The dynamic epigenome; an interface between nurture and nature Moshe Szyf Department of pharmacology and Therapeutics McGill University, Montreal Canada.

Slides:



Advertisements
Similar presentations
Does your DNA define you? Overview of epigenetics and its role in disease.
Advertisements

Epigenetics Epigenetics - Heritable changes in gene expression that operate outside of changes in DNA itself - stable changes in gene expression caused.
The control of gene expression by chromatin remodeling.
Gene Silencing Arlés Urrutia Biomedicine and Biotechnology Institute. Autonomous University of Barcelona. (IBB-UAB) Neurochemistry Lab.
Nutrition: A Lifespan Approach, by Simon Langley-Evans. © 2009 Simon Langley-Evans. 1 Learning objectives.
Epigenetics and Culture Kevin Ferriter Mariah Minder.
Gregor Mendel ( ) DNA (gene) mRNA Protein Transcription RNA processing (splicing etc) Translation Folding Post translational modifications Peptides/amino.
Genomics, Bioinformatics & Medicine
The role of Epigenetic Inheritance
Epigenetic correlates of human socioeconomic status Clyde Hertzman.
Methylation, Acetylation and Epigenetics
Epigenetic Regulation of the Glucocorticoid receptor in human brain associates with childhood abuse Patrick O McGowan, Aya Sasaki, ana c D’Alessio, Sergiy.
Epigenetics and the brain; the nature of nurture? Anthony Isles Behavioural Genetics Group Cardiff University.
Lecture 19 – Epigenomics – Plants
All the cells in the organism have the same DNA DNA is packed together with histones and other proteins into chromatin. Chromatin is a highly dynamic.
Epigenetics: DNA methylation I. Requirements for epigenetic materials Need to be transmitted faithfully during mitosis and meiosis (possibly along with.
1 Day Date Subject To be read prior to this class period: Th3/12Chapter 7 T3/17 students = epigenetics Richie Th3/19students = toxicology and cancer Anna,
UNC-Chapel Hill Superfund Research Program Assessing biological responses to contaminants An introduction to epigenetics & the exposome.
Epigenetics of Human Marie Černá Lecture No 426-H.
Epigenetics Heritable characteristics of the genome other than the DNA sequence Heritable during cell-division (mitosis) To a lesser extent also over generations.
DNA MODIFICATIONS AND LONG-TERM PATTERNS OF GENE EXPRESSION EPIGENETICS PART 1 Feb 19, 2015.
The bilateral interrelationship between chromatin and DNA methylation and its impact on cancer.
Companion PowerPoint slide set DNA wrap: Packaging matters
Early life stress changes the way our genes function.
Epigenetics Clyde Hertzman, MD Human Early Learning Partnership University of British Columbia, Vancouver.
Transcriptional - These mechanisms prevent transcription. Posttranscriptional - These mechanisms control or regulate mRNA after it has been produced.
Cell cycle regulation of DNMT1 and cancer. M M M M M M M M DNMT1 M M M M M M M M G0/G1SG2M DNMT1 transcription Enzymatic activity Steady state mRNA The.
Epigenetic Processes from a Molecular Perspective INBRE Meeting 2/16/10.
Epigenetic Regulation in the Nervous System
Genetic Variation is a Change in the DNA Sequence
DNA Mutations Mutations are changes to the genetic information of the cell. There are 2 different types of mutations – Drives evolution – Most are silent.
Histone Methylation Marks : Permanent or Reversible?
Outline Molecular Cell Biology Assessment Review from last lecture Role of nucleoporins in transcription Activators and Repressors Epigenetic mechanisms.
HOW ENVIRONTMENT CONTROL GENE EXPRESSION IN SUICIDE VICTIMS Martin Štefko.
EPIGENETICS #1 BIOT 412 Fall 2013.
Molecules and mechanisms of epigenetics. Adult stem cells know their fate! For example: myoblasts can form muscle cells only. Hematopoetic cells only.
Epigenetics Abira Khan. What is Epigenetics?  Histone code: Modifications associated with transcriptional activation- primarily methylation and acetylation-would.
Date of download: 5/28/2016 From: Changes in DNA Methylation in Neoplasia: Pathophysiology and Therapeutic Implications Ann Intern Med. 2001;134(7):
How do eucaryotic gene activator proteins increase the rate of transcription initiation? 1.By activating directly on the transcription machinery. 2.By.
The Importance of Epigenetic Phenomena in Regulating Activity of the Genetic Material Sin Chan.
GRADING RUBRIC Lab: Epigenetics HONORS BIOLOGY: UNIT 7 
Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer Digestion 2011;83:241–249 - DOI: / Fig. 1.a DNA methyltransferases.
EPIGENETICS Textbook Fall 2013.
P11. P11 Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression Philippe A. Melas,
Companion PowerPoint slide set DNA wrap: Packaging matters
Breanna Perreault and Xiao Liu D145 Presentation
EPIGENETICS Professor Victoria Sarafian, MD, PhD, DMSc.
Fig. 1. Epigenetic regulation by DNA methyltransferases methyl-binding proteins and histone modifying enzymes. DNA is methylated by DNA methyltransferases.
Regulation of Gene Expression
Companion PowerPoint slide set DNA wrap: Packaging matters
Chapter 18 Gene Expression.
Chromatin Regulation September 20, 2017.
Introduction to Genetic Analysis
Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene
GENETICS A Conceptual Approach
Daily Warm-Up Thursday, January 9th
Regulation of Gene Expression
Beyond genetics: epigenetic code in chronic kidney disease
Review Warm-Up What is the Central Dogma?
Review Warm-Up What is the Central Dogma?
Mira Jeong, Margaret A. Goodell  Experimental Hematology 
GENETICS A Conceptual Approach
Epigenetics modification
Same genes, different phenotypes
Role of histone modification in transcription. Development imprinting.
Figure 2 Histone acetylation regulates gene expression
Basic concepts of epigenetics
A Role for Epigenetics in Psoriasis: Methylated Cytosine–Guanine Sites Differentiate Lesional from Nonlesional Skin and from Normal Skin  Johann E. Gudjonsson,
Gene expression of epigenetic modulators, HDAC1 and Dnmt1, and the histone acetylation modification patterns by the prenatal/maternal BSp dietary treatment.
Chromatin status is influenced by DNA methylation and histone acetylation Chromatin status is influenced by DNA methylation and histone acetylation In.
Presentation transcript:

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

The programming of the genome is controlled by the epigenome The epigenome is composed of two components: 1) the chromatin which is associated with the DNA and 2) DNA methylation which 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 The dynamic epigenome and its implications

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

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

X CH 3 Transcription factor Transcription factor XAc AcAc CH 3 Sin3A MECP2 SUV39 HDACAc CH 3 HP1 X Fig. 3 DNA methylation silences gene expression by two mechanisms

N CH C N OHNHCH3 C DNA C N CH CHCHCHCH NHNHO DNA HOH CH3OH dMTase DNMT AdoMet AdoHcy The reversible methylation reaction The environment is dynamic, the chromatin is dynamic, would DNA methylation remain static throughout life?

environment CH 3 methylase demethylase active chromatin inactive chromatin dynamic Hypothesis: The steady state methylation pattern is a dynamic equilibrium between methylase and demethylase activities nutrientstoxinssocialbehavioralpathologicalphysiological

Methylated DNA is actively demethylated in a replication independent manner upon induction of histone acetylation by TSA CH 3 Human HEK cells GFP CH 3 X TSA demethylase Human HEK cells GFP No origin of replication-no replication-no passive demethylation

HDAC inhibitors induce replication-independent active demethylation Cervoni et al., J. Biol. Chem 276, (2001) Cervoni et al., J. Biol. Chem. 277, (2002) Detich et al.,J Biol. Chem. 278, (2003).

N CH C N O HNH CH3 C DNA C N CH CHCHCHCH N HNH O DNA dMTaseDNMT Is there in vivo evidence for a dynamic methylation pattern in postmitotic tissue?

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

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?

HIPPOCAMPAL GR(1 7 ) REGION 16 (5’ NGFI-A RE) METHYLATION TIMELINE LOW HIGH Mean C-Methylation GR (1 7 ) PROMOTER NGFI-A EMBRYO DAY 20 BIRTH DAY 1 ADULT DAY 90 WEANING DAY 21 PUP DAY 6 Age * * *

In the adult (day 90) rat hippocampal GR gene expression of Low LG-ABN offspring is reversed by TSA DNMT NGFI-A X High LGLow LG NGFI-A CH 3 Ac Demethylase HDAC TSA

demethylase DNMT SAM X NGFIA binding X Detich et al. J Biol. Chem. 278, (2003). SAM inhibits replication independent demethylation NGFI-A CH 3 Ac Is it possible to reverse the effects of maternal care on DNA methylation and behavior in the adult rat?

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

PKA Behavioural gene programming 5-HT cAMP NGFI-AHAT Demethylase MBD2? DNMT

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

Suicide study and control group

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

Genome wide organization of differentially methylated promoters

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

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