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The dynamic epigenome; an interface between nurture and nature

Explore the role of the dynamic epigenome in programming the genome and its implications on gene expression, phenotype, and intergenerational effects. Investigate how environmental factors, such as maternal care, can modify DNA methylation patterns and behavior. Understand the potential impact of non-genotoxic agents on health and disease.

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The dynamic epigenome; an interface between nurture and nature

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  1. The dynamic epigenome; an interface between nurture and nature Moshe Szyf Department of pharmacology and Therapeutics McGill University, Montreal Canada OHAO SPRING SYMPOSIUM Wednesday, March 26, 2008 Toronto ON

  2. The dynamic epigenome and its implications The programming of the genome is controlled by the epigenome The epigenome is composed of two components: 1) thechromatinwhich is associated with the DNA and 2)DNA methylationwhich is part of the covalent structure of the genome and is therefore a stable long-term signal DNA methylation is an interface between the dynamic environment and the static genome

  3. CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 DNA methylation reactions De novo methyltransferase Demethylase (DNMT3a, 3b and DNMT1?) CH3 DNA replication CH3 CH3 CH Maintenance DNA methyltransferase (DNMT1) CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

  4. Covalent modifications of the N-terminal tail of the canonical core histones Anders H. Lund et al. Genes Dev. 2004; 18: 2315-2335

  5. X CH3 CH3 X X Transcription factor Ac Ac MECP2 CH3 CH3 HP1 CH3 CH3 HDAC SUV39 Sin3A DNA methylation silences gene expression by two mechanisms Transcription factor Ac Ac Fig. 3

  6. HNH HNH CH3 AdoMet AdoHcy C CH N N CH C C CH DNMT O O N N dMTase DNA DNA HOH CH3OH The environment is dynamic, the chromatin is dynamic, would DNA methylation remain static throughout life? The reversible methylation reaction

  7. CH3 CH3 physiological behavioral pathological social nutrients toxins Hypothesis: The steady state methylation pattern is a dynamic equilibrium between methylase and demethylase activities CH3 CH3 inactive chromatin CH3 CH3 environment environment methylase demethylase active chromatin

  8. GFP GFP GFP CH3 CH3 Methylated DNA is actively demethylated in a replication independent manner upon induction of histone acetylation by TSA TSA GFP GFP demethylase Human HEK cells Human HEK cells Human HEK cells X No origin of replication-no replication-no passive demethylation

  9. HDAC inhibitors induce replication-independent active demethylation • Cervoni et al., J. Biol. Chem276, 40788 (2001) • Cervoni et al., J. Biol. Chem. 277, 25026 (2002) • Detich et al.,J Biol. Chem.278, 27586 (2003).

  10. HNH HNH CH3 C CH N N CH C C CH O O N N DNA DNA DNMT dMTase Is there in vivo evidence for a dynamic methylation pattern in postmitotic tissue?

  11. Environmental programming of gene activity Glucocorticoid receptor gene PUP (Day 1-6) LOW LG HIGH LG ADULT (Day 90) GR GENE GR GENE GR RECEPTORS GR RECEPTORS STRESS RESPONSE STRESS RESPONSE

  12. MECHANISM How are the long-term effects of maternal care on gene expression in the offspring maintained into adulthood? How are these differences transmitted across generations?

  13. HIPPOCAMPAL GR(17) REGION 16 (5’ NGFI-A RE) METHYLATION TIMELINE LOW HIGH NGFI-A * * * GR (17) PROMOTER 1.2 1.0 0.8 Mean C-Methylation 0.6 0.4 0.2 0 PUP DAY 6 ADULT DAY 90 EMBRYO DAY 20 BIRTH DAY 1 WEANING DAY 21 Age

  14. Ac NGFI-A NGFI-A Ac CH3 CH3 In the adult (day 90) rat hippocampal GR gene expression of Low LG-ABN offspring is reversed by TSA HDAC TSA DNMT X High LGLow LG Demethylase

  15. Is it possible to reverse the effects of maternal care on DNA methylation and behavior in the adult rat? Ac NGFI-A Ac CH3 CH3 SAM DNMT X X NGFIA binding NGFIA binding demethylase SAM SAM inhibits replication independent demethylation Detich et al. J Biol. Chem. 278, 20812-20820 (2003).

  16. Methionine treatment reverses Open Field Behavior of Adult (Day-90) Male Offspring of High LG-ABN maternal care (a) (b) * **

  17. Behavioural gene programming 5-HT cAMP NGFI-A HAT PKA Demethylase MBD2? DNMT

  18. DNA methylation and inter-individual phenotypic variance . Working hypothesis:environment epigenetic changes inter-individual epigenetic variation gene expression programming Phenotypic variation

  19. Suicide study and control group

  20. Methylation of the GR locus and its chromosomal neighborhood in suicide completers

  21. Genome wide organization of differentially methylated promoters

  22. chemical social What are the implications of a life-long dynamic epigenome? Signaling pathways Epigenome phenotype Non-genotoxic agents might have a profound effect on our genome and our health icluding obesity, diabetes, cnacer autoimmune disease

  23. Acknowledgements • Suchin Tendulkar, • Steven Andrews • Jing-Ni Ou • Nancy Detich • Nadia Cervoni • Nada BORGHOL • Steffan Hamm George Just MICHAEL MEANEY & IAN WEAVER SERGIY DYMOV, Patrick MacGowen Gustavo Turecki SHAFAAT RABBANI, Bushra Ateq, Nicholai Shukeir, Pouya Pakenshan Michael Hallet, Matt Suderman THIS RESEARCH IS SUPPORTED BY GRANTS FROM NCIC, CIHR, HSFP & THE NICHD

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