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The dynamic epigenome; an interface between nurture and nature
Moshe SzyfDepartment of pharmacology and Therapeutics
McGill University, Montreal Canada
Moshe SzyfDepartment of pharmacology and Therapeutics
McGill University, Montreal Canada
OHAO SPRING SYMPOSIUMWednesday, 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
CH3
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CH3 CH3
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CH3
CH3
CH3
CH3
CH3
CH3
CH3
MaintenanceDNA methyltransferase
DNA replicationCH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
De novo methyltransferaseDemethylase
CH3 CH
(DNMT3a, 3b and DNMT1?)
(DNMT1)
DNA methylation reactions
Anders H. Lund et al. Genes Dev. 2004; 18: 2315-2335
Covalent modifications of the N-terminal tail of the canonical core histones
XCH3 CH3
Transcription factor
Transcription factor
XAcAcAcAc AcAc
CH3 CH3
Sin3ASin3A
MECP2
SUV39
HDAC
AcAc
CHCH33 CHCH33
HP1
XFig. 3
DNA methylation silences gene expression by two mechanisms
NN
CHCH
CCNN
OO
HNHHNH
CH3CH3
CC
DNADNA
CC
NN
CHCH
CCHHNN
HNHHNH
OO
DNADNAHHOHOHCH3CH3OHOH
dMTasedMTase
DNMTDNMT
AdoMet AdoHcyAdoMet AdoHcy
The reversible methylation reactionThe reversible methylation reaction
The environment is dynamic, the chromatin is dynamic, would DNA methylation remain static throughout life?
environment environment
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CH3
CH3
CH3
CH3
CH3
meth
ylase
dem
ethylase
active chromatin
inactive chromatin
Hypothesis: The steady state methylation pattern is a dynamicdynamic
equilibrium between methylase and demethylase activities
nutrients
toxinssocialbehavioral pathological
physiological
Methylated DNA is actively demethylated in Methylated DNA is actively demethylated in a replication independent manner upon a replication independent manner upon induction of histone acetylation by TSAinduction of histone acetylation by TSA
CH3
Human HEK cellsHuman HEK cells
GFP GFP
CH3
X
TSA
demethylasedemethylase
Human HEK cells
GFP
GFP
GFP
No origin of replication-no replication-no passive demethylation
HDAC inhibitors induce replication-independent active demethylation
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CH3
CH3
demethylaseX
TSA
HAT binding
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Ac
Ac
CH3
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((++)) TTSSAA
- M H- M H - M H- M H
EcoRIEcoRI
controlcontrol
MM
U U (529bp) (529bp)
- R1 D1 X- R1 D1 X
Cervoni et al., J. Biol. Chem 276, 40788 (2001)Cervoni et al., J. Biol. Chem. 277, 25026 (2002)Detich et al.,J Biol. Chem. 278, 27586 (2003).
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CCNN
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HNHHNHCH3CH3
CC
DNADNA
CC
NN
CHCH
CCHHNN
HNHHNH
OO
DNADNAdMTasedMTase
DNMTDNMT
Is there in vivo evidence for a dynamic methylation pattern in
postmitotic tissue?
LOW LG HIGH LG
Glucocorticoid receptor gene
GR GENE
GR RECEPTORS
GR GENE
GR RECEPTORS
Environmental programming of gene activity
STRESS RESPONSE STRESS RESPONSE
PUP (Day 1-6)
ADULT (Day 90)QuickTime™ and a
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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(17) REGION 16(5’ NGFI-A RE) METHYLATION TIMELINE
LOW
HIGH
Mea
n C
-Met
hyl
atio
n
0
0.2
0.4
0.6
0.8
1.0
1.2 GR (17) PROMOTER
NGFI-A
EMBRYODAY 20
BIRTHDAY 1
ADULTDAY 90
WEANINGDAY 21
PUPDAY 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 LG Low LG
NGFI-ACH3CH3
Ac Ac
Demethylase
HDAC TSA
demethylase
DNMT
SAM
X
SAM
NGFIA binding NGFIA bindingX
Detich et al. J Biol. Chem. 278, 20812-20820 (2003).SAM inhibits replication independent demethylation
NGFI-ACH3CH3
Ac Ac
Is it possible to reverse the effects of maternal care on DNA methylationand 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-A
HAT
DemethylaseMBD2?
NGFI-ACH3CH3
Ac Ac
DNMT
DNA methylation and inter-individual phenotypicvariance
Working hypothesis:
environment
epigenetic changes
inter-individual epigenetic variation
gene expression programming
Phenotypic variation
.
Suicide study and control group
Male/Female 13/0 5/0 11/0 1/0Age (years) 36 ± 11 37 ± 11 33 ± 9 21PMI (hours) 23 ± 6.2 23 ± 3.7 23 ± 6.4 24pH 6.4 ± 0.2 6.6 ± 0.3 6.3 ± 0.2 6.42Childhood Abuse/Neglect 13/13 100% 0/5 0% 0/11 0% 0/1 0%Mood 9/13 69% 5/5 100% 3/11 27% 0/1 0%Alcohol/drug dependence 9/13 69% 3/5 60% 5/11 46% 0/1 0%Anxiety 3/13 23% 0/5 0% 1/11 9% 1/1 100%
The values are mean ± SD.
(n = 13) (n = 5) (n = 11) (n = 1)Suicide Additional Suicide Control Additional Control
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?
chemical social
Signaling pathways
Epigenome
phenotypeNon-genotoxic agents might have a profound effect on our genome
and our health icluding obesity, diabetes, cnacer autoimmune disease
AcknowledgementsAcknowledgements
• Suchin Tendulkar,• Steven Andrews• Jing-Ni Ou• Nancy Detich• Nadia Cervoni• Nada BORGHOL • Steffan Hamm George Just
MICHAEL MEANEY & IAN WEAVERSERGIY DYMOV, Patrick MacGowen Gustavo Turecki
SHAFAAT RABBANI, Bushra Ateq, Nicholai Shukeir, Pouya Pakenshan
Michael Hallet, Matt Suderman
THIS RESEARCH IS SUPPORTED BYGRANTS FROM NCIC, CIHR, HSFP & THE NICHD