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an introduction
R6
Definition
Epigenetics: all meiotically and mitotically
heritable changes in gene expression that are not
coded in the DNA sequence itself
DNA methylation
RNA associated silencing
Histone modification
Genes
Chromatin
Histone
nonhistone
chromosomal proteins
Nucleosome
Chromosome
Initiation of DNA
transcription
Methylation
Scaffold
protein
Histone
modification
Epigenetic diseases
Nature 2004;429:457-73
DNA methylation
DNA methylation
At promoter, DNA
methylation suppresses
transcription
DNA methyltransferase
Tumor suppressor
genes?
Methylation
azacytidine
decitabine
Cell 1980;
20:85-93
Blood 2002;100:2957-64
Blood 2004;103:1635-40
Time to leukemia
transformation or death
P<0.0001
AML1ETO(+)
Nature 2007;449:1073-78
Histone acetylation
(HDAC)
Role of histone
modification
DNA transcription
DNA repair
DNA replication
Cell 2007;128:693-705
Histone modification
the histone code
Acetylation
Methylation
Phosphorylation
Ubiquitylation
sumoylation
Nature
2007;447:407-12
Nature
2007;447:407-12
HDAC inhibitors
JCO 2007;25:3109-15
trichostatin A
sensitizes estrogen
receptor -negative
breast cancer cells
to tamoxifen
Oncogene
2004;23:1724-36
T24
Problems in epigenetics
agents in cancer therapy
Differentiation or cytotoxic agents?
Specificity and Selectivity of the
treatment targets?
Correction of epigenetic change and
underlying gene mutaion?
No survival benefit till now!!
Nature 2007;447:413-7
Scaffold protein
SATB1
More higher
structure than
chromatin
Play important role
in T-cell
development
Nat Genetics 2006;38:1229-30
SATB1
Nature 2008;452:187-193
Summary
Nature 2007;447:433-40
Summary
Methylation and HDAC
control of transcription through electric
change or 3-D conformational change of
chromatin
Control the phenotype
Application of cancer therapy?
Thank you
for
your attention
Cancer Res
1995;55:2279-83
Nature 2004;429:457-73
Cell 2007;128:655-68
Cell 2007;128:693-705