Prof. Girija Wagh - Epigenetics PE

Global
DNA methyla/on and its role in preclamp/c and preterm pregnancies: Understanding the epigene/cs
Girija Wagh Member of the Steering Commi@ee Organiza/on Gestosis Professor and Head Bhara/ Vidyapeeth University Medical College ,Pune India
5/7/12
girijawagh@gmail.com 9422000584
Conrad Waddington (1905-1975) is oZen credited with coining the term epigene/cs in 1942 as the branch of biology which studies the causal interac6ons between genes and their products, which bring the phenotype into being
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HISTORY : THE WISDOM OF THE PAST

Epigene/cs appears in the literature as far back as the mid 19th century, although the conceptual origins date back to Aristotle (384-322 BC). He believed in epigenesis: the development of individual organic form from the unformed
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Contrary to the belief

Having developed from miniscule fully-formed bodies. Even today the extent to which we are preprogrammed versus environmentally shaped awaits universal consensus.
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The eld of epigene/cs has emerged to bridge the gap between nature and nurture. Epigene)cs has always been all the weird and wonderful things that cant be explained by gene)cs.
Denise Barlow (Vienna, Austria) 2006
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Epigene/cs
The word epigene/c literally means in addi/on to changes in gene/c sequence. The term has evolved to include any process that alters gene ac/vity without changing the DNA sequence, and leads to modica/ons that can be transmi@ed to daughter cells (although experiments show that some epigene6c changes can be reversed).
Ques/ons today ??
Giving to understand the mul/factorial e/ology of preclampsia it is natural to wonder whether there are any more intrinsic mechanisms at intracellular level which 1 inuence the pathogenesis
And help in early detec/on
2 are inuences as the result of the disease which can

Aect the mother the baby and the future genera/ons
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Intracellular programming
Many processes are being elucidated And there is a lot of evidence today to state That epigene/cs
Cause as well as Result Due to the pathological processes of preclampsia and these also an give rise to las/ng eect to carry on for genera/ons to come
We have had a long-standing deal with biology

Whatever choices we make during our lives might ruin our short-term memory or make us fat or hasten death, but they won't change our genes our actual DNA. Which meant that when we had children of our own, the gene/c slate would be wiped clean.
DNA is just a tape carrying informa/on, and a tape is no good without a player. Epigene/cs is about the tape player.
Bryan Turner (Birmingham, UK)
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Bygren and other scien/sts have now amassed historical evidence sugges/ng that powerful environmental condi/ons (near death from starva/on, for instance) can somehow leave an imprint on the gene/c material in eggs and sperm. These gene/c imprints can short-circuit evolu/on and pass along new traits in a single genera/on.
Epigenome
These pa@erns of gene expression are governed by the cellular material the epigenome that sits on top of the genome, just outside it (hence the prex epi-, which means above).
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It is these epigene/c "marks" that tell your genes to switch on or o, to speak loudly or whisper.
It is through epigene/c marks that environmental factors like diet, stress and prenatal nutri)on can make an imprint on genes that is passed from one genera/on to the next.
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Epigene/c processes
Many types of epigene/c processes have been iden/edthey include
Methyla)on Acetyla)on Phosphoryla)on Ubiquityla)on sumolya)on.
Other epigene/c mechanisms too could exist These are natural and essen/al to many organism func/ons, but if they occur improperly, there can be major adverse health and behavioral eects.
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Out of these ..
Methyla/on and Histone modica/on is studied as it is easy reliable and not easily inuenced by storage and interpreta/on related issues
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Molecular Mechanisms that Mediate Epigene/c Phenomena

DNA methyla/on (CpG dinucleo/des) Histone modica/ons
Nucleosome
Histone Modica/ons
Adapted from Lund and Lohuizen Genes Dev 2004
Epigene/c Regula/on of Gene Expression
Epigene/c Regula/on of Gene Expression
Methylated DNA Histone
Histone Modica/on Status Correlates with Transcrip/onal Ac/vity
Gene ac/va/on correlated with H3-K9 acetyla)on Gene silencing associated with H3-K9 methyla)on
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Chroma/n remodeling (DNA methyla/on and histone modica/on) regulates several biological processes aec/ng embryonic development
Li, E. (2002). Chroma/n modica/on and epigene/c reprogramming in mammalian development. Nat Rev Genet 3, 662 673.
Epigene/c features are implicated in the pathogenesis of preeclampsia. Muta/ons in STOX1 were iden/ed in some unique familial cases of preeclampsia with apparent maternal-only transmission of suscep/bility.
Van Dijk M, Mulders J, Poutsma A et al: Maternal segrega6on of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family. Nat Genet 2005; 37: 514519.
Deciency of the imprinted Cdkn1c gene in mice can lead to hypertension and proteinuria during pregnancy, further implica/ng the role of imprinted genes in the development of preeclampsia. Epigene/c altera/ons of non-imprinted genes have also been suggested to be involved.
Kanayama N, Takahashi K, Matsuura T et al: Deciency in p57Kip2 expression induces preeclampsia-like symptoms in mice. Mol Hum Reprod 2002; 8: 11291135.
The SERPINA3 promoter was found to be hypomethylated in preeclampsia-associated placenta sugges/ng that the epigene/c altera/on of this gene may be associated with reduced trophoblas/c invasion and implica/ng this change as a poten/al biomarker for preeclampsia.
Chelbi ST, Mondon F, Jammes H et al: Expressional and epigene/c altera/ons of placental serine protease inhibitors: SERPINA3 is a poten/al marker of preeclampsia. Hypertension 2007; 49: 7683.
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Altered gene-specic methyla/on pa@erns of serine protease inhibitors (Chelbi et al., 2007), APC
(Muller et al., 2004)
and RASSF1A (Wang et al., 2010) gene promoters have been reported in pre-eclampsia
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IMPLICATIONS
It implies that certain factors in nurture and nature donot only have inuence in the pathogenesis of the disease process for that par/cular pregnancy but can have implica/ons for the future genera/ons . We therefore need to understand these in eects with more details and be able to convert these into clinical prac/ce
Preclampsia
Does seem to have an associa/on with altered nutri/on and is this really so ??? We always believed that the baby is a parasite !!! Also we tried supplemen/ng Vit E ,C Calcium with no much conclusive eect in various trials.
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Maternal nutri/on is an important determinant of one-carbon metabolism that lies at the heart of intrauterine epigene/c programming. Exchange of nutrients and other vital molecules between the mother and fetus takes place across the placenta and hence may play direct role in fetal programming. Pre-eclampsia (PE) originates in the placenta and altered maternal nutri)on may inuence epigene)c paOerns in the placenta, thereby aec)ng birth outcome.
Epigene/c regula/on of key genes involved in adult disease is currently considered to be the underlying mechanism for fetal programming
Symonds, M.E., Sebert, S.P., Hya@, M.A., and Budge, H. (2009). Nutri/onal programming of the metabolic syndrome. Nat Rev Endocrinol 5, 604610.
It also aects the angiogeneis

Dieren/al methyla/on of genes related to angiogenesis, blood vessel development, vasculature development, and blood vessel morphogenesis have also been reported (Uthus and Anderson, 2010). Promoter hypomethyla/on of several genes has been shown in early onset pre-eclamp/c placentas (Yuen et al., 2010).
OUR EXPERIENCE
We have published our observa/on related to preclampsia and nutri/on in rela/onship to omega 3 fa@y acids and now also DNA methyla/on
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Our earlier studies in pre-eclamp/c women have shown altered essen/al polyunsaturated fa@y acids levels, especially docosahexaenoic acid, which is one of the factors responsible for preeclampsia (Mehendale et al., 2008; Dangat et al., 2010).
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Membrane phospholipids are major methyl group acceptors docosahexaenoic acid levels may result in diversion of methyl groups toward DNA ul/mately resul/ng in DNA methyla/on as we have recently described in one carbon metabolic pathway (Kale et al., 2009).
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Further, several studies show high levels of homocysteine, another key cons/tuent of one-carbon metabolism in pre-eclampsia (Makedos et al., 2007; Singh et al., 2008; Guven et al., 2009).
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We have further tested the hypothesis that global DNA methyla/on pa@erns in placenta vary between normotensive and pre- eclamp/c women (both term and preterm) and may be associated with maternal blood pressure. The associa/ons between global DNA methyla/on pa@erns and maternal and neonatal characteris/cs were also studied.
STUDY REVEALED : Novel

(In normotensive and pre-eclamp6c women (both term and preterm) who were matched for age and socioeconomic status ) DNA methyla/on in pregnancies complicated with pre-eclampsia (both term and preterm) homocysteine levels in pre-eclamp/c (both term and preterm) when compared with normotensive women Posi/ve associa/on between global DNA methyla/on and SBP and DBP only in the term pre-eclamp/c group No associa/on of placental methyla/on pa@erns with birth outcome
The study reports the associa/on of placental global methyla/on pa@erns with blood pressure only in term preeclamp/c group indica/ng that dierences may exist in subsets of pre-eclamp/c women as suggested by others previously (Roberts and Catov, 2008).
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The methodology for es/ma/on of global methyla/on levels used in this study takes into account methyla/on of all CpGs irrespec/ve of their posi/on in the genome (promoter and nonpromoter CpG). This is in concurrence with studies indica/ng that CpG methyla/on in intragenic and intergenic regions are also cri/cal to gene expression (Fazzari and Greally, 2004).
German study
Yet another study
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Proled the DNA methyla/on of placentas from preeclampsia and IUGR pregnancies and their control counterparts using Illumina GoldenGate Methyla/on Cancer panel I array. Although the array mainly targets cancer- related genes, the pseudomalignant nature of the placenta makes it suitable for this study.
Chiu RW, Chim SS, Wong IH et al: Hypermethyla6on of RASSF1A in human and rhesus placentas. Am J 5/7/12 2007; 170: 941950. girijawagh@gmail.com 9422000584 Pathol 42
Among the 1505 CpG loci targeted by the array, 34 loci were iden/ed as hypomethylated in EOPET but none was dieren/ally methylated in LOPET. The dierent epigene/c proles in EOPET and LOPET placentas support the hypothesis that the two forms of preeclampsia are caused by dierent mechanisms.
EOPET
Is oZen associated with IUGR, is a severe form of preeclampsia
(76% associated with IUGR).
It is suggested to be ini/ated by abnormal placenta/on, caused by reduced perfusion with increased apoptosis of trophoblasts.
Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science 2005; 308: 15921594. Von Dadelszen P, Magee LA, Roberts JM: Subclassica6on of preeclampsia. Hypertens Pregnancy 2003; 22: 143148. Oudejans CB, van Dijk M, Oosterkamp M, Lachmeijer A, Blankenstein MA: Gene6cs of preeclampsia: paradigm shigs. Hum Genet 2007; 120: 607612.
LOPET
is considered to be a maternal syndrome, is a mild form of preeclampsia. It is usually associated with normal placental development and a predisposed maternal cons/tu/on, such as hypertension or diabetes.
Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science 2005; 308: 15921594. Oudejans CB, van Dijk M, Oosterkamp M, Lachmeijer A, Blankenstein MA: Gene6cs of preeclampsia: paradigm shigs. Hum Genet 5/7/12 120: 607612. 2007; girijawagh@gmail.com 9422000584 45
Epigene/c change may have a role in EOPET by altering gene expression and, as a consequence, abnormal placental development. Epigene/c changes may also result from hypoxic condi/ons associated with preeclampsia or an altered trophoblast composi/on in these placentas. Hypomethyla/on was found in many gene promoter regions in EOPET, but there was no dierence in the global DNA methyla/on level compared with other groups of placentas
The DNA methyla/on dierences of CpGs in CAPG, GLI2, KRT13 and TIMP3 were conrmed in an independent set of 26 placentas with EOPET and gesta/onal age-matched control pregnancies. Among these four genes, TIMP3 had the largest dierence in DNA methyla)on level with an over 15% reduc/on in EOPET compared with control placentas.
TIMP3 gene expression can be regulated by promoter DNA methyla/on in the placental /ssues.
Feng H, Cheung AN, Xue WC et al: Down-regula6on and promoter methyla6on of 6ssue inhibitor of metalloproteinase 3 in choriocarcinoma. Gynecol Oncol 2004; 94: 375382.
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TIMP3 is a family member of the matrix metalloproteinase inhibitors

Regulates : cell growth, invasion, migra/on transforma/on and apoptosis.
This gene is highly expressed in placenta and suggested to be important for implanta/on and decidualiza/on by regula/ng trophoblast invasion.
Feng H, Cheung AN, Xue WC et al: Down-regula6on and promoter methyla6on of 6ssue inhibitor of metalloproteinase 3 in choriocarcinoma. Gynecol Oncol 2004; 94: 375382. Apte SS, Maiei MG, Olsen BR: Cloning of the cDNA encoding human 6ssue inhibitor of etalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22.Genomics 1994; 19: 8690.
The hypomethyla/on of the TIMP3 promoter found in this study may increase TIMP3 expression and, in turn, reduce the invasiveness of trophoblast during placental development, which leads to placental hypoperfusion in EOPET.
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Intriguingly, hypermethyla/on of the TIMP3 promoter has been reported in choriocarcinoma and hyda/diform mole, condi/ons that have increased trophoblast invasiveness, which further supports the inverse rela/onship between TIMP3 promoter methyla/on and trophoblast invasiveness.
Feng H, Cheung AN, Xue WC et al: Down-regula6on and promoter methyla6on of 6ssue inhibitor of metalloproteinase 3 in choriocarcinoma. Gynecol Oncol 2004; 94: 375382. Xue WC, Chan KY, Feng HC et al: Promoter hypermethyla6on of mul6ple genes in hyda6diform mole and choriocarcinoma. J Mol Diagn 2004; 6: 326334
It has also been shown that TIMP3 could inhibit angiogenesis by blocking the vascular endothelial growth factor from binding its receptor, a well-known defect that is found in the trophoblast of preeclamp/c pregnancies.
Qi JH, Ebrahem Q, Moore N et al: A novel func6on for 6ssue inhibitor of metalloproteinases-3 (TIMP3): inhibi6on of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407415. Noris M, Perico N, Remuzzi G: Mechanisms of disease: pre-eclampsia. Nat Clin Pract Nephrol 2005; 1: 98114; quiz 120
Although the cause of the epigene/c modica/on is unknown, it may be related to the hypoxic environment of the cells. TIMP3 expression was increased in the rst trimester trophoblasts on hypoxic treatment. This implies that the increased expression of TIMP3 under hypoxic condi/on, a hallmark in preeclamp/c trophoblast, may be mediated by the epigene/c altera/on on its promoter.
Shahrzad S, Bertrand K, Minhas K, Coomber BL: Induc6on of DNA hypomethyla6on by tumor hypoxia. Epigene6cs 2007; 2: 119125. Gheorghe CP, Mohan S, Oberg KC, Longo LD: Gene expression paierns in the hypoxic murine placenta: a role in epigenesis? Reprod Sci 2007; 14: 223233. Koklanaris N, Nwachukwu JC, Huang SJ et al: First-trimester trophoblast cell model gene response to hypoxia. Am J Obstet Gynecol 2006; 194: 687693. 5/7/12 girijawagh@gmail.com 9422000584 53
USEFUL BIOMARKER !
The signicant reduc/on of DNA methyla/on in TIMP3 promoter of EOPET placentas could be useful as a biomarker for the disorder. CVS ?!!
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During pregnancy, 3 to 6% of cell-free DNA in maternal blood plasma is derived from the placenta. Therefore, one can detect abnormali/es in the fetal DNA directly from the maternal blood without going through invasive methods such as amniocentesis and CVS. It has been shown that there is an over vefold increase in circula/ng fetal DNA in the maternal plasma of preeclamp/c pregnancies compared with their control counterparts
Dennis Lo YM, Chiu RW: Prenatal diagnosis: progress through plasma nucleic acids. 5/7/12 Nat Rev Genet 2007; 8: 7177. girijawagh@gmail.com 9422000584
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Epigene/c considera/ons in preterm delivery

Spontaneous preterm parturi/on is syndromic in nature, and mul/ple mechanisms of disease are likely to be involved
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Many a@empts have been made

To study Epigene/c inuences Other factors have been found to be confounding !!!
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EPIGENETIC REGULATION OF COX-2 GENE PROMOTER IN PRETERM LABOR

Joel LARMA, BEGONA CAMPOS, LESLIE MYATT, University of Cincinna6, Cincinna6, Ohio, University of Cincinna6, Obstetrics and Gynecology, Cincinna6,
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Myometrium was studied at CS

The COX 2 gene, from the -1294 promoter region to the + 275 region of the gene, did not present a DNA methyla/on pa@ern in genomic DNA isolated from the myometrium of unlabored and labored parturients at a gesta/onal age less than 37 weeks who underwent a Cesarean sec/on
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This study iden/ed maternal and fetal DNA variants that predispose to preterm labor with intact membranes leading to preterm delivery Importantly,TIMP2 consistently was found in the dierent networks (maternal and fetal) that are associated with preterm labor/ delivery with intact membranes.
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The observed associa/on between TIMP2 and spontaneous preterm labor with intact membranes is novel and implicates extracellular matrix metabolism as an important factor that predisposes to preterm parturi/on
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TIMP2 (Tissue inhibitor of metalloproteinase 2)

Modulates the ac/on of MMP2
Matrix Metalloproteinase 2
Implicated in the metabolism of Collagen IV in uterus as well as cervix
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What do we have then

Environmental factors have intergene/c inuences which modify the process of trophoblas/c invasion They aect cellular level mechanisms Harbour the poten/al to carry it not only to the aected fetus but also to the next genera/on
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What we need to do ?
Be more intense with what we have Nutri/onal assessment Careful clinical assessment Conscious interven/ons
Will go a long way in helping us alleviate this condi/on

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Prof. Girija Wagh - Epigenetics PE

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Global

HISTORY : THE WISDOM OF THE PAST

Contrary to the belief

2 are inuences as the result of the disease which can

We have had a long-standing deal with biology

Molecular Mechanisms that Mediate Epigene/c Phenomena

Adapted from Lund and Lohuizen Genes Dev 2004

Epigene/c Regula/on of Gene Expression

Epigene/c Regula/on of Gene Expression

Methylated DNA Histone

Histone Modica/on Status Correlates with Transcrip/onal Ac/vity

It also aects the angiogeneis

STUDY REVEALED : Novel

TIMP3 is a family member of the matrix metalloproteinase inhibitors

Epigene/c considera/ons in preterm delivery

Many a@empts have been made

EPIGENETIC REGULATION OF COX-2 GENE PROMOTER IN PRETERM LABOR

Myometrium was studied at CS

TIMP2 (Tissue inhibitor of metalloproteinase 2)

Implicated in the metabolism of Collagen IV in uterus as well as cervix

What do we have then

Will go a long way in helping us alleviate this condi/on

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