàíî ñ ìóòàöèåé â ÄÍÊ. Áîëåå òîãî, ýòî èçìåíåíèå â
3.3. ßäåðíàÿ îðãàíèçàöèÿ
3.4. Ïðèîíû
3.5. Íîâîå ÿâëåíèå
4. Çàêëþ÷èòåëüíûå ñîîáðàæåíèÿ
Áëàãîäàðíîñòè
Ëèòåðàòóðà
ôåíîòèïå äîëæíî áûòü ïîõîæèì íà ïåðåêëþ÷åíèå òèïà
«ÂÊËÞ×ÅÍλ èëè «ÂÛÊËÞ×ÅÍλ, à íå ãðàäóàëü-
íîé ðåàêöèåé, è îíî äîëæíî íàñëåäîâàòüñÿ äàæå åñëè
ïåðâîíà÷àëüíûå óñëîâèÿ, âûçâàâøèå ýòî ïåðåêëþ÷å-
íèå, èñ÷åçàþò. Òàêèì îáðàçîì, â ÷èñëî ýïèãåíåòè÷åñêèõ
ÿâëåíèé ÿ âêëþ÷àþ ïåðåêëþ÷åíèå ìåæäó ëèçèñîì è ëè-
çîãåíèåé ó áàêòåðèîôàãà ëÿìáäà (Ptashne, 2004), ïåðå-
êëþ÷åíèå ïèëåé ó óðîïàòîãåííîé Escherichia coli (Hern-
day et al., 2003), ýôôåêò ïîëîæåíèÿ íåñòàáèëüíîãî òèïà
ó Drosophila (Henikoff, 1990), íàñëåäóåìûå èçìåíåíèÿ
â êîðòèêàëüíîì ïàòòåðíå ó Tetrahymena (Frankel 1990),
ïðèîííûå áîëåçíè (Wickner et al., 2004) è èíàêòèâàöèþ
Õ-õðîìîñîìû (Lyon, 1993).
69-é ñèìïîçèóì ñîñòîÿëñÿ â 100-þ ãîäîâùèíó ãå-
íåòèêè êàê îáëàñòè èññëåäîâàíèé â Ëàáîðàòîðèè Êîëä
Ñïðèíã Õàðáîð, ÷òî äåëàåò î÷åíü ñâîåâðåìåííûì ðàñ-
ñìîòðåíèå ýïèãåíåòèêè. Ó÷èòûâàÿ ýòîò èñòîðè÷åñêèé
êîíòåêñò, ÿ ñ÷åë óìåñòíûì ðàññìîòðåòü èçó÷åíèå ýïèãå-
íåòèêè â ñâåòå ïðåäûäóùèõ ñèìïîçèóìîâ Êîëä Ñïðèíã
Õàðáîð. Õîòÿ 69-é ñèìïîçèóì áûë ïåðâûì, ïîñâÿùåí-
íûìè ñïåöèàëüíî ýòîé òåìå, ýïèãåíåòè÷åñêèå ÿâëåíèÿ
è èõ èçó÷åíèå îêàçàëèñü ïðåäñòàâëåííûìè íà ïðîòÿ-
æåíèè âñåé èñòîðèè ýòîé âûäàþùåéñÿ ñåðèè ñèìïî-
çèóìîâ. Ïðåäëàãàåìàÿ ìíîþ èñòîðèÿ ñóæàåòñÿ äàëåå
ìîèìè ñîáñòâåííûìè îãðàíè÷åíèÿìè è ïðåäïî÷òåíèÿ-
ìè. Äëÿ áîëåå ïîëíîé è àêàäåìè÷åñêîé êàðòèíû ÿ ìîãó
ïîðåêîìåíäîâàòü ñâûøå 1000 îáçîðîâ ïî ýïèãåíåòèêå,
íàïèñàííûõ çà ïîñëåäíèå ïÿòü ëåò.
Ïðåäñòàâëÿÿ ýòîò õðîíîëîãè÷åñêèé îò÷åò, ÿ íàäåþñü
ïåðåäàòü ñâîå îùóùåíèå îò òîãî, êàê êîëëåêöèÿ âíåø-
14 Ãëàâà 1. Ýïèãåíåòèêà: îò ÿâëåíèÿ ê îáëàñòè íàóêè
íå íåñîïîñòàâèìûõ ÿâëåíèé ñëèëàñü âîåäèíî â îáëàñòü
èññëåäîâàíèé, çàòðàãèâàþùóþ âñå ðàçäåëû áèîëîãèè, à
òàêæå ïîêàçàòü, ÷òî èçó÷åíèå ýïèãåíåòèêè îñíîâûâàåò-
ñÿ íà ñòðåìëåíèè îáúÿñíèòü íåîæèäàííîå — âîçìîæíî,
â áîëüøåé ñòåïåíè, ÷åì ëþáàÿ äðóãàÿ îáëàñòü áèîëîãè-
÷åñêèõ èññëåäîâàíèé.
2. Èñòîðèÿ ýïèãåíåòèêè
íà ñèìïîçèóìàõ Êîëä Ñïðèíã
Õàðáîð
 1941 ãîäó, âî âðåìÿ 9-ãî ñèìïîçèóìà, âåëèêèé ãåíåòèê-
äðîçîôèëèñò Ãåðìàí Ìåëëåð (H.J. Muller) îïèñàë ðåçóëü-
òàòû äàëüíåéøåé ðàçðàáîòêè ÿâëåíèÿ, ïåðâîíà÷àëüíî
íàçâàííîãî èì «eversporting displacement», — ÿâëåíèÿ,
êîãäà êðóïíûå õðîìîñîìíûå ïåðåñòðîéêè ïðèâîäèëè
ê ìóòàíòíîé ìîçàè÷íîé ýêñïðåññèè ãåíîâ âáëèçè òî÷-
êè ðàçðûâà (Muller, 1941). Êî âðåìåíè ñèìïîçèóìà îí
íàçûâàë ýòî «ìîçàèöèçìîì, îáóñëîâëåííûì ýôôåêòîì
ïîëîæåíèÿ» («position effect variegation»). Áûëî íàäåæíî
óñòàíîâëåíî, ÷òî çàòðàãèâàåìûå ãåíû áûëè ïåðåíåñåíû
«â ñîñåäñòâî ñ ãåòåðîõðîìàòèíîâûì ðàéîíîì», ÷òî ïåðå-
íåñåííûå ýóõðîìàòèíîâûå ó÷àñòêè «áûëè ÷àñòè÷íî, íî
â ðàçíîé ñòåïåíè, òðàíñôîðìèðîâàíû â ñîñòîÿíèå ãåòå-
ðîõðîìàòèíà — ‘ãåòåðîõðîìàòèíèçèðîâàíû’» è ÷òî äîáàâ-
ëåíèå ýêñòðàêîïèé ãåòåðîõðîìàòèíîâûõ õðîìîñîì «ïî-
çâîëÿëî çàòðîíóòîìó ãåíó ñòàíîâèòüñÿ áîëåå íîðìàëüíûì
â ñâîåì ôóíêöèîíèðîâàíèè». Â òî âðåìÿ ýòî ïîñëåäíåå
íàáëþäåíèå âûçûâàëî íåäîóìåíèå è áûëî íåîæèäàííûì,
õîòÿ òåïåðü ìû çíàåì, ÷òî ýòî ðåçóëüòàò òèòðîâàíèÿ ëè-
ìèòèðóþùèõ êîìïîíåíòîâ ãåòåðîõðîìàòèíà.
Íà 16-ì ñèìïîçèóìå (1951) âûñøèé ïðèîðèòåò èìå-
ëî äåòàëüíîå ïîíèìàíèå ãåíà. Ýòèì ìîæíî îáúÿñíèòü,
ïî÷åìó â ïîíèìàíèè ìîçàèöèçìà, îáóñëîâëåííîãî ýô-
ôåêòîì ïîëîæåíèÿ (PEV), èìåë ìåñòî íåçíà÷èòåëüíûé
ïðîãðåññ, õîòÿ è áûëè îòêðûòû íîâûå ïðèìåðû ýòîãî
ÿâëåíèÿ. Îäíàêî ïåðâûé äîêëàä÷èê îòìåòèë, ÷òî PEV
ñòàíåò çàõâàòûâàþùåé îáëàñòüþ áóäóùèõ èññëåäîâà-
íèé (Goldschmidt, 1951). Áàðáàðà ÌàêÊëèíòîê îòìå-
òèëà, ÷òî õðîìîñîìíûå ýôôåêòû ïîëîæåíèÿ ÿâëÿþòñÿ
îñíîâîé ðàçëè÷èé â «ìóòàáèëüíûõ ëîêóñàõ» êóêóðóçû,
è âûñêàçàëà ïðåäïîëîæåíèå, ÷òî íàáëþäàâøàÿñÿ åþ
èçìåí÷èâîñòü ìóòàáèëüíîñòè, âîçìîæíî, êîðåíèòñÿ â
òåõ æå ìåõàíèçìàõ, ÷òî ëåæàò â îñíîâå PEV ó Drosophila
(McClintock, 1951).
Êî âðåìåíè 21-ãî ñèìïîçèóìà èäåè ÌàêÊëèíòîê î
«êîíòðîëèðóþùèõ ýëåìåíòàõ» ïîëó÷èëè äàëüíåéøåå
ðàçâèòèå (McClintock, 1956). Äâå èç íèõ èìåëè îñîáî
áëèçêîå îòíîøåíèå ê ýïèãåíåòèêå. Â ñèñòåìå êîíòðî-
ëèðóþùåãî ýëåìåíòà Spm îíà îáíàðóæèëà âàðèàíòû,
ïîçâîëèâøèå åé ðàçëè÷àòü trans-äåéñòâóþùèå ôàêòîðû,
êîòîðûå ìîãóò «ïîäàâëÿòü» ãåí (óìåíüøàòü èëè óñòðà-
íÿòü åãî ôåíîòèïè÷åñêîå âûðàæåíèå), à íå çàñòàâëÿòü
åãî ìóòèðîâàòü. Îíà òàêæå îòìåòèëà, ÷òî íåêîòîðûå
êîíòðîëèðóþùèå ýëåìåíòû ìîãëè ïîäàâëÿòü äåéñòâèå
ãåíà íå òîëüêî â òîì ëîêóñå, êóäà îíè âñòàâëåíû, íî è â
ëîêóñàõ, êîòîðûå ðàñïîëîæåíû íà íåêîòîðîì ðàññòîÿ-
íèè ñ òîé èëè äðóãîé ñòîðîíû îò íåãî. Äðóãèå èññëåäî-
âàòåëè òàêæå îáíàðóæèâàëè ýòîò «ýôôåêò ðàñïðîñòðàíå-
íèÿ». Øóëüö ïðåäñòàâèë áèîõèìè÷åñêèå è ôèçè÷åñêèå
õàðàêòåðèñòèêè öåëûõ Drosophila, ñîäåðæàùèõ ðàçíûå
êîëè÷åñòâà ãåòåðîõðîìàòèíà (Schultz, 1956). Õîòÿ ýòà
ðàáîòà áûëà âåñüìà ïðèìèòèâíîé, à ñäåëàííûå íà åå
îñíîâå âûâîäû èìåëè îãðàíè÷åííîå çíà÷åíèå, îíà ÿâè-
ëàñü ïðèìåðîì ïåðâûõ ïîïûòîê ðàñ÷ëåíèòü ñòðóêòóðó
ãåòåðîõðîìàòèíà è ïðîäåìîíñòðèðîâàëà, íàñêîëüêî
òðóäíîé îêàæåòñÿ ýòà ïðîáëåìà.
Äâà ñîîáùåíèÿ íà 23-ì ñèìïîçèóìå ÿâèëèñü âåõàìè
â ñâåòå íàøåãî ñåãîäíÿøíåãî ñèìïîçèóìà. Âî-ïåðâûõ,
Áðèíê îïèñàë ñâîè îøåëîìëÿþùèå íàáëþäåíèÿ «ïàðà-
ìóòàöèé» â ëîêóñå R ó êóêóðóçû. Åñëè äâå àëëåëè (Rst è
Rr) ñ ðàçíûìè ôåíîòèïàìè â ãîìîçèãîòíîì ñîñòîÿíèè
êîìáèíèðóþòñÿ è îáðàçóþò ãåòåðîçèãîòó, è ýòî ðàñòåíèå
Rst/Rr, â ñâîþ î÷åðåäü, ñíîâà ñêðåùèâàåòñÿ, ïîëó÷àþùå-
åñÿ â ðåçóëüòàòå ïîòîìñòâî, êîòîðîå ñîäåðæèò àëëåëü Rr,
âñåãäà áóäåò èìåòü ôåíîòèï Rst, õîòÿ àëëåëü Rst áîëüøå
íå ïðèñóòñòâóåò (Brink, 1958). Îäíàêî ýòîò ôåíîòèï ÿâ-
ëÿåòñÿ ìåòàñòàáèëüíûì — â ïîñëåäóþùèõ ñêðåùèâàíè-
ÿõ îí ðåâåðòèðóåò ê íîðìàëüíîìó ôåíîòèïó Rr. Áðèíê
ïðåäïîëàãàë, ÷òî ñëîâî «ïàðàìóòàöèÿ» «äîëæíî èñïîëü-
çîâàòüñÿ â ýòîì êîíòåêñòå â ñâîåì áóêâàëüíîì ñìûñëå,
êàê óêàçûâàþùåå íà ÿâëåíèå, îòëè÷íîå îò ìóòàöèè, íî
è íå ïîëíîñòüþ íåïîõîæåå íà íåå». Âî-âòîðûõ, Íýí-
íè ïîøåë î÷åíü äàëåêî â ïîïûòêàõ ñôîðìóëèðîâàòü
«êîíöåïòóàëüíûå è îïåðàöèîíàëüíûå ðàçëè÷èÿ ìåæäó
ãåíåòè÷åñêèìè è ýïèãåíåòè÷åñêèìè ñèñòåìàìè» (Nan-
ney, 1958). Ïî ñóùåñòâó îí îïðåäåëèë ýïèãåíåòèêó
èíà÷å, ÷åì ïåðâîíà÷àëüíî ïðåäïîëàãàëîñü Óîääèíãòî-
íîì (Waddington) (äåòàëè ñì. Haig, 2004). Îí ñ÷åë íå-
îáõîäèìûì ïîñòóïèòü òàêèì îáðàçîì, äëÿ òîãî ÷òîáû
îïèñàòü ÿâëåíèÿ, íàáëþäàâøèåñÿ èì ó Tetrahymena. Îí
ïîëó÷èë äàííûå î òîì, ÷òî ïðîèñõîæäåíèå öèòîïëàçìû
êîíúþãèðóþùèõ ðîäèòåëüñêèõ êëåòîê âëèÿåò íà äåòåð-
ìèíàöèþ òèïà ñïàðèâàíèÿ ïîëó÷àþùåãîñÿ ïîòîìñòâà.
Äàííîå èì îïðåäåëåíèå îõâàòûâàëî è íàáëþäåíèÿ,
ñäåëàííûå äðóãèìè èññëåäîâàòåëÿìè, âêëþ÷àÿ ðàáîòó
Áðèíêà ïî ëîêóñó R è ðàáîòó ÌàêÊëèíòîê, îòìå÷åííóþ
íà 21-ì ñèìïîçèóìå.
Íà 29-ì ñèìïîçèóìå çíà÷èòåëüíûé èíòåðåñ âûçâàëà
ãèïîòåçà èíàêòèâàöèè Õ-õðîìîñîìû ó ñàìîê ìëåêîïè-
òàþùèõ, íåçàäîëãî äî ýòîãî ïðåäëîæåííàÿ Ìýðè Ëàé-
îí (Lyon, 1961). Ãàðòëåð, Áîéòëåð è Íàíñ ïðåäñòàâèëè
íîâûå äàííûå â åå ïîääåðæêó (Beutler, 1964; Gartler and
Linder, 1964; Nance, 1964). Áîéòëåð äàë îáçîð ìíîãî÷èñ-
ëåííûõ ïðèìåðîâ ìîçàè÷íîé ýêñïðåññèè ñöåïëåííûõ ñ
Õ ãåíîâ ó æåíùèí, êîòîðûå ñâèäåòåëüñòâîâàëè â ïîëüçó
ñëó÷àéíîé ïðèðîäû Õ-èíàêòèâàöèè. Îñíîâûâàÿñü íà
òùàòåëüíîì êîëè÷åñòâåííîì àíàëèçå ïðîäóêòà ãåíà,
ñöåïëåííîãî ñ Õ, Íàíñ çàêëþ÷èë, ÷òî èíàêòèâàöèÿ
Õ-õðîìîñîìû ïðîèñõîäèò äî íàñòóïëåíèÿ 32-êëåòî÷íîé
ñòàäèè ýìáðèîíà.
38-é ñèìïîçèóì íà òåìó «Ñòðóêòóðà è ôóíêöèÿ õðî-
ìîñîì» ÿâèëñÿ âîçâðàòîì ê èçó÷åíèþ ýóêàðèîòè÷åñêèõ
õðîìîñîì — ê ýòîìó âðåìåíè çíà÷èòåëüíûé ïðîãðåññ
áûë äîñòèãíóò â èçó÷åíèè ïðîêàðèîòè÷åñêèõ è ôàãîâûõ
ñèñòåì, è, êàê ñëåäñòâèå, â ðàñöâåòàþùåé îáëàñòè ìî-
ëåêóëÿðíîé áèîëîãèè â ìûøëåíèè â îñíîâíîì äîìèíè-
ðîâàëà ýêñïðåññèÿ áàêòåðèàëüíûõ ãåíîâ. Îäíàêî ðîñëî
è ïîíèìàíèå ðîëè õðîìàòèíà (ÄÍÊ ñ ãèñòîíàìè è íå-
 2. Èñòîðèÿ ýïèãåíåòèêè íà ñèìïîçèóìàõ Êîëä Ñïðèíã Õàðáîð
ãèñòîíîâûìè áåëêàìè) ó ýóêàðèîò, íî áûëî íåÿñíî, ñâÿ-
çàíà ëè åãî ðîëü ñî ñòðóêòóðîé õðîìîñîìû, ñ åå ôóíêöè-
ÿìè èëè æå è ñ òåì, è äðóãèì (Swift, 1974). Òåì íå ìåíåå,
íåñêîëüêî ãðóïï íà÷àëè âûñêàçûâàòü ïðåäïîëîæåíèÿ,
÷òî ñ òðàíñêðèïöèåé ãåíîâ èëè ñ îáùåé ñòðóêòóðîé
õðîìîñîì ñâÿçàíà ïîñòòðàíñëÿöèîííàÿ ìîäèôèêàöèÿ
áåëêîâ õðîìàòèíà, â òîì ÷èñëå ãèñòîíîâ (Allfrey et al.,
1974; Louie et al., 1974; Weintraub, 1974). Â âîçäóõå âèòàë
ëèøü íàìåê íà ýïèãåíåòè÷åñêèå ÿâëåíèÿ. Âûñêàçûâà-
ëèñü ãèïîòåçû î òîì, ÷òî ó ýóêàðèîò áîëüøèíñòâî ãåíîâ
ðåãóëèðóþòñÿ ïîâòîðÿþùåéñÿ ÄÍÊ — îò÷àñòè èñõîäÿ
èç òîãî ôàêòà, ÷òî îòêðûòûå ÌàêÊëèíòîê êîíòðîëèðó-
þùèå ýëåìåíòû ïîâòîðåíû â ãåíîìå. Ñîîáùàëîñü, îä-
íàêî, ÷òî áîëüøàÿ ÷àñòü ïîâòîðÿþùèõñÿ íóêëåîòèäíûõ
ïîñëåäîâàòåëüíîñòåé ÄÍÊ íå ñöåïëåíà ñ ãåíàìè (Pea-
cock et al., 1974; Rudkin and Tartof, 1974). C ó÷åòîì ýòèõ
íàáëþäåíèé èäåÿ î òîì, ÷òî ïîâòîðÿþùèåñÿ ýëåìåíòû
ðåãóëèðóþò ýêñïðåññèþ ãåíîâ, â çíà÷èòåëüíîé ìåðå
óòðàòèëà ïîääåðæêó ñî ñòîðîíû ïðèñóòñòâîâàâøèõ.
×òî, îäíàêî, áîëåå âàæíî, â ýòèõ æå ñàìûõ èññëåäîâà-
íèÿõ îáíàðóæèëîñü, ÷òî áîëüøàÿ ÷àñòü ïîâòîðÿþùåéñÿ
ÄÍÊ ëîêàëèçîâàíà â ãåòåðîõðîìàòèíå.
42-é ñèìïîçèóì ïðîäåìîíñòðèðîâàë, ÷òî çà ÷åòû-
ðå ãîäà ïîðàçèòåëüíîå êîëè÷åñòâî òåõíè÷åñêèõ è èí-
òåëëåêòóàëüíûõ äîñòèæåíèé ïîëíîñòüþ ïðåîáðàçèëè
èçó÷åíèå ýóêàðèîòè÷åñêèõ õðîìîñîì (Chambon 1978).
Ê èõ ÷èñëó îòíîñèëèñü èñïîëüçîâàíèå ôåðìåíòîâ ðå-
ñòðèêöèè ÄÍÊ, ðàçðàáîòêà òåõíîëîãèè ðåêîìáèíàíò-
íûõ ÄÍÊ, ðóòèííîå ðàçäåëåíèå áåëêîâ è íóêëåèíîâûõ
êèñëîò, âîçìîæíîñòü ïðîâåäåíèÿ Ñàóçåðí- è Íîðçåðí-
àíàëèçà, áûñòðîå ñåêâåíèðîâàíèå ÄÍÊ è ÐÍÊ è èììó-
íîôëóîðåñöåíöèÿ íà õðîìîñîìàõ. Áûëà ïðåäñòàâëåíà
íóêëåîñîìíàÿ ãèïîòåçà è áûë îòêðûò ñïëàéñèíã è ÐÍÊ.
Îñíîâíîé èíòåðåñ íà ýòîì ñèìïîçèóìå ïðèâëåêëè áèî-
õèìè÷åñêèå è öèòîëîãè÷åñêèå ðàçëè÷èÿ â ñòðóêòóðå
õðîìàòèíà, îñîáåííî ìåæäó àêòèâíî òðàíñêðèáèðóå-
ìûìè è íåàêòèâíûìè ãåíàìè. Åñëè, îäíàêî, ãîâîðèòü
î òîì, ÷òî èìåëî íàèáîëåå áëèçêîå îòíîøåíèå ê ýïèãå-
íåòèêå, òî Âàéíòðàóá ñ ñîòðóäíèêàìè ïðåäñòàâèë ñâîè
ñîîáðàæåíèÿ îòíîñèòåëüíî òîãî, êàêèì îáðàçîì õðîìà-
òèí ìîæåò îáóñëîâëèâàòü ìîçàè÷íóþ ýêñïðåññèþ ãåíîâ
ó îðãàíèçìà (Weintraub et al., 1978).
45-é ñèìïîçèóì ÿâèëñÿ òîðæåñòâîì îòêðûòèé Áàð-
áàðû ÌàêÊëèíòîê — ïîäâèæíûõ ãåíåòè÷åñêèõ ýëåìåí-
òîâ (Yarmolinsky, 1981). Âûïîëíåííûå â ìåõàíèñòè÷å-
ñêîì ïëàíå èññëåäîâàíèÿ áàêòåðèàëüíîé òðàíñïîçèöèè
ïðîäåìîíñòðèðîâàëè ÷ðåçâû÷àéíûé ïðîãðåññ è âïîëíå
îïðàâäàííî ñîñòàâèëè îêîëî ïîëîâèíû âñåõ ïðåäñòàâ-
ëåííûõ ñîîáùåíèé, â òî âðåìÿ êàê äðóãèå äîêëàäû ñî-
äåðæàëè äàííûå î òîì, ÷òî òðàíñïîçèöèÿ è ðåãóëèðóåìàÿ
ðåîðãàíèçàöèÿ ãåíîìà ïðîèñõîäÿò íå òîëüêî ó êóêóðó-
çû, íî è ó äðóãèõ ýóêàðèîò, â òîì ÷èñëå ó ìóõ, ëüâèíî-
ãî çåâà, òðèïàíîñîì, ãðèáà Ascobolus è ïî÷êóþùèõñÿ
äðîææåé. Â êîíòåêñòå ýòîãî ñîâåùàíèÿ âñå íàáëþäàâ-
øèåñÿ ñëó÷àè ìîçàè÷íîé ýêñïðåññèè áûëè îòíåñåíû
íà ñ÷åò òðàíñïîçèöèé. Áîëåå òîãî, èìåëà ìåñòî ñêðû-
òàÿ òåíäåíöèÿ âñåðüåç ñ÷èòàòü, ÷òî êîíòðîëèðóþùèå
ýëåìåíòû îòâåòñòâåííû çà áîëüøóþ ÷àñòü ðåãóëÿöèè
ãåíîâ (Ñampbell, 1981), ÷òî ïðèâåëî íåêîòîðûõ ó÷àñò-
íèêîâ ê ïðåäïîëîæåíèþ, ÷òî «åäèíñòâåííîé ôóíêöèåé
15
ýòèõ ýëåìåíòîâ ÿâëÿåòñÿ ñòèìóëèðîâàíèå ãåíåòè÷åñêîé
èçìåí÷èâîñòè».  ñóùíîñòè, èäåÿ î òîì, ÷òî çà ðåãóëè-
ðóåìóþ ýêñïðåññèþ â ìîçàèöèçìå, îáóñëîâëåííîì ýô-
ôåêòîì ïîëîæåíèÿ, îòâåòñòâåí ãåòåðîõðîìàòèí, áûëà
ïîñòàâëåíà ïîä ñîìíåíèå. Ïî îòíîøåíèþ ê áóäóùèì
ýïèãåíåòè÷åñêèì èññëåäîâàíèÿì, âåðîÿòíî, íàèáîëü-
øåå âíèìàíèå çàñëóæèâàëî òâåðäîå îáîñíîâàíèå íàëè-
÷èÿ «ìîë÷àùèõ» êàññåò òèïîâ ñïàðèâàíèÿ («silent mating
cassetttes») ó Saccharomyces cerevisiae (Haber et al., 1981;
Klar et al., 1981; Nasmyth et al. 1981; Rine et al., 1981).
 ïîðÿäêå ïîäãîòîâêè ê 47-ìó ñèìïîçèóìó ó ïîçâî-
íî÷íûõ áûëà óñòàíîâëåíà îáùàÿ êîððåëÿöèÿ, ñîãëàñíî
êîòîðîé îáùèé óðîâåíü ìåòèëèðîâàíèÿ öèòîçèíîâ â
ÄÍÊ-ïîñëåäîâàòåëüíîñòÿõ CpG íèæå äëÿ ãåíîâ, êîòî-
ðûå òðàíñêðèáèðóþòñÿ, ÷åì äëÿ òåõ, êîòîðûå íå òðàíñ-
êðèáèðóþòñÿ. Îäíàêî èìåëèñü èñêëþ÷åíèÿ èç ýòîãî
îáùåãî ïðàâèëà, è áîëåå äåòàëüíûé àíàëèç ïîêàçàë, ÷òî
íàèáîëåå âàæíûì ÿâëÿåòñÿ ìåòèëèðîâàíèå ñïåöèôè÷å-
ñêèõ ó÷àñòêîâ ïðîìîòîðà ãåíà (Cedar et al., 1983; Doerfler
et al., 1983; La Volpe et al., 1983). Áàçèðóÿñü íà ñèñòåìàõ
ðåñòðèêöèè-ìîäèôèêàöèè ó áàêòåðèé, ïîëàãàëè, ÷òî
ìåòèëèðîâàíèå ÄÍÊ ïðåäîòâðàùàåò ñâÿçûâàíèå êëþ-
÷åâûõ ðåãóëÿòîðíûõ áåëêîâ. Ê òîìó æå áûëî ïîêàçàíî,
÷òî ïàòòåðíû ìåòèëèðîâàíèÿ ÄÍÊ ó ïîçâîíî÷íûõ ìî-
ãóò íàñëåäîâàòüñÿ ÷åðåç ìèòîç, ÷òî ïðèâîäèëî ê ãèïîòå-
çå î òîì, ÷òî ìåòèëèðîâàíèå ÄÍÊ ìîæåò ñëóæèòü ñðåä-
ñòâîì òðàíñêðèïöèîííîé «ïàìÿòè»â ïðîöåññå äåëåíèÿ
êëåòîê â õîäå ðàçâèòèÿ (Shapiro and Mohandas, 1983).
Åùå îäíèì ãëàâíûì îòêðûòèåì, èìåþùèì îòíîøåíèå
ê ýïèãåíåòèêå, áûëà èäåíòèôèêàöèÿ íóêëåîòèäíûõ ïî-
ñëåäîâàòåëüíîñòåé ÄÍÊ ïî òó èëè äðóãóþ ñòîðîíó îò
«ìîë÷àùèõ êàññåò òèïîâ ñïàðèâàíèÿ» ó ïî÷êóþùèõñÿ
äðîææåé, êîòîðûå îòâå÷àþò çà òðàíñêðèïöèîííóþ ðå-
ïðåññèþ ãåíîâ, íàõîäÿùèõñÿ âíóòðè ýòèõ êàññåò; îíè,
òàêèì îáðàçîì, îêàçàëèñü ïåðâûìè íóêëåîòèäíûìè ïî-
ñëåäîâàòåëüíîñòÿìè ÄÍÊ, íåîáõîäèìûìè äëÿ õðîìî-
ñîìíûõ ýôôåêòîâ ïîëîæåíèÿ (Abraham et al., 1983).
«Ìîëåêóëÿðíàÿ áèîëîãèÿ ðàçâèòèÿ» áûëà òåìîé
50-ãî ñèìïîçèóìà, è íà íåì òîæå áûë ïðåäñòàâëåí ðÿä
âàæíûõ äîñòèæåíèé. Âîçìîæíî, îäíèì èç ñàìûõ âîë-
íóþùèõ óñïåõîâ áûëî îñîçíàíèå âñåìè òîãî ôàêòà, ÷òî
ôóíäàìåíòàëüíûå ìîëåêóëÿðíûå ñâîéñòâà ÿâëÿþòñÿ
êîíñåðâàòèâíûìè â õîäå ýâîëþöèè — íàïðèìåð, RAS
÷åëîâåêà ôóíêöèîíèðóåò â ïî÷êóþùèõñÿ äðîææàõ, ãî-
ìåîáîêñíûå áåëêè êîíñåðâàòèâíû ó ìóõ è ÷åëîâåêà (Ru-
bin et al., 1985). Íîâûå ïîïûòêè ïîíÿòü õðîìîñîìíûé
èìïðèíòèíã íà÷àëèñü ñ ðàçðàáîòêè òåõíèêè ÿäåðíûõ
ïåðåñàäîê ó ìûøåé (Solter et al., 1985). Ýòè èññëåäîâà-
íèÿ ïîêàçàëè, ÷òî â îòöîâñêîì è ìàòåðèíñêîì ãåíîìàõ
íîâîé çèãîòû õðàíèòñÿ èíôîðìàöèÿ î ïðîèñõîæäåíèè
îò òîãî èëè äðóãîãî ðîäèòåëÿ; âàæíà íå ïðîñòî ÄÍÊ
ñàìà ïî ñåáå; õðîìîñîìû ñîäåðæàò äîïîëíèòåëüíóþ
èíôîðìàöèþ, ÷åðåç êîãî èç ðîäèòåëåé îíè ïðîøëè, è
ýòà èíôîðìàöèÿ íåîáõîäèìà äëÿ óñïåøíîãî ðàçâèòèÿ
ýìáðèîíà. Ïîëàãàëè, ÷òî ÷àñòè÷íî îòâåò ëåæèò â òîì
ôàêòå, ÷òî îò ïðîèñõîæäåíèÿ õðîìîñîìû îò òîãî èëè
äðóãîãî ðîäèòåëÿ çàâèñèò äèôôåðåíöèàëüíàÿ ýêñïðåñ-
ñèÿ ãåíîâ (Cattanach and Kirk, 1985).
Èìåëñÿ ðÿä èññëåäîâàíèé, íàïðàâëåííûõ íà ïîíè-
ìàíèå ñëîæíîé ðåãóëÿöèè êîìïëåêñà bithorax; îñîáåí-
16 Ãëàâà 1. Ýïèãåíåòèêà: îò ÿâëåíèÿ ê îáëàñòè íàóêè
íî ñëåäóåò îòìåòèòü ñîîáùåíèå Ëüþèñà, êîòîðûé ñïå-
öèàëüíî îñòàíîâèëñÿ íà ñòðàííîé ïðèðîäå èçâåñòíûõ
trans-ðåãóëÿòîðîâ ýòîãî ëîêóñà; ïî÷òè âñå îíè ÿâëÿþò-
ñÿ ðåïðåññîðàìè äàííîãî ëîêóñà (Lewis, 1985). Òàêèì
îáðàçîì, ïîääåðæàíèå ãåíà â «ìîë÷àùåì» ñîñòîÿíèè
íà ïðîòÿæåíèè ìíîãèõ êëåòî÷íûõ óäâîåíèé ÿâëÿåòñÿ
îáÿçàòåëüíûì äëÿ íîðìàëüíîãî ðàçâèòèÿ. Ýòî ïðîòèâî-
ðå÷èëî âåñüìà ðàñïðîñòðàíåííîìó â òî âðåìÿ ìíåíèþ,
ñîãëàñíî êîòîðîìó òàì, ãäå áóäóò ïðèíèìàòüñÿ êðèòè-
÷åñêèå ðåãóëÿòîðíûå ðåøåíèÿ, êàñàþùèåñÿ ðàçâèòèÿ,
èìååò ìåñòî àêòèâàöèÿ/èíäóêöèÿ ãåíà.
Ê òîìó âðåìåíè äëÿ ðÿäà îðãàíèçìîâ áûëà ðàçðàáî-
òàíà òåõíèêà ÄÍÊ-òðàíñôîðìàöèè è èíñåðöèîííîãî
ìóòàãåíåçà. Îäèí èç ïðèìåðîâ îñîáåííî ïðîäóêòèâíîãî
è èìåþùåãî îòíîøåíèå ê ýïèãåíåòèêå èñïîëüçîâàíèÿ
ýòîé òåõíîëîãèè áûë ïîëó÷åí íà Drosophila. Áûë ñîçäàí
òðàíñïîçîí P-ýëåìåíò ñ ãåíîì white (öâåò ãëàç) íà íåì
è îí «ïðûãàë» ïî âñåìó ãåíîìó (Rubin et al., 1985). Ýòî
äàëî âîçìîæíñòü êàðòèðîâàòü âî âñåì ãåíîìå Drosophila
ñàéòû, ãäå ìîã ïðîèñõîäèòü PEV.
Ýòîò ñèìïîçèóì âûñâåòèë òàêæå ïåðâûå ãåíåòè÷åñêèå
ïîäõîäû ê ðàñ÷ëåíåíèþ (dissection) ÿâëåíèé äåòåðìèíà-
öèè ïîëà è êîìïåíñàöèè äîçû ïîëîâûõ õðîìîñîì ó Dros-
ophila (Belote et al., 1985; Maine et al., 1985) è Caenorhabdi-
tis elegans (Hodgkin et al., 1985; Wood et al., 1985).
58-é ñèìïîçèóì îòâåë ãëàâíîå ìåñòî ïðàçäíîâàíèþ
40-é ãîäîâùèíû îòêðûòèÿ, ñäåëàííîãî Óîòñîíîì è
Êðèêîì. ×àñòüþ ýòîãî òîðæåñòâà áûëà âûåçäíàÿ «òóñîâ-
êà», ïîñâÿùåííàÿ ýïèãåíåòè÷åñêèì ÿâëåíèÿì: ãîâîðè-
ëîñü îá èäåíòèôèêàöèè íîâûõ ÿâëåíèé, íà÷àëå ìîëå-
êóëÿðíîãî àíàëèçà äðóãèõ ÿâëåíèé, íà ðÿäå ñèñòåì áûë
äîñòèãíóò ñóùåñòâåííûé ïðîãðåññ, ïîçâîëÿþùèé ïðåä-
ëàãàòü ãèïîòåçû è òåñòèðîâàòü èõ.
Ó òðèïàíîñîì ãåíû ñåìåéñòâà Ãåíîâ Âàðèàáåëüíûõ Ïî-
âåðõíîñòíûõ àíòèãåíîâ (VSG — Variable Surface antigene
Genes), ëîêàëèçîâàííûõ âîçëå òåëîìåð, â îñíîâíîì «ìîë-
÷àò», è â êàæäûé äàííûé ìîìåíò ýêñïðåññèðóåòñÿ òîëüêî
îäèí VSG. Õîòÿ ýòîò îðãàíèçì, ïî-âèäèìîìó, íå ñîäåð-
æèò ìåòèëèðîâàííîé ÄÍÊ, ñîîáùàëîñü, ÷òî «ìîë÷àùèå»
ãåíû VSG ñîäåðæàò íîâîå ìèíîðíîå îñíîâàíèå, β-D-
ãëþêîçèëãèäðîêñèìåòèëóðàöèë (Borst et al., 1993). Ýòî
îñíîâàíèå, ïî-âèäèìîìó, çàíèìàåò â ÄÍÊ ìåñòî òèìè-
äèíà. Íåòðóäíî ïðîâåñòè ïàðàëëåëè ìåæäó ýòèì îñíîâà-
íèåì è ìåòèëèðîâàíèåì öèòîçèíà ó äðóãèõ îðãàíèçìîâ —
ýòè ìîäèôèêàöèè âàæíû äëÿ ïîääåðæàíèÿ «ìîë÷àùåãî»
ãåíà. Íî êàê ýòî îñíîâàíèå ââîäèòñÿ â ÄÍÊ èëè êàê îíî
îñóùåñòâëÿåò òàêóþ ôóíêöèþ, áûëî íåÿñíî.
Ïðîãðåññ áûë òàêæå äîñòèãíóò â èçó÷åíèè ýïèãåíåòè-
÷åñêèõ ÿâëåíèé ó ïîçâîíî÷íûõ, â òîì ÷èñëå õðîìîñîì-
íîãî èìïðèíòèíãà è èíàêòèâàöèè Õ-õðîìîñîìû (Ariel et
al., 1993; Li et al., 1993; Tilghman et al., 1993; Willard et al.,
1993). Ê ýòîìó âðåìåíè ñòàëî ÿñíî, ÷òî ó ìëåêîïèòàþùèõ
ìíîãèå ëîêóñû ïîäâåðæåíû èìïðèíòèíãó; â äèïëîèäíûõ
êëåòêàõ ýêñïðåññèðóåòñÿ ëèøü îäíà àëëåëü, è ýêñïðåññèÿ
çàâèñèò îò åå ïðîèñõîæäåíèÿ îò òîãî èëè äðóãîãî ðîäèòåëÿ.
Îñîáûé èíòåðåñ ïðåäñòàâëÿë ëîêóñ Igf2-H19, ãëàâíûì îá-
ðàçîì ïîòîìó, ÷òî îí ñîäåðæàë äâà ñîñåäíèõ ãåíà, êîòîðûå
ðåãóëèðîâàëèñü ïðîòèâîïîëîæíûì îáðàçîì. Igf2 ýêñïðåñ-
ñèðóåòñÿ â îòöîâñêîé õðîìîñîìå, òîãäà êàê ìàòåðèíñêàÿ
êîïèÿ ðåïðåññèðîâàíà; â òî æå âðåìÿ îòöîâñêàÿ àëëåëü
H19 ðåïðåññèðîâàíà, à ìàòåðèíñêàÿ àëëåëü ýòîãî ãåíà
ýêñïðåññèðóåòñÿ. Èíòåðåñíî, ÷òî ìåòèëèðîâàííûå CpG
íàáëþäàëèñü íà îòöîâñêîé õðîìîñîìå íåïîñðåäñòâåííî
«ââåðõ ïî òå÷åíèþ» îò îáîèõ ãåíîâ. Ïðåäïîëîæèëè, ÷òî
äèôôåðåíöèàëüíîå ìåòèëèðîâàíèå ðåãóëèðóåò äîñòóï
ýòèõ äâóõ ãåíîâ ê áëèçëåæàùåìó ýíõàíñåðíîìó ýëåìåí-
òó — ýòîò ýíõàíñåð ðàñïîëîæåí áëèæå ê H19 è íåïîñðåä-
ñòâåííî «âíèç ïî òå÷åíèþ» îò íåãî (Tilghman et al., 1993).
Ìîæíî áûëî ïðåäñòàâèòü ñåáå âçàèìîèñêëþ÷àþùóþ êîí-
êóðåíöèþ ìåæäó ýòèìè äâóìÿ ãåíàìè çà ýíõàíñåð; êîãäà
ãåí H19 ìåòèëèðîâàí, ýíõàíñåð ñâîáîäåí è àêòèâèðóåò áî-
ëåå óäàëåííûé ãåí Igf2. Â ïîëüçó èäåè, ÷òî ìåòèëèðîâàíèå
ÄÍÊ èãðàåò ðåãóëÿòîðíóþ ðîëü â ýòîì ïðîöåññå, ñâèäå-
òåëüñòâîâàëè ýêñïåðèìåíòû ñ ìûøàìè. Ìóòàöèÿ ïåðâîãî
ãåíà ïîçâîíî÷íûõ, êîäèðóþùåãî 5-ìåòèëöèòîçèí-ÄÍÊ-
ìåòèëòðàíñôåðàçó â ES-êëåòêàõ, ïîêàçàëà, ÷òî ïî ìåðå
ðàçâèòèÿ ýìáðèîíîâ îòöîâñêàÿ êîïèÿ H19 ñòàíîâèëàñü
ãèïîìåòèëèðîâàííîé, è ýòîò ãåí ñòàíîâèëñÿ òðàíñêðèï-
öèîííî àêòèâíûì (Li et al., 1993).
Âàæíûì øàãîì â ðàñøèôðîâêå òîãî, êàê 5MeCpG
îïîñðåäóåò ñâîè ýôôåêòû, ÿâèëàñü î÷èñòêà ïåðâîãî
êîìïëåêñà, ñâÿçûâàþùåãîñÿ ñ 5MeCpG â ÄÍÊ (MeCP1 —
5Me
CpG DNA-binding complex) (Bird 1993). MeCP1 íå
òîëüêî ñâÿçûâàåòñÿ ñ ÄÍÊ, íî è, ñâÿçàâøèñü «ââåðõ ïî
òå÷åíèþ» îò ðåïîðòåðíîãî ãåíà, âûçûâàåò ðåïðåññèþ
ýòîãî ãåíà. Õîòÿ ýòî è íå îáúÿñíÿëî ðåãóëÿöèþ â ëîêóñå
Igf2-H19, íî äàâàëî âîçìîæíûé ìåõàíèçì äëÿ îáúÿñíå-
íèÿ îáùåé êîððåëÿöèè ìåæäó ìåòèëèðîâàíèåì ÄÍÊ è
ðåïðåññèåé ãåíà.
Ãåíåòè÷åñêîå êàðòèðîâàíèå íà ïðîòÿæåíèè ðÿäà ëåò
ïîçâîëèëî èäåíòèôèöèðîâàòü òó ÷àñòü Õ-õðîìîñîìû
÷åëîâåêà, êîòîðàÿ ÿâëÿåòñÿ êðèòè÷íîé äëÿ èíàêòè-
âàöèè Õ-õðîìîñîìû. Èññëåäîâàíèÿ ýòîãî öåíòðà
Õ-èíàêòèâàöèè ñ èñïîëüçîâàíèåì ìîëåêóëÿðíîãî êëî-
íèðîâàíèÿ ïðèâåëè ê îòêðûòèþ ãåíà Xist (Willard et al.,
1993), íåêîäèðóþùåé ÐÍÊ ðàçìåðîì ~17 ò.î., êîòîðûé
ýêñïðåññèðóåòñÿ òîëüêî íà íåàêòèâíîé Õ-õðîìîñîìå.
Ìûøèíàÿ âåðñèÿ Xist îêàçàëàñü íà óäèâëåíèå ãîìîëî-
ãè÷íîé ïî ñòðóêòóðå è íóêëåîòèäíîé ïîñëåäîâàòåëüíî-
ñòè è îáåùàëà ñòàòü ïðåêðàñíîé ìîäåëüíîé ñèñòåìîé äëÿ
«ðàñ÷ëåíåíèÿ» òîãî ïóòè, íà êîòîðîì ýòà ÐÍÊ ôóíêöè-
îíèðóåò è ðåïðåññèðóåò áîëüøóþ ÷àñòü Õ-õðîìîñîìû.
Äâà çàñëóæèâàþùèõ âíèìàíèÿ îòêðûòèÿ áûëè îïè-
ñàíû ó Neurospora (Selker et al., 1993). Âî-ïåðâûõ, áûëî
ïîêàçàíî, ÷òî ìåòèëèðîâàíèå öèòîçèíîâ â ÄÍÊ íå îãðà-
íè÷åíî äèíóêëåîòèäàìè CpG, à ìîæåò ïðîèñõîäèòü êàê
áóäòî áû â ëþáîì ÄÍÊ-êîíòåêñòå. Âòîðûì îòêðûòèåì
ñòàëî îïèñàíèå óäèâèòåëüíîãî ÿâëåíèÿ èíäóöèðóåìûõ
ïîâòîðàìè òî÷å÷íûõ ìóòàöèé (RIP — repeat-induced
point mutation). Êîãäà â ãàïëîèäíîì ãåíîìå èìååòñÿ äó-
ïëèêàöèÿ íåêîé ïîñëåäîâàòåëüíîñòè (ñöåïëåííàÿ èëè
íåñöåïëåííàÿ), è ýòîò ãåíîì ïîñðåäñòâîì êîíúþãàöèè
ïðîâîäèòñÿ ÷åðåç ïîëîâîé öèêë, íóêëåîòèäíûå ïîñëå-
äîâàòåëüíîñòè ñòàíîâÿòñÿ «RIPîâàííûìè». Ïðîèñõîäÿò
äâà ñîáûòèÿ: îáå êîïèè äóïëèöèðîâàííîé ÄÍÊ ïðèîá-
ðåòàþò ìóòàöèè òèïà G:C  A:T, à ÄÍÊ â ïðåäåëàõ íå-
ñêîëüêèõ ñîòåí ïàð îñíîâàíèé «RIPîâàííûõ» ïîñëåäî-
âàòåëüíîñòåé ñòàíîâèòñÿ ìåòèëèðîâàííîé. Ýòà äâîéíàÿ
àòàêà íà ãåíîì âåñüìà ýôôåêòèâíà — 50 % íåñöåïëåí-
íûõ ëîêóñîâ ïîäâåðæåíû RIP, òîãäà êàê òåñíî ñöåïëåí-
 2. Èñòîðèÿ ýïèãåíåòèêè íà ñèìïîçèóìàõ Êîëä Ñïðèíã Õàðáîð
íûå ëîêóñû äîñòèãàþò 100 % — è ëåãêî ïîäàâëÿåò ôóíê-
öèþ ãåíîâ.
Ãåí brown ó Drosophila, áóäó÷è òðàíñëîöèðîâàí â ñî-
ñåäñòâî ñ ãåòåðîõðîìàòèíîì, äåìîíñòðèðóåò äîìèíàíò-
íûé PEV; òðàíñëîöèðîâàííàÿ êîïèÿ ìîæåò âûçâàòü ðå-
ïðåññèþ êîïèè äèêîãî òèïà. Â õîäå ïîèñêîâ ýíõàíñåðîâ
è ñóïðåññîðîâ ýòîãî ÿâëåíèÿ trans-èíàêòèâàöèè Õåíè-
êîô (Henikoff) îòêðûë, ÷òî äóïëèêàöèÿ ãåíà, ëîêàëè-
çîâàííîãî âáëèçè ãåòåðîõðîìàòèíà, ïîâûøàåò óðîâåíü
ðåïðåññèè íà íîðìàëüíîé êîïèè (Martin-Morris et al.,
1993). Õîòÿ ìåõàíèçì, ëåæàùèé â îñíîâå ýòîãî ñîáûòèÿ,
îñòàâàëñÿ çàãàäî÷íûì, ïîñòóëèðîâàëè, ÷òî ýòî ÿâëåíèå
ìîãëî áû áûòü àíàëîãè÷íûì RIP ó Neurospora, õîòÿ îíî
äîëæíî ïðîèñõîäèòü â îòñóòñòâèè ìåòèëèðîâàíèÿ ÄÍÊ,
êîòîðîå ó Drosophila íå ïðîèñõîäèò.
Ïîë Øåäë (Paul Schedl) èçëîæèë êîíöåïöèþ õðîìî-
ñîìíûõ «ãðàíè÷íûõ ýëåìåíòîâ» (Vazquez et al., 1993).
Ïåðâûå òàêèå ýëåìåíòû áûëè ëîêàëèçîâàíû ñ òîé èëè
äðóãîé ñòîðîíû ðàéîíà «ïóôà» â ëîêóñå òåïëîâîãî øîêà
ó Drosophila è îïðåäåëåíû ïî íåîáû÷íîé ñòðóêòóðå èõ
õðîìàòèíà — óñòîé÷èâîìó ê íóêëåàçå êîðó âåëè÷èíîé
~300 ï.í., îãðàíè÷åííîìó ãèïåð÷óâñòâèòåëüíûìè ê
íóêëåàçå ñàéòàìè. Ïîñòóëèðîâàëè, ÷òî òàêèå ýëåìåí-
òû ðàçäåëÿþò äîìåíû õðîìàòèíà âäîëü ïî äëèíå õðî-
ìîñîìû. Äâà òåñòà in vivo ñâèäåòåëüñòâîâàëè â ïîëüçó
ýòîé ãèïîòåçû: (1) Îãðàíè÷èâàÿ òó èëè äðóãóþ ñòîðîíó
ðåïîðòåðíîãî ãåíà, ãðàíè÷íûå ýëåìåíòû ýôôåêòèâíî
óñòðàíÿëè õðîìîñîìíûå ýôôåêòû ïîëîæåíèÿ, êîãäà
ýòîò êîíñòðóêò ñëó÷àéíûì îáðàçîì âñòàâëÿëñÿ â ãå-
íîì. (2) Ãðàíè÷íûé ýëåìåíò îïðåäåëÿëñÿ òàêæå ïî åãî
ñïîñîáíîñòè áëîêèðîâàòü ôóíêöèþ ýíõàíñåðà. Áóäó÷è
âñòàâëåí ìåæäó ïðîìîòîðîì ãåíà è åãî ýíõàíñåðîì, ãðà-
íè÷íûé ýëåìåíò áëîêèðîâàë ýêñïðåññèþ äàííîãî ãåíà.
Õîòÿ è íå â ñòîëü îïðåäåëåííîì âèäå, ýòà êîíöåïöèÿ
ãðàíè÷íûõ ýëåìåíòîâ áûëà ðàçðàáîòàíà è äëÿ äðóãèõ
îðãàíèçìîâ, îñîáåííî íà ãëîáèíîâîì ëîêóñå ó ìëåêî-
ïèòàþùèõ (Clark et al., 1993).
Èññëåäîâàíèÿ íà ïî÷êóþùèõñÿ äðîææàõ âûñâåòèëè
ðàçâèâàþùèéñÿ ìåõàíèñòè÷åñêèé ïîäõîä [a mechanistic
inroad] ê ñâÿçàííûì ñ õðîìàòèíîì ýïèãåíåòè÷åñêèì ÿâ-
ëåíèÿì. Áûëî óæå óñòàíîâëåíî, ÷òî ñàéëåíñåðû â «ìîë-
÷àùèõ» ëîêóñàõ òèïà ñïàðèâàíèÿ ÿâëÿþòñÿ ñàéòàìè äëÿ
íåñêîëüêèõ ñâÿçûâàþùèõñÿ ñ ÄÍÊ áåëêîâ. Èõ ñâÿçûâà-
íèå îêàçàëîñü çàâèñèìûì îò êîíòåêñòà, ïðèìåðîì ÷åãî
ìîæåò áûòü áåëîê Rap1, êîòîðûé íå òîëüêî èãðàåò âàæ-
íóþ ðîëü â ñàéëåíñèíãå, íî è ñâÿçûâàåòñÿ «ââåðõ ïî òå-
÷åíèþ» îò ðÿäà ãåíîâ, àêòèâèðóÿ òðàíñêðèïöèþ (îáçîð
ñì. Laurenson and Rine, 1992).
Íà ïðîòÿæåíèè ðÿäà ëåò áûëè óñòàíîâëåíû ìíîãî-
÷èñëåííûå ñâÿçè ìåæäó ðåïëèêàöèåé ÄÍÊ è òðàíñ-
êðèïöèîííî «ìîë÷àùèìè» ðàéîíàìè ãåíîìà. Íåàê-
òèâíàÿ Õ-õðîìîñîìà, ãåòåðîõðîìàòèí è «ìîë÷àùèå»
èìïðèíòèðîâàííûå ëîêóñû — âñå îíè, êàê ñîîáùàëîñü,
ïîçäíî ðåïëèöèðóþòñÿ â ôàçå S ïî ñðàâíåíèþ ñ òðàíñ-
êðèïöèîííî àêòèâíûìè ðàéîíàìè ãåíîìà. Êðîìå òîãî,
áûëî ïîêàçàíî, ÷òî óñòàíîâëåíèå ñàéëåíñèíãà â «ìîë-
÷àùèõ» ëîêóñàõ òèïà ñïàðèâàíèÿ òðåáóåò ïðîõîæäåíèÿ
÷åðåç ôàçó S, ÷òî çàñòàâëåò ïðåäïîëàãàòü, ÷òî «ìîë÷à-
ùèé» õðîìàòèí äîëæåí áûòü ïîñòðîåí íà íåäàâíî ðå-
ïëèöèðîâàííîé ÄÍÊ. Òàê, îãðîìíûé èíòåðåñ âûçûâàë
17
òîò ôàêò, ÷òî îäèí èç ñàéëåíñåðîâ îêàçàëñÿ òî÷êîé íà-
÷àëà ðåïëèêàöèè ÄÍÊ («îðèäæèíîì»), à åãî àêòèâíîñòü
â ýòîì êà÷åñòâå íåëüçÿ áûëî îòäåëèòü îò ôóíêöèè ñàé-
ëåíñèíãà (Fox et al., 1993). Áîëåå òîãî, ìóòàíòû â íå-
äàâíî èäåíòèôèöèðîâàííîì êîìïëåêñå ðàñïîçíàâàíèÿ
«îðèäæèíà» (ORC — origin recognition complex) «ïîðòè-
ëè» ñàéëåíñèíã (Bell et al., 1993; Fox et al., 1993).
Åùå îäèí ïîäõîä ê «ðàñ÷ëåíåíèþ» ñòðóêòóðû ãåòåðî-
õðîìàòèíà è åå âëèÿíèå íà ýêñïðåññèþ ãåíîâ îáóñëîâèëî
îòêðûòèå, ïîêàçàâøåå, ÷òî òåëîìåðû ó Saccharomyces cer-
evisiae ïðèâîäÿò â äåéñòâèå PEV, àíàëîãè÷íûé íàáëþäàå-
ìîìó ó Drosophila. Ðåïîðòåðíûå ãåíû, âñòàâëåííûå îêîëî
òåëîìåð, îáíàðóæèâàþò ìîçàè÷íóþ ýêñïðåññèþ â êîëî-
íèè äðîææåé. Ðåïðåññèðîâàííîå ñîñòîÿíèå çàâèñèò îò
ìíîãèõ ãåíîâ (SIR2, SIR3, SIR4) èç òåõ, ÷òî íåîáõîäèìû
äëÿ ñàéëåíñèíãà â «ìîë÷àùèõ» ëîêóñàõ òèïà ñïàðèâàíèÿ.
Áûëè îïèñàíû íåñêîëüêî êëþ÷åâûõ àñïåêòîâ, êàñàþ-
ùèõñÿ ñòðóêòóðû «ìîë÷àùåãî» õðîìàòèíà è ðåãóëÿöèè
ìîçàè÷íîé ýêñïðåññèè. Çàñëóæèâàåò óïîìèíàíèÿ òîò
ôàêò, ÷òî öèòîëîãè÷åñêè ãåòåðîõðîìàòèí îïðåäåëÿåòñÿ
êàê êîíäåíñèðîâàííûé õðîìàòèí, íî «ìîë÷àùèé» õðî-
ìàòèí ó S. cerevisiae íèêîãäà íå óäàâàëîñü âèçóàëèçèðî-
âàòü òàêèì îáðàçîì. Òåì íå ìåíåå, èç-çà ñõîäñòâà ñ PEV ó
Drosophila «ìîë÷àùèé» õðîìàòèí ó äðîææåé âñåãäà áûëè
ñêëîííû ðàññìàòðèâàòü êàê ôóíêöèîíàëüíûé ýêâèâà-
ëåíò ãåòåðîõðîìàòèíà (îïèñàíî â Weintraub, 1993).
Íà îñíîâå èññëåäîâàíèé íà äðîææàõ íà÷àë ôîðìè-
ðîâàòüñÿ ðÿä ôóíäàìåíòàëüíûõ êîíöåïöèé. Âî-ïåðâûõ,
ñòàëî î÷åâèäíûì âàæíîå çíà÷åíèå ãèñòîíîâ Í3 è Í4. Â
÷àñòíîñòè, àìèíîòåðìèíàëüíûé «õâîñò» ãèñòîíîâ Í3 è
Í4 îêàçàëñÿ íåïîñðåäñòâåííûì ó÷àñòíèêîì ôîðìèðî-
âàíèÿ «ìîë÷àùåãî» ãåòåðîõðîìàòèíà (Thompson et al.,
1993). Ñïåöèôè÷åñêèå ìóòàöèè â «õâîñòàõ» ýòèõ ãèñòî-
íîâ îáëåã÷àëè èëè ïîðòèëè ñàéëåíñèíã è ïîçâîëÿëè äó-
ìàòü, ÷òî è îáùèé çàðÿä îñòàòêîâ íà «õâîñòàõ», è ñïåöè-
ôè÷åñêèå îñòàòêè â ñîñòàâå «õâîñòîâ» âíîñÿò âêëàä â
ñàéëåíñèíã. Êðîìå òîãî, íà çàðå èñïîëüçîâàíèÿ èììó-
íîïðåöèïèòàöèè õðîìàòèíà (ChIP) áûëî ïðîäåìîí-
ñòðèðîâàíî, ÷òî ëèçèíû â àìèíîòåðìèíàëüíîì «õâîñòå»
ãèñòîíà Í4 ãèïîàöåòèëèðîâàíû â ðàéîíàõ «ìîë÷àùåãî»
õðîìàòèíà ïî ñðàâíåíèþ ñ îñòàëüíîé ÷àñòüþ ãåíîìà.
Áîëåå òîãî, îäíà èç ãèñòîíîâûõ ìóòàöèé ïîçâîëèëà
èäåíòèôèöèðîâàòü H4K16 ãèñòîíîâ (êîòîðûé ìîæåò
áûòü àöåòèëèðîâàí) êàê êðèòè÷íûé äëÿ ôîðìèðîâàíèÿ
«ìîë÷àùåãî» õðîìàòèíà.
Òåëîìåðû îêàçàëèñü ïðîñòåéøåé ñèñòåìîé äëÿ áî-
ëåå ãëóáîêîãî ïîíèìàíèÿ òîãî, êàêèì îáðàçîì áåëêè Sir
îïîñðåäóþò ñàéëåíñèíã. Áûëà ðàçðàáîòàíà êîíöåïöèÿ
ðåêðóòèðîâàíèÿ áåëêîâ ñàéëåíñèíãà. Ãîâîðÿ êîðîòêî,
îêàçàëîñü, ÷òî áåëîê Rap1, ñâÿçûâàþùèéñÿ ñ òåëîìåð-
íîé ÄÍÊ, âçàèìîäåéñòâóåò ñ Sir3 è Sir4 äâóãèáðèäíûì
ñïîñîáîì (by two-hybrid methods — îïèñàíî â Palladino
et al. 1993). Òàêèì îáðàçîì, Rap1 ìîæåò «ðåêðóòèðîâàòü»
ýòè áåëêè Sir ê òåëîìåðíîìó ðàéîíó ãåíîìà. Èìåëèñü
äàííûå î òîì, ÷òî Sir3 è Sir4 ìîãóò ñâÿçûâàòüñÿ äðóã ñ
äðóãîì è ÷òî (è ýòî îñîáåííî âàæíî) Sir3 è, âîçìîæíî,
Sir4 âçàèìîäåéñòâóþò ñ «õâîñòàìè» ãñòîíîâ Í3 è Í4
(Thompson et al., 1993). Áîëåå òîãî, ñâåðõýêñïðåññèÿ
Sir3 çàñòàâëÿåò åãî «ðàñïðîñòðàíÿòüñÿ» ïî õðîìàòèíî-
âîé ôèáðèëëå âíóòðü îò òåëîìåðû, ïîçâîëÿÿ ïðåäïî-
18 Ãëàâà 1. Ýïèãåíåòèêà: îò ÿâëåíèÿ ê îáëàñòè íàóêè
ëàãàòü, ÷òî îí ÿâëÿåòñÿ ëèìèòèðóþùèì êîìïîíåíòîì
«ìîë÷àùåãî» õðîìàòèíà è ìîæåò «ïîëèìåðèçîâàòüñÿ»
âäîëü õðîìàòèíà (Renauld et al., 1993). Âñå âìåñòå ïî-
êàçûâàëî, ÷òî ñóùåñòâóåò, îêàçûâàåòñÿ, îáøèðíàÿ ñåòü
âçàèìîäåéñòâèé, âàæíàÿ äëÿ ñàéëåíñèíãà, — áåëêè Sir
èíèöèèðóþò ñáîðêó íà òåëîìåðíîé ÄÍÊ, áëàãîäàðÿ
èõ âçàèìîäåéñòâèþ ñ Rap1, à çàòåì ïîëèìåðèçóþòñÿ îò
òåëîìåðû âäîëü õðîìàòèíîâîãî âîëîêíà, ïðåäïîëîæè-
òåëüíî ñâÿçûâàÿñü ñ «õâîñòàìè» ãèñòîíîâ Í3 è Í4.
Ïåðåêëþ÷åíèå ìåæäó òðàíñêðèïöèîííûìè ñîñòîÿ-
íèÿìè ïðè ìîçàè÷íîé òåëîìåðíîé ýêñïðåññèè îêàçà-
ëîñü ðåçóëüòàòîì êîíêóðåíöèè â îòíîøåíèè ýêñïðåñ-
ñèè ìåæäó «ìîë÷àùèìè» è àêòèâíûìè ãåíàìè (Aparicio
and Gottschling, 1994; îïèñàíî â Weintraub, 1993). Åñëè
òðàíñêðèïöèîííûé àêòèâàòîð äëÿ òåëîìåðíîãî ãåíà äå-
ëåòèðîâàí, áàçîâûé ìåõàíèçì òðàíñêðèïöèè ýòîãî ãåíà
îêàçûâàåòñÿ íåäîñòàòî÷íûì äëÿ ýêñïðåññèè, è ýòîò ãåí
îêàçûâàåòñÿ êîíñòèòóòèâíî ñàéëåíñèðîâàííûì. Íàî-
áîðîò, ñâåðõýêñïðåññèÿ àêòèâàòîðà çàñòàâëÿëà òåëîìåð-
íûé ãåí ýêñïðåññèðîâàòüñÿ ïîñòîÿííî — ýòî ãåí íèêîã-
äà íå áûë ñàéëåíñèðîâàí. Â îòñóòñòâèå SIR3 (èëè SIR2
èëè SIR4) áàçàëüíàÿ ýêñïðåññèÿ ãåíà áûëà äîñòàòî÷íîé,
òîãäà êàê óâåëè÷åííàÿ äîçà SIR3 ïîâûøàëà äîëþ êëå-
òîê, êîòîðûå áûëè ñàéëåíñèðîâàíû. Õîòÿ òðàíñêðèï-
öèîííûé àêòèâàòîð ìîã ïðåîäîëåòü ñàéëåíñèíã íà
ïðîòÿæåíèè âñåãî êëåòî÷íîãî öèêëà, îí áûë íàèáîëåå
ýôôåêòèâíûì, êîãäà êëåòêè áûëè îñòàíîâëåíû â ôàçå
S — ïðåäïîëîæèòåëüíî, êîãäà õðîìàòèí ðåïëèöèðóåòñÿ
è, îòñþäà, îêàçûâàåòñÿ íàèáîëåå ÷óâñòâèòåëüíûì ê êîí-
êóðåíöèè. Íåñêîëüêî óäèâëÿåò, ÷òî êëåòêè, îñòàíîâëåí-
íûå íà G2/M, òàêæå ìîæíî áûëî ëåãêî ïåðåêëþ÷èòü,
÷òî çàñòàâëÿëî ïðåäïîëàãàòü, ÷òî «ìîë÷àùèé» õðîìàòèí
åùå íå áûë ïîëíîñòüþ ñîáðàí ê ýòîìó âðåìåíè.
Áûëî ïîêàçàíî, ÷òî «ìîë÷àùèé» õðîìàòèí ó äðîæ-
æåé íå ïîääàåòñÿ äåéñòâèþ íóêëåàç è ôåðìåíòîâ ìî-
äèôèêàöèè ÄÍÊ; ýòî ïîçâîëÿåò ïðåäïîëîæèòü, ÷òî ëå-
æàùàÿ â åãî îñíîâå ÄÍÊ ãîðàçäî ìåíåå äîñòóïíà, ÷åì
áîëüøàÿ ÷àñòü ãåíîìà (îïèñàíî â Thompson et al. 1993).
Îêàçàëîñü òàêæå, ÷òî èìååò ìåñòî èåðàðõèÿ ñàé-
ëåíñèíãà â ãåíîìå äðîææåé: íàèáîëåå ÷óâñòâèòåëíû ê
ïåðòóðáàöèÿì òåëîìåðû, çàòåì èäåò HML, à íàèìåíåå
÷óâñòâèòåëåí HMR. Äåéñòâèòåëüíî, êîãäà ãåí SIR1 ìó-
òèðîâàë, ëîêóñû HM, â íîðìå ïîëíîñòüþ ñàéëåíñèðî-
âàííûå, îáíàðóæèâàëè ìîçàè÷íóþ ýêñïðåññèþ (Pillus
and Rine, 1989).
Íàêîíåö, Sir3 è Sir4 áûëè ëîêàëèçîâàíû íà ïåðè-
ôåðèè ÿäðà, êàê è òåëîìåðû. Ïðåäïîëîæèëè, ÷òî ÿäðî
îðãàíèçîâàíî òàêèì îáðàçîì, ÷òî ÿäåðíàÿ îáîëî÷êà
îáåñïå÷èâàåò ñïåöèàëüíóþ ñðåäó äëÿ ñàéëåíñèíãà (Pal-
ladino et al., 1993).
Schizosaccharomyces pombe òîæå èìåþò «ìîë÷àùèå»
êàññåòû òèïîâ ñïàðèâàíèÿ, êîòîðûå, êàê ïîäîçðåâàþò,
âåäóò ñåáÿ àíàëîãè÷íî êàññåòàì òèïîâ ñïàðèâàíèÿ ó
S. cerevisiae. Îäíàêî ó S. pombe â èñòîðèè ñ ïåðåêëþ÷å-
íèåì òèïîâ ñïàðèâàíèÿ áûë äîïîëíèòåëüíûé ïîâîðîò.
 ýëåãàíòíîé ñåðèè ýêñïåðèìåíòîâ Ýéìàð Êëàð (Amar
Klar) âûäâèíóë ïðåäïîëîæåíèå î òîì, êàêèì îáðàçîì
â êëåòêå «ìåòêà» èìïðèíòèðóåòñÿ íà îäíîé íèòè ÄÍÊ
(Klar and Bonaduce, 1993). Ýòà ìåòêà ïðîÿâëÿåòñÿ, ïîñëå
äâóõ êëåòî÷íûõ äåëåíèé, â îäíîé èç ÷åòûðåõ «âíó÷àòûõ»
êëåòîê êàê äâóíèòåâîé ðàçðûâ, îáëåã÷àþùèé ïåðåêëþ-
÷åíèå òèïà ñïàðèâàíèÿ. Ó ýòèõ äðîææåé îòñóòñòâóþò
êàêèå-ëèáî èçâåñòíûå ìîäèôèêàöèè ÄÍÊ (ìåòèëèðî-
âàíèå è ò.ï.); îòñþäà ïîñòóëèðóåòñÿ, ÷òî íà íèòè ÄÍÊ
îñòàâëÿåòñÿ ìåòêà êàêîãî-òî èíîãî òèïà.
Òåìîé 59-ãî ñèìïîçèóìà áûëà «Ìîëåêóëÿðíàÿ ãåíå-
òèêà ðàêà». Êîíöåïöèÿ ýïèãåíåòè÷åñêîé ðåãóëÿöèè â
îíêîãåíåçå íà÷àëà ðàçâèâàòüñÿ ïîñëå òîãî, êàê óòâåðäè-
ëàñü èäåÿ ãåíîâ-ñóïðåññîðîâ îïóõîëåé. Áûëà îïóáëèêî-
âàíà ïàðà èññëåäîâàíèé â ïîëüçó òàêèõ ïðåäñòàâëåíèé,
íî èíòåðåñíûé ïîâîðîò â ýòîé èñòîðèè âîçíèê â èññëå-
äîâàíèÿõ ïàöèåíòîâ ñ ñèíäðîìîì Áýêâèòà-Âèäåìàííà
è îïóõîëÿìè Óèëìñà. Ìóòàöèè ó ïàöèåíòîâ îáîèõ òè-
ïîâ áûëè êàðòèðîâàíû â ëîêóñå, âêëþ÷àâøåì èìïðèí-
òèðîâàííûå ãåíû H19-IGF2. Ôåéíáåðã ñ ñîàâòîðàìè
(Feinberg et al., 1994) îòêðûë ó òàêèõ áîëüíûõ «óòðàòó
èìïðèíòèíãà» (LOI — loss of imprinting) äëÿ ýòèõ ãåíîâ —
ìàòåðèíñêèé ëîêóñ óòðà÷èâàë ñâîé èìïðèíò, H19 áûë
ðåïðåññèðîâàí, à IGF2 – ýêñïðåññèðîâàí. Òàêèì îáðà-
çîì, LOI, êîòîðàÿ â ïðèíöèïå ìîãëà áû ïðîèñõîäèòü â
äðóãèõ ìåñòàõ ãåíîìà, ìîãëà âûçûâàòü ëèáî áèàëëåëü-
íóþ ýêñïðåññèþ, ëèáî èñ÷åçíîâåíèå ãåíîâ, êðèòè÷íûõ
äëÿ îíêîãåíåçà, ëèáî è òî è, äðóãîå.
×åðåç ïàðó ëåò íà ïóòè ê 63-ìó ñèìïîçèóìó íà òåìó
«Ìåõàíèçìû òðàíñêðèïöèè» ïðîèçîøëè âàæíûå ñî-
áûòèÿ, êîòîðûå âïîñëåäñòâèè ïîâëèÿþò íà ïîíèìàíèå
ìîëåêóëÿðíûõ ìåõàíèçìîâ íåñêîëüêèõ ýïèãåíåòè÷å-
ñêèõ ôåíîìåíîâ. Áûëè èäåíòèôèöèðîâàíû ôåðìåíòû,
ìîäèôèöèðóþùèå ãèñòîíû, à èìåííî, àöåòèëàçû è äåà-
öåòèëàçû ãèñòîíîâ. Íåêîòîðûå èç ýòèõ ýíçèìîâ èãðàëè
êðèòè÷åñêóþ ðîëü â ðåãóëèðîâàíèè ýêñïðåññèè ãåíîâ
è ïîçâîëèëè ïîäîéòè ê ãåííûì ïðîäóêòàì, íåïîñðåä-
ñòâåííî âëèÿþùèì íà PEV è ñàéëåíñèíã. Íà ñèìïîçèóìå
áûëà ïðåäñòàâëåíà âåðõóøêà ýòîãî àéñáåðãà (ñì. Losick,
1998). Ìîëåêóëÿðíîå «ðàñ÷ëåíåíèå» ñàéëåíñèðóþùèõ
áåëêîâ Sir3 è Sir4 ó äðîææåé âûÿâèëî ïîëèâàëåíòíóþ
ïðèðîäó èõ âçàèìîäåéñòâèé è ïîêàçàëî, êàêèì îáðàçîì
ñåòü âçàèìîäåéñòâèé ìåæäó âñåìè áåëêàìè Sir, ãèñòîíà-
ìè è ðàçíîîáðàçíûìè ôàêòîðàìè, ñâÿçûâàþùèìèñÿ ñ
ÄÍÊ, ôîðìèðóåò «ìîë÷àùèé» õðîìàòèí. Êðîìå òîãî,
áûëè ïîêàçàíû ìîëåêóëÿðíûå äåòàëè òîãî, êàê ðàçíî-
îáðàçíûå ëîêóñû (òåëîìåðû, ðÄÍÊ, ëîêóñû ÍÌ è äâó-
íèòåâûå ðàçðûâû) ìîãóò êîíêóðèðîâàòü çà îãðàíè÷åí-
íûå ðåñóðñû áåëêîâ Sir. Ïðè íàðóøåíèè ñïîñîáíîñòè
ñïåöèôè÷åñêîãî ëîêóñà ðåêðóòèðîâàòü ôàêòîðû ñàé-
ëåíñèíãà óðîâíè ñîäåðæàíèÿ áåëêîâ Sir â äðóãèõ ëîêóñàõ
ïîâûøàëèñü (Cockell et al., 1998). Ýòî ïðÿìî äîêàçûâà-
ëî, ÷òî ðàáîòàåò ïðèíöèï äåéñòâèÿ ìàññ è ÷òî ñàéëåí-
ñèíã â îäíîì ëîêóñå ìîæåò âëèÿòü íà ýïèãåíåòè÷åñêèé
ñàéëåíñèíã â äðóãèõ ëîêóñàõ (èäåÿ, ïåðâîíà÷àëüíî âû-
äâèíóòàÿ â èññëåäîâàíèÿõ PEV ó Drosophila, íî âñå åùå
íå ïðîâåðåííàÿ) (Locke et al., 1988). Åùå îäíî îòêðûòèå
ïîçâîëèëî îáúÿñíèòü, êàêèì îáðàçîì ìåòèëèðîâàíèå
ÄÍÊ ìîæåò ðåãóëèðîâàòü ýêñïðåññèþ ãåíîâ ÷åðåç õðî-
ìàòèí. Áûëè èäåíòèôèöèðîâàíû áåëêîâûå êîìïëåêñû,
ñîñòîÿùèå èç MeCP2, êîòîðûå ñâÿçûâàþòñÿ è ñ ìåòè-
ëèðîâàííîé ÄÍÊ, è ñ äåàöåòèëàçîé ãèñòîíîâ (Wade et
al., 1998). Ìåòèëèðîâàííàÿ ÄÍÊ ìîãëà ñëóæèòü òî÷êîé
ðåêðóòèðîâàíèÿ äåàöåòèëàç ê ëîêóñó è òàêèì îáðàçîì
îáëåã÷àòü ñàéëåíñèíã áëèçëåæàùèõ ãåíîâ.

Êîíöåïöèÿ ãðàíè÷íûõ ýëåìåíòîâ áûëà ðàñïðîñòðà-
íåíà ñ Drosophila íà ìëåêîïèòàþùèõ (÷åòêèå äàííûå
áûëè ïîëó÷åíû íà ëîêóñå β-ãëîáèíà), ïîêàçûâàÿ òàêèì
îáðàçîì, ÷òî ãðàíèöû õðîìàòèíà, âåðîÿòíî, äåéñòâè-
òåëüíî êîíñåðâàòèâíû ó ìíîãîêëåòî÷íûõ è, âîçìîæíî,
ó âñåõ ýóêàðèîò (Bell et al., 1998).
Íà 64-ì ñèìïîçèóìå, òåìîé êîòîðîãî áûë «Ñèãíà-
ëèíã è ýêñïðåññèÿ â èììóííîé ñèñòåìå», áûëè ïðèâå-
äåíû äàííûå î òîì, êàê âîçíèêàåò ìîíîàëëåëüíàÿ ýêñ-
ïðåññèÿ, è î òîì, ÷òî îíà ìîæåò áûòü ðàñïðîñòðàíåíà
áîëåå øèðîêî, ÷åì äóìàëè ðàíüøå. Ìîíîàëëåëüíàÿ ýêñ-
ïðåññèÿ â ëîêóñàõ èììóíîãëîáóëèíîâ íà ïðîòÿæåíèè
íåêîòîðîãî âðåìåíè áûëà î÷åâèäíà äëÿ ëèìôîöèòîâ —
îíà ãàðàíòèðîâàëà ïðîäóêöèþ åäèíñòâåííîãî òèïà ðå-
öåïòîðîâ â êàæäîé ëèìôîèäíîé êëåòêå (Mostoslavsky et
al., 1999). Àëëåëü, êîòîðàÿ áóäåò ýêñïðåññèðîâàòüñÿ, âû-
áèðàåòñÿ íà ðàííèõ ñòàäèÿõ ðàçâèòèÿ, î÷åâèäíî, ñëó÷àé-
íûì îáðàçîì: îáå àëëåëè âíà÷àëå íàõîäÿòñÿ â ðåïðåññè-
ðîâàííîì ñîñòîÿíèè, íî ÷åðåç íåêîòîðîå âðåìÿ îäíà èç
íèõ äåìåòèëèðóåòñÿ. Áûëî íåÿñíî, êàê ïðîèñõîäèò âû-
áîð îäíîé èç àëëåëåé, íî ýòî ÿâëåíèå îáíàðóæèâàåòñÿ
è â äðóãèõ ëîêóñàõ, ãäå íåîáõîäèìîñòü ìîíîàëëåëèçìà
áûëà íå ñòîëü î÷åâèäíà. Íàïðèìåð, ýêñïðåññèðóåòñÿ
òîëüêî îäíà àëëåëü ãåíîâ, êîäèðóþùèõ öèòîêèíû IL-2
è IL-4 (Pannetier et al., 1999).
Íàèáîëåå çíà÷èòåëüíîå ñîîáùåíèå íà 65-ì ñèìïî-
çèóìå, èìåþùåå îòíîøåíèå ê ýïèãåíåòèêå, êàñàëîñü
îòêðûòèÿ òîãî, ÷òî áåëîê Sir2 ÿâëÿåòñÿ äåàöåòèëàçîé ãè-
ñòîíîâ (Imai et al., 2000). Ýòî áûë åäèíñòâåííûé áåëîê
Sir, ó êîòîðîãî áûëè î÷åâèäíûå ãîìîëîãè ó âñåõ äðóãèõ
ýóêàðèîò è êîòîðûé ðåãóëèðîâàë PEV. Ñîçäàâàëîñü âïå-
÷àòëåíèå, ÷òî ýòîò ôåðìåíò â îñíîâíîì îòâå÷àåò çà óäà-
ëåíèå àöåòèëüíûõ êîìïîíåíòîâ ãèñòîíîâ â «ìîë÷àùåì»
õðîìàòèíå. Êðîìå òîãî, ïîñêîëüêó ýòî áûë ôåðìåíò, çà-
âèñèìûé îò NAD, îí ñâÿçûâàë ðåãóëÿöèþ ñàéëåíñèíãà
(ãåòåðîõðîìàòèíà) ñ êëåòî÷íîé ôèçèîëîãèåé.
68-é ñèìïîçèóì íà òåìó «Ãåíîì Homo sapiens» ÿâèëñÿ
âàæíîé âåõîé â ãåíåòèêå, è õîòÿ âñå åùå îñòàåòñÿ ïðî-
äåëàòü áîëüøóþ ãåíåòè÷åñêóþ ðàáîòó, ïîëíîå ñåêâåíè-
ðîâàíèå ýòîãî è äðóãèõ ãåíîìîâ îçíà÷àëî, ÷òî ïðèøëî
âðåìÿ ïåðåõîäèòü íà «íàäãåíåòè÷åñêèé» óðîâåíü — â
áóêâàëüíîì çíà÷åíèè ñëîâà «ýïèãåíåòèêà».
Ýòîò èñòîðè÷åñêèé îò÷åò âûñâå÷èâàåò íåñêîëüêî
òåì, îáùèõ ñî ìíîãèìè äðóãèìè îáëàñòÿìè èññëåäî-
âàíèÿ. Âî-ïåðâûõ, îí äåìîíñòðèðóåò ýïèçîäè÷åñêóþ
ïðèðîäó äîñòèæåíèé â ýïèãåíåòèêå. Âî-âòîðûõ, ïî
ìåðå ïîñòèæåíèÿ ìîëåêóëÿðíûõ ìåõàíèçìîâ, ëåæàùèõ
â îñíîâå ýïèãåíåòè÷åñêèõ ÿâëåíèé, ñòàëî ëåã÷å ñâÿçû-
âàòü ýïèãåíåòèêó ñ áèîëîãè÷åñêîé ðåãóëÿöèåé â öåëîì.
Â-òðåòüèõ, îí ïîêàçàë, ÷òî èññëåäîâàòåëè, êîòîðûõ ìû
â íàñòîÿùåå âðåìÿ ñ÷èòàåì êîðèôåÿìè íàóêè, óñòàíî-
âèëè ýòè ñâÿçè î÷åíü ðàíî — ïîòðåáîâàëîñü ëèøü íåêî-
òîðîå âðåìÿ, ÷òîáû áîëüøèíñòâî îñòàëüíûõ «óâèäåëè»
î÷åâèäíîå.
3. 69-é ñèìïîçèóì
Ñ ãîäàìè âûÿâèëîñü íåñêîëüêî óíèâåðñàëüíûõ ïðèí-
öèïîâ, îáùèõ äëÿ âñåõ ýïèãåíåòè÷åñêèõ ÿâëåíèé, è ýòè
ïðèíöèïû îïðåäåëÿþò ýêñïåðèìåíòàëüíûå ïîäõîäû â
3. 69-é ñèìïîçèóì 19
íàøèõ ïîïûòêàõ ïîíÿòü äåòàëè. Âî-ïåðâûõ, ðàçëè÷èÿ
ìåæäó äâóìÿ ôåíîòèïè÷åñêèìè ñîñòîÿíèÿìè («ÂÊËÞ-
×ÅÍλ è «ÂÛÊËÞ×ÅÍλ) âñåãäà êîððåëèðóþò ñ ñî-
îòâåòñòâóþùèì ðàçëè÷èåì ñòðóêòóðû â êëþ÷åâîé ðå-
ãóëÿòîðíîé òî÷êå — ôîðìà òðàíñëèðóåòñÿ â ôóíêöèþ.
Îòñþäà, îñíîâíàÿ çàäà÷à çàêëþ÷àåòñÿ â èäåíòèôèêàöèè
ýòèõ äâóõ ðàçëè÷íûõ ñòðóêòóð, êîìïîíåíòîâ, èç êîòîðûõ
ýòè ñòðóêòóðû ñîñòîÿò, è êîìïîçèöèîííûõ ðàçëè÷èé
ìåæäó íèìè. Âî-âòîðûõ, ýòè ðàçëè÷àþùèåñÿ ñòðóêòóðû
äîëæíû îáëàäàòü ñïîñîáíîñòüþ ïîääåðæèâàòü è âîñ-
ïðîèçâîäèòü ñåáÿ â îêðóæåíèè êîíêóðèðóþùèõ ôàêòî-
ðîâ è ñèë ýíòðîïèè. Òàêèì îáðàçîì, êàæäàÿ ñòðóêòóðà
íóæäàåòñÿ â ñàìîóñèëåíèè, èëè â êîíòóðàõ ïîëîæèòåëü-
íîé îáðàòíîé ñâÿçè, îáåñïå÷èâàþùèõ åå ïîääåðæàíèå
è âîñïðîèçâåäåíèå íà ïðîòÿæåíèè ìíîãèõ êëåòî÷íûõ
äåëåíèé; â íåêîòîðûõ ñëó÷àÿõ, òàêèõ êàê èíàêòèâàöèÿ
Õ-õðîìîñîìû, ýòî âðåìÿ îêàçûâàåòñÿ ñðàâíèìûì ñî âðå-
ìåíåì æèçíè.
Íà 69-ì ñèìïîçèóìå ïðîäîëæàëîñü óòî÷íåíèå ìíî-
ãèõ ìåõàíèñòè÷åñêèõ ïðèíöèïîâ, óñòàíîâëåííûõ íà
ïðåäûäóùèõ ñèìïîçèóìàõ, íî áûëè è íîâûå ðàçðàáîò-
êè. ×òîáû ïîìåñòèòü ýòè íîâûå ðàçðàáîòêè â íàø êîí-
òåêñò, âàæíî îòìåòèòü, ÷òî âàæíîå âëèÿíèå íà ýïèãåíå-
òèêó îêàçàëè åùå äâà îòêðûòèÿ. Îäíèì áûëî îòêðûòèå
ÐÍÊ-èíòåðôåðåíöèè è ðîäñòâåííûõ, áàçèðóþùèõñÿ íà
ÐÍÊ, ìåõàíèçìàõ ðåãóëÿöèè. Äðóãèì áûëî îòêðûòèå
ìåõàíèçìîâ, ëåæàùèõ â îñíîâå ãèïîòåçû ïðèîíîâ. Çà
ïîñëåäíåå äåñÿòèëåòèå îáå ýòè îáëàñòè áûñòðî ðàçâèâà-
ëèñü, è íåêîòîðûå èç ýòèõ èññëåäîâàíèé âíåñëè âêëàä â
íàøè çíàíèÿ îá ýïèãåíåòèêå, áàçèðóþùåéñÿ íà õðîìà-
òèíå, òîãäà êàê äðóãèå íàìåòèëè íîâûå ïåðñïåêòèâû â
ïðîáëåìå íàñëåäñòâåííîé ïåðåäà÷è ôåíîòèïîâ.
Ìíîãèå äîñòèæåíèÿ, ïðåäñòàâëåííûå íà ýòîì ñèì-
ïîçèóìå, äåòàëüíî îïèñûâàþòñÿ â ðàçíûõ ãëàâàõ ýòîé
êíèãè, ïîýòîìó ÿ âîçäåðæóñü çäåñü îò îáñóæäåíèÿ ýòèõ
òåì. Îäíàêî ÿ çàòðîíó íåñêîëüêî óñïåøíûõ è ïåðñïåê-
òèâíûõ èññëåäîâàíèé, êîòîðûå ïðèâëåêëè ìîå âîîá-
ðàæåíèå è êîòîðûå íå îñâåùàþòñÿ íà ýòèõ ñòðàíèöàõ.
 êîíöå ÿ ïîïûòàþñü ñôîðìóëèðîâàòü íàèáîëåå âàæíûå
êîíöåïöèè, âûíåñåííûå ìíîþ èç ýòîãî ñèìïîçèóìà.
3.1. Ãèïîòåçà ãèñòîíîâîãî êîäà
 õîäå ðàññìîòðåíèÿ ìîäèôèêàöèé ãèñòîíîâ è èõ ïî-
òåíöèàëüíîãî èíôîðìàöèîííîãî ñîäåðæàíèÿ ñîñòîÿëîñü
ìíîãî äèñêóññèé îòíîñèòåëüíî «ãèïîòåçû ãèñòîíîâîãî
êîäà» (Jenuwein and Allis 2001). Áîëüøèíñòâî ýòèõ ñïîðîâ,
â êîòîðûõ ÿ ïðèíèìàë ó÷àñòèå èëè î êîòîðûõ ìíå ðàññêà-
çûâàëè, áûëè íåôîðìàëüíûìè è äîâîëüíî îæèâëåííû-
ìè. Ñòîðîííèêè «êîäà» ïðèâîäèëè òàêèå ïðèìåðû, êàê
òðèìåòèëèðîâàíèå ãèñòîíà Í3 ïî K9 è åãî ïîâûøåííîå
ñðîäñòâî ê êëàññó ÍÐ1 áåëêîâ ãåòåðîõðîìàòèíà (Jenuwein
and Allis, 2001). Èõ ïðîòèâíèêè ïðèâîäèëè áèîõèìè÷å-
ñêèå è ãåíåòè÷åñêèå äàííûå î òîì, ÷òî íà ñâÿçûâàíèå ñ
ÄÍÊ èëè íà ôåíîòèï ñóùåñòâåííî âëèÿåò ñóììàðíûé
çàðÿä íà àìèíîòåðìèíàëüíîì «õâîñòå» ãèñòîíà Í4, íå-
çàâèñèìî îò òîãî, ãäå ýòîò çàðÿä ðàñïîëîæåí (Megee et
al., 1995; Zheng and Hayes, 2003).
Ãðþíøòåéí (Grunstein) ïðåäñòàâèë äàííûå, âêëþ-
÷àâøèå àíàëèç ìîäèôèêàöèé (àöåòèëèðîâàíèÿ) ãèñòî-
20 Ãëàâà 1. Ýïèãåíåòèêà: îò ÿâëåíèÿ ê îáëàñòè íàóêè
íîâ è ñâÿçàííûõ ñ õðîìàòèíîì áåëêîâ âî âñåì ãåíîìå
S. cerevisiae ñ èñïîëüçîâàíèåì ñïåöèôè÷åñêèõ àíòèòåë è
ìåòîäà ChIP-Chip (Millar et al., 2004). Îí ñäåëàë àêöåíò
íà àññîöèèðîâàííîì ñ àöåòèëèðîâàíèåì H4K16 ýïèãå-
íåòè÷åñêîì ïåðåêëþ÷åíèè ê ñâÿçûâàíèþ èëè íåñâÿçû-
âàíèþ îïðåäåëåííûõ áåëêîâ õðîìàòèíà, ïîääåðæèâàÿ
òàêèì îáðàçîì ãèïîòåçó ãèñòîíîâîãî êîäà. Íåêîòîðûå
èç åãî äàííûõ, õîòÿ îíè è íå îáñóæäàëèñü, ïî-âèäèìîìó,
ñâèäåòåëüñòâóþò â ïîëüçó ñîîáùåíèé äðóãèõ èññëåäîâà-
òåëåé î òîì, ÷òî äëÿ áîëüøîé ÷àñòè ãåíîìà íåò êîððåëÿ-
öèè ìåæäó ñïåöèôè÷åñèêìè ìîäèôèêàöèÿìè ãèñòîíîâ
è ýêñïðåññèåé ãåíîâ (ò.å. âñå àêòèâíûå ãåíû èìåþò îäè-
íàêîâûå ìåòêè, è ýòè ìåòêè îòñóòñòâóþò íà íåàêòèâíûõ
ãåíàõ) (Schubert et al., 2004; Dion et al., 2005). Ó÷èòûâàÿ
âñþ ñîâîêóïíîñòü ýòèõ ðåçóëüòàòîâ, ÿ ïîäîçðåâàþ, ÷òî â
êà÷åñòâå ìåõàíèçìîâ ðåãóëèðîâàíèÿ ñòðóêòóðû õðîìà-
òèíà è ýêñïðåññèè ãåíîâ îáû÷íî èñïîëüçóþòñÿ è ñïåö-
èôè÷åñêèå ìîäèôèêàöèè, è âëèÿíèå îáùåãî çàðÿäà.
3.2. Äèíàìè÷åñêèé «ìîë÷àùèé» õðîìàòèí
ß äîëæåí ïðèçíàòüñÿ, ÷òî, îñíîâûâàÿñü íà ñòàòè÷åñêèõ
èçîáðàæåíèÿõ ãåòåðîõðîìàòèíà è íà ðåôðàêòåðíîé
ïðèðîäå «ìîë÷àùåãî» õðîìàòèíà, ÿ áûë óáåæäåí, ÷òî,
îäíàæäû óñòàíîâèâøèñü, ãåòåðîõðîìàòèíîâîå ñîñòîÿíèå
îñòàåòñÿ ïðî÷íûì, êàê ãðàíèò. Òîëüêî êîãäà íàñòóïàåò
âðåìÿ ðåïëèêàöèè ÄÍÊ, ýòà íåïðîáèâàåìàÿ ñòðóêòóðà
ñòàíîâèòñÿ ðåëàêñèðîâàííîé. Äóìàÿ òàêèì îáðàçîì, ÿ íå-
ðàçóìíî èãíîðèðîâàë ïðèíöèïû ðàâíîâåñíîé äèíàìèêè,
ñ êîòîðûìè ïîçíàêîìèëñÿ â êóðñå õèìèè. Îäíàêî ê ýòèì
óðîêàì çàñòàâèëè âîçâðàòèòüñÿ èññëåäîâàíèÿ «ìîë÷à-
ùåãî» õðîìàòèíà è ãåòåðîõðîìàòèíà, ãäå áûëî ïîêàçàíî,
÷òî áåëêè ñàéëåíñèíãà ó äðîææåé (Sir3) è áåëêè ãåòåðîõ-
ðîìàòèíà â êëåòêàõ ìëåêîïèòàþùèõ (ÍÐ1) íàõîäÿòñÿ â
ñîñòîÿíèè äèíàìè÷åñêîãî ðàâíîâåñèÿ — ýòè áåëêè áûñòðî
îáìåíèâàþòñÿ ìåæäó ãåòåðîõðîìàòèíîì è ðàñòâîðèìûì
êîìïàðòìåíòîì — äàæå êîãäà õðîìàòèí íàõîäèòñÿ â ñâîåì
íàèáîëåå íåïðîíèöàåìîì ñîñòîÿíèè (Cheng and Garten-
berg, 2000; Cheutin et al., 2003). Îñîçíàíèå äèíàìè÷åñêèõ
êà÷åñòâ õðîìàòèíà âûíóäèëî ìåíÿ èíà÷å âçãëÿíóòü íà òî,
êàêèì îáðàçîì ïîääåðæèâàåòñÿ è âîñïðîèçâîäèòñÿ åãî
ýïèãåíåòè÷åñêîå ñîñòîÿíèå. Ýòîò âçãëÿä ïðåäïîëàãàåò,
÷òî â íåêîòîðûõ ñèñòåìàõ ýïèãåíåòè÷åñêîå ñîñòîÿíèå
ìîæåò áûòü ðåâåðòèðîâàíî â ëþáîå âðåìÿ, à íå òîëüêî â
õîäå ðåïëèêàöèè ÄÍÊ. Îòñþäà ìû ìîæåì çàêëþ÷èòü, ÷òî
äëÿ «ìîë÷àùåãî» õðîìàòèíà ìåõàíèçìû óñèëåíèÿ è âîñ-
ïðîèçâåäåíèÿ äîëæíû ôóíêöèîíèðîâàòü ïîñòîÿííî.
Øèðîêî ðàñïðîñòðàíåíî ìíåíèå, ÷òî ìåòèëèðîâàíèå
ãèñòîíîâ ÿâëÿåòñÿ ìîäèôèêàöèåé, íàêëàäûâàþùåé íà
õðîìàòèí «ïåðìàíåíòíóþ» ìåòêó (îáçîð ñì. Kubicek and
Jenuwein, 2004). Â ïðîòèâîïîëîæíîñòü âñåì äðóãèì ìî-
äèôèêàöèÿì ãèñòîíîâ (íàïðèìåð, ôîñôîðèëèðîâàíèþ,
àöåòèëèðîâàíèþ, óáèêâèòèíèðîâàíèþ) íåò èçâåñòíûõ
ôåðìåíòîâ, êîòîðûå ìîãëè áû îáðàòèìî óäàëÿòü ìåòèëü-
íóþ ãðóïïó ñ àìèíîãðóïïû ëèçèíà èëè àðãèíèíà. Áîëåå
òîãî, ñ÷èòàåòñÿ, ÷òî óäàëåíèå ìåòèëüíîé ãðóïïû ïðî-
ñòûì ãèäðîëèçîì â ôèçèîëîãè÷åñêèõ óñëîâèÿõ íåâûãîä-
íî è, òàêèì îáðàçîì, âðÿä ëè ïðîèñõîäèò ñïîíòàííî.
Íåñêîëüêî ñîîáùåíèé ñëåãêà ïîêîëåáàëè ñèñòåìó
âåðîâàíèé òåõ, êòî äóìàë, ÷òî ìåòêè ìåòèëèðîâàíèÿ
ÿâëÿþòñÿ ïåðìàíåíòíûìè. Âî-ïåðâûõ, áûëî ïîêàçàíî,
÷òî ÿäåðíàÿ ïåïòèäèëàðãèíèíäåèìèíàçà (PAD4) ìî-
æåò óäàëÿòü ìîíîìåòèëèðîâàíèå ñ îñòàòêîâ àðãèíèíà
(R) ãèñòîíà Í3 (Cuthbert et al., 2004; Wang et al., 2004).
Õîòÿ ðåçóëüòàòîì ýòîãî ïðîöåññà óäàëåíèÿ ìåòèëüíîãî
êîìïîíåíòà ÿâëÿåòñÿ êîíâåðòàöèÿ îñòàòêà àðãèíèíà â
öèòðóëëèí, è, ñëåäîâàòåëüíî, ýòî íå ÿâëÿåòñÿ èñòèí-
íîé ðåâåðñèåé äàííîé ìîäèôèêàöèè, îí, òåì íå ìåíåå,
ïðåäñòàâëÿåò ñîáîé ìåõàíèçì ýëèìèíàöèè ïåðìàíåíò-
íîé ìåòèëüíîé ìåòêè.
Ðîáèí Îëøàéð (Robin Allshire) ïðèâåë ïðîâîöèðóþ-
ùèé ãåíåòè÷åñêèé àðãóìåíò, ñîãëàñíî êîòîðîìó ãåí tis2
èç S. pombe ðåâåðòèðóåò äèìåòèëèðîâàíèå ïî K9 â ãè-
ñòîíå Í3 (R. Allshire, ëè÷íîå ñîîáùåíèå). Âîçìîæíî, îí
áûë íà âåðíîì ïóòè, ïîñêîëüêó ÷åðåç íåñêîëüêî ìåñÿ-
öåâ ïîñëå ñèìïîçèóìà áûëî ïîêàçàíî, ÷òî íåðîäñòâåí-
íûé ôåðìåíò LSD1 èç ìëåêîïèòàþùèõ ñïåöèôè÷åñêè
äåìåòèëèðóåò äè- è ìîíîìåòèëû íà ãèñòîíå Í3 ïî K4
(Shi et al., 2004), ðåâåðòèðóÿ «àêòèâíóþ» ìåòêó õðîìàòè-
íà. Âåñüìà èíòåðåñíî, ÷òî LSD1 íå ðàáîòàåò íà òðèìå-
òèëèðîâàííîì H3K4 — òàêèì îáðàçîì, ìåòèëèðîâàíèå
ìîæåò áûòü ðåâåðòèðîâàíî â õîäå ïðîöåññà ìàðêèðîâ-
êè, íî ðåâåðñèÿ íåâîçìîæíà, êîëü ñêîðî ìåòêà ïîëíî-
ñòüþ ñîçðåëà.
Îäíàêî Ñòèâ Õåíèêîô (Steve Henikoff) îïèñàë ñïî-
ñîá, êîòîðûì ìîãëà áû ýëèìèíèðîâàòüñÿ ïåðìàíåíòíàÿ
òðèìåòèëëèçèíîâàÿ ìåòêà. Îí ïîêàçàë, ÷òî âàðèàíòíûé
ãèñòîí Í3.3 ìîæåò çàìåùàòü êàíîíè÷åñêèé ãèñòîí Í3
íåçàâèñèìûì îò ðåïëèêàöèè è ñîïðÿæåííûì ñ òðàíñ-
êðèïöèåé îáðàçîì (Henikoff et al., 2004). Ïî ñóùåñòâó
ãèñòîí, ñîäåðæàùèé ìåòèëüíûå ìåòêè äëÿ ñàéëåíñèíãà,
ìîã áû áûòü óäàëåí è çàìåíåí ãèñòîíîì, áîëåå ïîäõîäÿ-
ùèì äëÿ òðàíñêðèïöèè. Êîãäà áûë èçîëèðîâàí ñóììàð-
íûé õðîìàòèí, îêàçàëîñü, ÷òî ãèñòîí Í3.3 èìåë íà ñåáå
íàìíîãî áîëüøå ìåòîê ìåòèëèðîâàíèÿ õðîìàòèíà (íà-
ïðèìåð, K79me), ÷åì êàíîíè÷åñêèé ãèñòîí Í3.
Ïðè ðàññìîòðåíèè âñåõ ýòèõ ðåçóëüòàòîâ ñîçäàåòñÿ
âïå÷àòëåíèå, ÷òî ìîæåò è íå áûòü ïðîñòîé ìîëåêóëÿð-
íîé ìîäèôèêàöèè ãèñòîíîâ, êîòîðàÿ ñëóæèò êàê ìåòêà
ïàìÿòè äëÿ âîñïðîèçâåäåíèÿ ñîñòîÿíèÿ «ìîë÷àùåãî»
õðîìàòèíà â õîäå êëåòî÷íîãî äåëåíèÿ. Ñêîðåå, äîëæåí
èìåòü ìåñòî òîíêèé íàáîð âçàèìîäåéñòâèé, óâåëè÷è-
âàþùèõ âåðîÿòíîñòü òîãî, ÷òî «ìîë÷àùåå» ñîñòîÿíèå
áóäåò ïîääåðæèâàòüñÿ, õîòÿ è íå ãàðàíòèðóþùèõ ýòî.
3.3. ßäåðíàÿ îðãàíèçàöèÿ
Êîððåëÿöèè ìåæäó ÿäåðíîé ëîêàëèçàöèåé è ýêñïðåññèåé
ãåíîâ áûëè óñòàíîâëåíû óæå ìíîãî ëåò íàçàä (Mirkovitch
et al., 1987). Íà îñíîâå ýòèõ íàáëþäåíèé íà÷àëî ôîðìèðî-
âàòüñÿ ìíåíèå, ÷òî â êëåòêå èìåþòñÿ ñïåöèàëüíûå êîì-
ïàðòìåíòû, êîòîðûìè îãðàíè÷åíû ýêñïðåññèÿ ãåíîâ èëè
ñàéëåíñèíã. Ïðèâîäèëè äîâîäû â ïîëüçó òîãî, ÷òî òàêàÿ
îðãàíèçàöèÿ íåîáõîäèìà äëÿ ïîääåðæàíèÿ ñëîæíîñòè
ãåíîìà è åãî ðåãóëÿöèè â ðàáîòîñïîñîáíîì ñîñòîÿíèè.
Ýòà èäåÿ áûëà ïîääåðæàíà èññëåäîâàíèÿìè íà S. cer-
evisiae, ãäå òåëîìåðû ïðåèìóùåñòâåííî ëîêàëèçîâàëèñü
íà ïåðèôåðèè ÿäðà, êàê è êëþ÷åâûå êîìïîíåíòû êîì-
ïëåêñà ñàéëåíñèíãà, òàêèå êàê Sir4 (Palladino et al., 1993).
Ðåçóëüòàòîì ìóòàöèé, âûñâîáîæäàþùèõ òåëîìåðû èëè

Sir4 ñ ÿäåðíîé ïåðèôåðèè, ÿâëÿåòñÿ óòðàòà òåëîìåðíîãî
ñàéëåíñèíãà (Laroche et al., 1998; Andrulis et al., 2002).
Áîëåå òîãî, èñêóññòâåííàÿ ïðèâÿçêà ÷àñòè÷íî ñàéëåíñè-
ðîâàííîãî ãåíà ê ýòîé ïåðèôåðèè äåëàëà åãî ïîëíîñòüþ
ñàéëåíñèðîâàííûì (Andrulis et al., 1998).
 î÷åíü èíôîðìàòèâíîì ýêñïåðèìåíòå Ãàññåð ïî-
êàçàë, ÷òî åñëè òåëîìåðû è ñàéëåíñèðóþùèé êîìïëåêñ
âûñâîáîæäàþòñÿ ñ ïåðèôåðèè è ìîãóò ñâîáîäíî ïåðå-
ìåùàòüñÿ ïî âñåìó ÿäðó, ëåãêî óñòàíàâëèâàåòñÿ òåëî-
ìåðíûé ñàéëåíñèíã (Gasser et al., 2004). Òàêèì îáðàçîì,
ïî-âèäèìîìó, íåò îñîáîé íóæäû ëîêàëèçîâàòü ëîêóñû â
êîìïàðòìåíòå. Ýòî â áîëüøåé ìåðå ñîãëàñóåòñÿ ñ äàííû-
ìè î òîì, ÷òî áûñòðîå ïåðåìåùåíèå áåëêîâ õðîìàòèíà
íà õðîìîñîìû è ñ õðîìîñîì ìîæåò, êðîìå òîãî, îïîñðå-
äîâàòü òàêóþ ýôôåêòèâíóþ ðåãóëÿöèþ, êàê ñàéëåíñèíã.
Âîçìîæíî, ÷òîáû ïîääåðæèâàòü âûñîêèå ëîêàëüíûå
êîíöåíòðàöèè ñâÿçàííûõ ñ ýòèì ôàêòîðîâ â ñïåöè-
àëüíûõ (ñòðåññîâûõ?) óñëîâèÿõ, êàêàÿ-òî ëîêàëèçàöèÿ
è íåîáõîäèìà. Èëè æå ýòî ìîæåò áûòü êîìáèíàöèåé
äîìåíîâ, ñîáðàííûõ âìåñòå â õîäå ýâîëþöèè, êîòîðàÿ
äàâíî ðàáîòàåò áåç âñÿêîé êîíå÷íîé öåëè.
3.4. Ïðèîíû
Âèêíåð äàë îáçîð ïðèîíîâ è êðèòåðèè äëÿ èõ îïðåäå-
ëåíèÿ, è èç åãî îïèñàíèÿ ñòàíîâèòñÿ ÿñíûì, ÷òî îíè
(ïðèîíû) — ýòî ÷àñòü ýïèãåíåòè÷åñêîãî ëàíäøàôòà
(Wickner et al., 2004a,b). Â ïðîñòåéøåì ìîëåêóëÿðíîì
ñìûñëå ïðèîíû — ýòî áåëêè, êîòîðûå ìîãóò âûçûâàòü
íàñëåäóåìûå ôåíîòèïè÷åñêèå èçìåíåíèÿ, äåéñòâóÿ íà
ðîäñòâåííûé ýòèì áåëêàì ãåííûé ïðîäóêò è èçìåíÿÿ
åãî. Íèêàêèõ èçìåíåíèé íóêëåîòèäíîé ïîñëåäîâàòåëü-
íîñòè ÄÍÊ íå ïðîèñõîäèò; ñêîðåå, ïðèîí, â îáùåì
ñëó÷àå, íàâÿçûâàåò ñâîåìó ñóáñòðàòó íåêîå ñòðóêòóð-
íîå èçìåíåíèå. Ïðèîíû, îòíîñÿùèåñÿ ê ëó÷øå âñåãî
èçó÷åííîìó è ïîíÿòîìó êëàññó, çàñòàâëÿþò ðàñòâîðèìûå
ôîðìû áåëêà ïðåîáðàçîâûâàòüñÿ â àìèëîèäíûå âîëîêíà.
Âî ìíîãèõ ñëó÷àÿõ ýòà àìèëîèäíàÿ ôîðìà ñíèæàåò èëè
âîâñå óñòðàíÿåò íîðìàëüíóþ àêòèâíîñòü äàííîãî áåëêà,
âûçûâàÿ òàêèì îáðàçîì èçìåíåíèå â ôåíîòèïå. Âèêíåð
îïðåäåëèë åùå îäèí êëàññ ïðèîíîâ, êîòîðûå íå ôîðìè-
ðóþò àìèëîèäíûõ íèòåé. Ýòî ôåðìåíòû, äëÿ àêòèâàöèè
êîòîðûõ òðåáóåòñÿ ñâîÿ æå ôåðìåíòàòèâíàÿ àêòèâíîñòü.
Åñëè êëåòêà îáëàäàåò ëèøü íåàêòèâíûìè ôîðìàìè ýòîãî
ýíçèìà, òîãäà íåîáõîäèì âíåøíèé èñòî÷íèê àêòèâíîãî
ýíçèìà, ÷òîáû ïîëîæèòü íà÷àëî òîìó, ÷òî çàòåì ñòàíåò
ñàìîâîñïðîèçâîäÿùèìñÿ ïðèçíàêîì, ïîêà ïî êðàéíåé
ìåðå îäíà àêòèâíàÿ ìîëåêóëà ïåðåäàåòñÿ êàæäîé êëåòêå.
Îí ïðèâåë äâà ïðèìåðà è âûðàçèë óâåðåííîñòü â òîì, ÷òî
ýòîò êëàññ áåëêîâ ñîñòàâèò íîâóþ ãðóïïó ýïèãåíåòè÷å-
ñêèõ ìåõàíèçìîâ äëÿ èññëåäîâàíèÿ.
Øè ïðåäñòàâèë ïðåäâàðèòåëüíûå äàííûå î òîì,
ïðèîííàÿ ìîäåëü ìîæåò îáúÿñíèòü íàó÷åíèå è ïàìÿòü
ó Aplysia (Si et al., 2004). Â íåéðîíàëüíûõ êëåòêàõ ýòîãî
ìîëëþñêà òðàíñëÿöèÿ ðÿäà çàïàñåííûõ èÐÍÊ â áåëêè
âàæíà äëÿ ïîääåðæàíèÿ êðàòêîâðåìåííîé ïàìÿòè. Îí
îáíàðóæèë, ÷òî ðåãóëÿòîð áåëêîâîé òðàíñëÿöèè, CPEB,
ìîæåò ñóùåñòâîâàòü â äâóõ ôîðìàõ è ÷òî àêòèâèðîâàí-
íàÿ ôîðìà CPEB äåéñòâóåò äîìèíàíòíî, âîñïðîèçâîäÿ
ñåáÿ. Ïðîâåðêà ýòîé èäåè âñå åùå íàõîäèòñÿ â ñàìîì
4. Çàêëþ÷èòåëüíûå ñîîáðàæåíèÿ 21
íà÷àëå, íî îáåùàåò ôàíòàñòè÷åñêèå íîâûå ïîäõîäû íà
òåìó î òîì, êàêèì îáðàçîì ìû ïîìíèì.
3.5 Íîâîå ÿâëåíèå
Îïèñàíèå íîâîãî è íåîæèäàííîãî ôåíîìåíà âñåãäà ïî-
ðàæàåò íàøå âîîáðàæåíèå. Îäíî ñîîáùåíèå â îñîáåí-
íîñòè çàíèìàëî ìîè ìûñëè íà ïðîòÿæåíèè íåñêîëüêèõ
íåäåëü ïîñëå ñèìïîçèóìà. Ñòàíäàðòíûé ãåíåòè÷åñêèé
àíàëèç ìóòàíòíûõ àëëåëåé ãåíà HOTHEAD, ðåãóëèðóþ-
ùåãî ñëèÿíèå îðãàíîâ ó Arabidopsis, ïîêàçàë, ÷òî îáû÷íûå
ïðàâèëà ìåíäåëåâñêîé ãåíåòèêè çäåñü íå âûïîëíÿþòñÿ
(Lolle et al., 2005). Îêàçàëîñü, ÷òî åñëè ãåòåðîçèãîòíûå
(HOTHEAD/hothead) ðàñòåíèÿ ñàìîîïûëÿþòñÿ è ïðîèçâî-
äÿò ãîìîçèãîòíîå ðàñòåíèå hothead/hothead, à çàòåì ýòîìó
ãîìîçèãîòíîìó ðàñòåíèþ hothead/hothead äàþò ñàìîîïû-
ëèòüñÿ, ïîòîìñòâî îò ýòîãî ãîìîçèãîòíîãî ðîäèòåëÿ
ðåâåðòèðóåò ê ãåíîòèïó HOTHEAD/hothead ñ ÷àñòîòîé äî
15 %. Ýòîò ïîòðÿñàþùå âûñîêèé óðîâåíü ðåâåðñèè ê äèêî-
ìó òèïó äàâàë, íà íóêëåîòèäíîì óðîâíå, òî÷íûé äóáëèêàò
ãåíà äèêîãî òèïà, íàáëþäàâøåãîñÿ â ïðåäøåñòâóþùèõ
ïîêîëåíèÿõ. Ýòà ðåâåðñèÿ íå îãðàíè÷èâàëàñü ëîêóñîì
HOTHEAD — íåñêîëüêî äðóãèõ ëîêóñîâ îáíàðóæèâàëè
ñõîäíûå ÷àñòîòû ðåâåðñèè ê àëëåëÿì äèêîãî òèïà. Îäíàêî
äëÿ âñåõ ýòèõ ðåâåðñèé òðåáîâàëîñü, ÷òîáû ðîäèòåëü áûë
ãîìîçèãîòíûì hothead/hothead. Ïðîäóêò ãåíà HOTHEAD
íå äàåò íèêàêîãî î÷åâèäíîãî îáúÿñíåíèÿ, êàê òàêîå ìî-
æåò ïðîèñõîäèòü, íî ïðîøåäøèå îáñóæäåíèÿ îïðåäåëåí-
íî çàñòàâëÿþò ïðåäïîëàãàòü, ÷òî íåêàÿ àðõèâíàÿ êîïèÿ
ãåíà äèêîãî òèïà ïåðåäàâàëàñü â ðÿäó ïîñëåäîâàòåëüíûõ
ïîêîëåíèé, âîçìîæíî ÷åðåç ÐÍÊ. Õîòÿ ìîæíî âîçðà-
çèòü, ÷òî ýòî ÿâëåíèå ëåæèò âíå ñôåðû «ýïèãåíåòèêè», —
ïîñêîëüêó ñâÿçàíî ñ èçìåíåíèÿìè â íóêëåîòèäíîé ïî-
ñëåäîâàòåëüíîñòè ÄÍÊ, — íàñëåäñòâåííàÿ ïåðåäà÷à
ýòîé ïðåäïîëàãàåìîé àðõèâíîé êîïèè íå ïîä÷èíÿåòñÿ
íîðìàëüíûì ãåíåòè÷åñêèì ïðàâèëàì. Òàê èëè èíà÷å, ýòîò
ôåíîìåí ÷ðåâàò îãðîìíûìè ïîñëåäñòâèÿìè äëÿ ãåíåòè-
êè, îñîáåííî â îáëàñòè ýâîëþöèîííîãî ìûøëåíèÿ.
4. Çàêëþ÷èòåëüíûå
ñîîáðàæåíèÿ
Èòàê, ÷òî åùå íóæíî ñäåëàòü, ÷òîáû ïîíÿòü ýïèãåíåòè÷å-
ñêèå ìåõàíèçìû? Ïî áîëüøåé ÷àñòè ìû âñå åùå ñîáèðàåì
(îòêðûâàåì) èõ îòäåëüíûå êîìïîíåíòû. Òî÷íî òàê æå,
êàê ïîëíàÿ ïîñëåäîâàòåëüíîñòü ãåíîìà ÷ðåçâû÷àéíî îá-
ëåã÷èëà ïðîãðåññ â îáëàñòè ãåíåòèêè, òàê è áîëåå ÿñíîå
ïîíèìàíèå ýïèãåíåòèêè ïðèäåò, âåðîÿòíî, òîãäà, êîãäà
ñòàíóò èçâåñòíûìè âñå ñîñòàâíûå ÷àñòè. Óñïåõè, äîñòèã-
íóòûå çà ïîñëåäíåå äåñÿòèëåòèå, î÷åíü âäîõíîâëÿþò.
Ïðèçíàþñü, ÿ íå â ñîñòîÿíèè ðàçëè÷èòü, áëèçêè ëè
ìû èëè äàëåêè îò òî÷íîãî, â ìåõàíèñòè÷åñêîì ïëàíå,
ïîíèìàíèÿ òîãî, êàêèì îáðàçîì ïîääåðæèâàþòñÿ è
âîñïðîèçâîäÿòñÿ ýïèãåíåòè÷åñêèå ñîñòîÿíèÿ. Ïåðâûì,
âîçìîæíî, ïðèäåò ïîíèìàíèå ôåíîìåíîâ, áàçèðóþ-
ùèõñÿ íà ïðèîíàõ; òå æå ÿâëåíèÿ, êîòîðûå áàçèðóþòñÿ
íà õðîìàòèíå, ïî-âèäèìîìó, íàèáîëåå äàëåêè îò ýòî-
ãî. Ïîëèâàëåíòíàÿ ïðèðîäà âçàèìîäåéñòâèé, êîòîðûå,
ïî-âèäèìîìó, íåîáõîäèìû äëÿ óñòàíîâëåíèÿ ñàéëåí-
ñèðîâàííîãî ñîñòîÿíèÿ íà õðîìîñîìå, óâåëè÷èâàåò
22 Ãëàâà 1. Ýïèãåíåòèêà: îò ÿâëåíèÿ ê îáëàñòè íàóêè
ñëîæíîñòü ïðîáëåìû. Ïîñëåäíÿÿ åùå áîëåå óñëîæíÿ-
åòñÿ äèíàìè÷åñêîé ïðèðîäîé «ìîë÷àùåãî» õðîìàòèíà.
Âîçìîæíîñòü óçíàòü áîëüøå î äâèæåíèè êîìïîíåíòîâ
â õðîìàòèíîâûå ñòðóêòóðû è èç íèõ òðåáóåò äëÿ îêîí-
÷àòåëüíîãî ïîíèìàíèÿ ïðèìåíåíèÿ óñîâåðøåíñòâîâàí-
íûõ èëè ñîâñåì íîâûõ ìåòîäîâ. Èììóíîïðåöèïèòàöèÿ
õðîìàòèíà, îêàçàâøàÿñÿ âàæíîé â óñòàíîâëåíèè òîãî,
êàêèå êîìïîíåíòû íàõîäÿòñÿ â ñîñòàâå ñòðóêòóðû, âðå-
ìåííî çàñëîíèëà îò íàñ äèíàìèêó.
ß ïîäîçðåâàþ, ÷òî, ó÷èòûâàÿ ýòó ñëîæíîñòü, ïðîñòîå
èçìåðåíèå êîíñòàíò ñâÿçûâàíèÿ è ðàâíîâåñèÿ äëÿ âñåõ
êîìïîíåíòîâ è ïîïûòêè ïîëó÷èòü ñèñòåìó äèôôåðåí-
öèàëüíûõ óðàâíåíèé äëÿ èìèòàöèè ýïèãåíåòè÷åñêèõ
ïåðåêëþ÷àòåëåé ìîãóò îêàçàòüñÿ íåýôôåêòèâíîé òðàòîé
ðåñóðñîâ è íå îáÿçàòåëüíî ïðèâåäóò ê ëó÷øåìó ïîíèìà-
íèþ. Ñêîðåå, ÿ ïðåäïîëàãàþ, ÷òî ïîòðåáóåòñÿ ðàçðàáîò-
êà ìàòåìàòè÷åñêîãî ïîäõîäà íîâîãî òèïà â êîìáèíàöèè
ñ íîâûìè ýêñïåðèìåíòàëüíûìè ìåòîäàìè èçìåðåíèÿ
äëÿ îêîí÷àòåëüíîãî ïîíèìàíèÿ ýïèãåíåòè÷åñêèõ ñî-
áûòèé.  ÷àñòíîñòè ìîæåò ïîòðåáîâàòüñÿ ðàçðàáîòêà
ñèñòåì in vitro, íàäåæíî âîñïðîèçâîäÿùèõ ýïèãåíåòè-
÷åñêîå ïåðåêëþ÷åíèå ìåæäó ñîñòîÿíèÿìè.
Èäåÿ êîíêóðåíöèè ìåæäó äâóìÿ ñîñòîÿíèÿìè â áîëü-
øèíñòâå ýïèãåíåòè÷åñêèõ ÿâëåíèé, âåðîÿòíî, îòðàæàåò
«ãîíêó âîîðóæåíèé», ïðîèñõîäÿùóþ íà ìíîãèõ óðîâíÿõ
êëåòêè, çà êîòîðîé ñëåäóþò ïîïûòêè èñïðàâèòü «ñîïóò-
ñòâóþùèé óùåðá». Íàïðèìåð, áåëêè ñàéëåíñèíãà âîç-
íèêëè, âîçìîæíî, äëÿ çàùèòû ãåíîìà îò òðàíñïîçîíîâ.
Îäíàêî, ïîñêîëüêó áåëêè ñàéëåíñèíãà ðàáîòàþò ÷åðåç ïî-
ñðåäñòâî âåçäåñóùèõ íóêëåîñîì, ñòàíîâÿòñÿ ðåïðåññèðî-
âàííûìè íåêîòîðûå êðèòè÷íûå ãåíû. ×òîáû ïðåîäîëåòü
ýòî, âîçíèêëè ìîäèôèêàöèè ãèñòîíîâ (íàïðèìåð, ìåòè-
ëèðîâàíèå H3K4 è H3K79) è çàìåùåíèå âàðèàíòíûìè
ãèñòîíàìè, ÷òîáû ïðåäîòâðàùàòü ñâÿçûâàíèå áåëêîâ ñàé-
ëåíñèíãà ñ êðèòè÷íûìè ãåíàìè.  çàâèñèìîñòè îò ïîñëå-
äóþùèõ ñîáûòèé ýòè èçìåíåíèÿ ìîãóò áûòü êîîïòèðîâàíû
äëÿ äðóãèõ ïðîöåññîâ — íàïðèìåð, ìîæåò ñòàòü ïîëåçíîé
ðåïðåññèÿ íåêîòîðûõ ãåíîâ áåëêàìè ñàéëåíñèíãà («ìîë-
÷àùèå» ëîêóñû òèïà ñïàðèâàíèÿ). Ìåõàíèçìû ñàéëåíñèí-
ãà ìîãóò êîîïòèðîâàòüñÿ è äëÿ äðóãèõ ôóíêöèé, òàêèõ êàê
ñòèìóëÿöèÿ ðàñõîæäåíèÿ õðîìîñîì. È òàê äàëåå…
ß æäó ñåêâåíèðîâàíèÿ ãåíîìîâ íîâûõ îðãàíèçìîâ,
ïîñêîëüêó ýòî ìîæåò ïðèâåñòè íàñ ê ïîíèìàíèþ ïî-
ñëåäîâàòåëüíîñòè ýâîëþöèîííûõ ñîáûòèé, ïðèâåäøèõ
ê âîçíèêíîâåíèþ ýïèãåíåòè÷åñêèõ ïðîöåññîâ, êîòîðûå
ìû íàáëþäàåì ñåãîäíÿ. Íàïðèìåð, ó S. cerevisiae îòñóò-
ñòâóåò àïïàðàò RNAi, íî ó ìíîãèõ äðóãèõ ãðèáîâ îí åñòü.
Çàïîëíÿÿ íåêîòîðûå ôèëîãåíåòè÷åñêèå ïðîáåëû ìåæäó
âèäàìè, ìû ìîæåì âûÿñíèòü, êàêèå ñîáûòèÿ ïðèâåëè ê
òîìó, ÷òî S. cerevisiae áîëüøå íå «íóæäàþòñÿ» â ýòîé ñè-
ñòåìå.
Èçó÷åíèå ýïèãåíåòèêè, âîçìîæíî, áîëåå, ÷åì êàêàÿ-
ëèáî äðóãàÿ îáëàñòü áèîëîãè÷åñêèõ èññëåäîâàíèé,
îñíîâûâàåòñÿ íà ñòðåìëåíèè ïîíÿòü íåîæèäàííûå íà-
áëþäåíèÿ, íà÷èíàÿ ñ ìîçàèöèçìà, îáóñëîâëåííîãî ýô-
ôåêòîì ïîëîæåíèÿ, äî ïîëÿðíîé ñâåðõäîìèíàíòíîñòè
â ôåíîòèïå callipyge (Georges et al., 2004). Íàäåæäà ïî-
íÿòü ÷òî-òî íåîáû÷íîå ñëóæèò äëÿ íàñ ïðèìàíêîé, íî
ñêîðî ìû ïðèõîäèì â âîñòîðã ïðè âèäå ðàçóìíîñòè èñ-
ïîëüçóåìûõ ìåõàíèçìîâ. Ýòèì ìîæíî îáúÿñíèòü, ïî-
÷åìó ýòà îáëàñòü ïðèâëåêëà íåïðîïîðöèîíàëüíî ìíîãî
âåñåëûõ è ñâåòëûõ óìîâ. ß ïîäîçðåâàþ, ÷òî òàê è áóäåò
ïðîäîëæàòüñÿ ïî ìåðå äîñòèæåíèÿ íàìè áîëåå âûñîêî-
ãî óðîâíÿ ìàñòåðñòâà è îòêðûòèÿ íîâûõ è íåîæèäàííûõ
ýïèãåíåòè÷åñêèõ ÿâëåíèé.
Áëàãîäàðíîñòè
ß áëàãîäàðþ ìîèõ êîëëåã â Óíèâåðñèòåòå ×èêàãî è
Ðàêîâîì èññëåäîâàòåëüñêîì öåíòðå Ôðåäà Õàò÷èíñî-
íà, êîòîðûå ñäåëàëè ìîè ñîáñòâåííûå èññëåäîâàíèÿ
ïî ýïèãåíåòèêå ñòîëü ïðèÿòíûìè; ÿ áëàãîäàðåí òàêæå
Íàöèîíàëüíûì èíñòèòóòàì çäîðîâüÿ çà ôèíàíñîâóþ
ïîääåðæêó.
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