Epigenetics role in diseases

Chromatin
 Walther Flemming first used the term Chromatin in 1882.
 Chromatin structure: DNA wrapping around nucleosomes
– a “beads on a string” structure.
 In non-dividing cells there are two types of chromatin:
euchromatin and heterochromatin.

Schematic figure of chromatin and histone structure.
Muhonen P , and Holthofer H Nephrol. Dial. Transplant.
2009;24:1088-1096
© The Author [2009].

Chromatin Fibers
30 nm
chromatin fiber
11 nm
(beads)
Chromatin as seen in the electron microscope.
(source: Alberts et al., Molecular Biology of The Cell, 3rd Edition)

 The basic repeating unit of
chromatin.
 It is made up by five histone
proteins: H2A, H2B, H3, H4
as core histones and H1 as a
linker.
 It provides the lowest level
of compaction of double-
strand DNA into the cell
nucleus.
 It often associates with
transcription.
Nucleosome
H2A H2B
H3
H4
1974: Roger Kornberg discovers nucleosome who won Nobel Prize in 2006.

Core Histones are highly conserved proteins - share a structural
motif called a histone fold including three α helices connected by two
loops and an N-terminal tail

Histone Octamer
 Each core histone forms pairs as a dimer
contains 3 regions of interaction with dsDNA;
 H3 and H4 further assemble tetramers.
 The histone octamer
organizes 146 bp of DNA
in 1.65 helical turn of DNA:
 48 nm of DNA packaged in a disc of 6 x 11nm
< 6 nm >
<11nm>

The N-terminal tails protrude from the core

EPIGENETICS
• Coined by Conrad Waddington to describe changes in
gene expression during development
• Refers to a change in gene expression without a
change in the sequence of the gene
OR
• Modifications in gene expression brought about by
heritable, but potentially reversible, changes in DNA
methylation and/or chromatin structure
• Provide an “extra layer” of transcriptional control that
regulates gene expression

Examples of epigenetic modifications observed
in genome
• Position effects
• Paramutation
• Transvection
• Protein conformation
• Imprinting
• X-inactivation
• Histone modification
• DNA methylation
• RNA silencing

Structure & Epigenetics of Euchromatin versus
Heterochromatin
Paula Vertino, Henry Stewart Talks
Me

Histone Modifications
Me
P
Ub
Su
Ac Me
Acetylation
Methylation
Ubiquitination
Sumoylation
Phosphorylation
‘Histone Code’

Bhaumik, Smith, and Shilatifard, 2007.
Types of Histone Modifications

• Covalently attached groups (usually to histone tails)
• Reversible and Dynamic
– Enzymes that add/remove modification
– Signals
• Have diverse biological functions
Cell, 111:285-91, Nov. 1, 2002
Methyl Acetyl Phospho Ubiquitin SUMO
Features of Histone Modifications

• Small vs. Large groups
• One or up to three groups per residue
Jason L J M et al. J. Biol. Chem. 2005
Ub = ~8.5 kDa
H4 = 14 kDa
Contd..

• Writers: enzymes that add a mark
• Readers: proteins that bind to and “interpret” the mark
• Erasers: enzymes that remove a mark
Tarakhovsky, A., Nature Immunology, 2010.
Histone Modifications and Modifiers

• Others: Sumoylation (Lysine), ADP Ribosylation (Glutamate)
Residue Modification Modifying Enzyme
Lysine
Acetylation
Deacetylation
HAT
HDAC
Lysine
Methylation
Demethylation
HMT
HDM
Lysine
Ubiquitylation
Deubiquitylation
Ub ligase
Ub protease
Serine/Threonine
Phosphorylation
Dephosphorylation
Kinase
Phosphatase
Arginine
Methylation
Demethylation
PRMT
Deiminase/Demethylase

• Do not bind to DNA themselves
– Can be recruited by:
• Histone modifications (through
chromodomains, bromodomains,
etc.)
• Transcription factors
• RNA (fission yeast, mammals, plants)
• DNA damage
• Act as transcriptional co-regulators
• Enhance activities of transcriptional
repressors or activators
– Co-repressor: ex. HDACs
– Co-activator: ex. HATs

General Roles of Histone Modifications
• Intrinsic
– Single nucleosome changes
– Example: histone variant specific modifications (H2AX)
• Extrinsic
– Chromatin organization: nucleosome/nucleosome interactions
– Alter chromatin packaging, electrostatic charge
– Example: H4 acetylation
• Effector-mediated
– Recruitment of other proteins to the chromatin via
• Bromodomains bind acetylation
• Chromo-like royal domains (chromo, tudor, MBT) and PHD bind
methylation
• 14-3-3 proteins bind phosphorylation
Kouzarides, Cell 2007
- Prevent binding: H3S10P prevents Heterochromatin
Protein 1 binding

Euchromatin
 A lightly packed form of chromatin;
 Gene-rich;
 At chromosome arms;
 Associated with active
transcription.

Heterochromatin
 A tightly packed form of chromatin;
 At centromeres and telomeres;
 Contains repetitious sequences;
 Gene-poor;
 Associated with repressed
transcription.

Wade P A Hum. Mol. Genet. 2001.
Gene Regulation
Moggs and Orphanides, Toxicological Sciences, 2004.
DNA Damage

Epigenetic
changes
DNA
methylation
Histone
modifications
RNA silencing

Histone Acetylation
• Two enzyme types involved in histone acetylation
– HAT: histone acetyltransferase
– HDAC: histone deacetylase
• Note that acetylation eliminates the
positive charge from the amino acid.
• It is thought that this changes the
chromatin conformation to a form
more open to transcription.
• ⬆ acetylation = ⬆gene expression.

HAT/HDAC and Hydrophobic
Hormones
• It is thought that hydrophobic hormones like thyroid
hormone and glucocorticoid influence gene expression by
binding to either HDAC or HAT proteins.
⬆ acetylation =
⬆gene expression.

Role of histone acetylation
• Acetylated histones open up the chromatin
and enable transcription. Histones are
acetylated by HAT (histone acetylases)
which are parts of many chromatin
remodeling and transcription complexes.

Role of histone de-acetylation
• Deacetylated histones are tightly packed
and less accessible to transcription factors.
• Histones are deacetylated by HDAC (histone
de-acetylase) proteins.

Acetylation of Lysines
Acetylation of the lysines at the N
terminus of histones removes
positive charges, thereby
reducing the affinity between
histones and DNA.
This makes RNA polymerase and
transcription factors easier to
access the promoter region.
Histone acetylation enhances
transcription while histone
deacetylation represses
transcription.

DNA methylation
• Occurs at 5’ position of
cytosine within the
CpG dinucleotide
• Approx 70% CpGs are
methylated
• methylated CpGislands
are associated with
transcriptional
silencing

Methylation of Arginines and Lysines
 Arginine can be
methylated to form
mono-methyl,
symmetrical di-methyl
and asymmetrical di-
methylarginine.
 Lysine can be
methylated to form
mono-methyl,
di-methyl
and tri-methylarginine.

Effects of DNA methylation on gene expression.
Ling C , and Groop L Diabetes 2009;58:2718-2725
Copyright © 2014 American Diabetes Association, Inc.

CpG dinculeotide
• Dinucletide repeat CpG accounts for approx 1% genome
• CpGs generally under represented in human genome, but
occur close to expected frequency in small regions (~1kb)
called CpG islands
• Approx 45,000 such islands – most reside within or near
promoters or 1st exon of gene
• CpG islands have “open” chromatin structure
– Contains nucleosomes enriched in acetylated histone
(decreased affinity for DNA and each other)

How does methylation occur??
• De novo methylation occurs via group of enzymes known
as de novo methyl transferases (DNMTs)
– Include DNMT1, DNMT3a, DNMT3b
– Highly expressed in embryonic cells
– Highly specific programme of methylation to include
repetitive DNA/parasitic DNA, etc
– Changes with development of cell types
– Accessory factors also required
– ds RNA may direct methylation; ~ Xist known to trigger
X inactivation prior to methylation
• Considered that transcriptional repression may be trigger
for methylation rather than effect

Repression of transcription
Open chromatin; active transcription
De novo methyl transferases
Methylation of CpGs
Repressor complex;
methyl domain binding positions
histone deactelyases
Closed chromatin;
transcriptional silence

DNA Methylation
5-methylcytosine
S-adenosylmethionine
DNA methyltransferase
deoxycytosine
N
N
O
OH H
-O
O
N
N
N
O
OH H
-O
O
N
CH3

Histone phosphorylation (H3)
 Histones are phosphorylated during mitosis.
 Histones are also phosphorylated by signal
transduction pathways like the ERK pathway in
response to external signals. It is not known how
(and if) this phosphorylation contributes to gene
expression.

Schematic figure of epigenetic regulation mechanism.
Muhonen P , and Holthofer H Nephrol. Dial. Transplant.
2009;24:1088-1096
© The Author [2009].

Mark Transcriptionally relevant sites Biological Role
Methylated cytosine
(meC)
CpG islands Transcriptional Repression
Acetylated lysine
(Kac)
H3 (9,14,18,56), H4 (5,8,13,16), H2A,
H2B
Transcriptional Activation
Phosphorylated
serine/threonine
(S/Tph)
H3 (3,10,28), H2A, H2B Transcriptional Activation
Methylated argine
(Rme)
H3 (17,23), H4 (3) Transcriptional Activation
Methylated lysine
(Kme)
H3 (4,36,79)
H3 (9,27), H4 (20)
Transcriptional Repression
Ubiquitylated lysine
(Kub)
H2B (123/120)
H2A (119)
Transcriptional Repression
Sumoylated lysine
(Ksu)
H2B (6/7), H2A (126) Transcriptional Repression
Chromatin modifications

Techniques to Study Histone Modifications
• Chromatin immunoprecipitation (ChIP): Strategy for
localizing histone marks
• ChIP-qPCR: if you know the target gene
• ChIP-chip, ChIP-seq, or other genome-wide techniques:
unbiased
• Limitations:
» Antibody specificity
» Inherent biases of localization methods
• Mass Spectrometry:
• Requires digestion of histones

Massively parallel sequencing
Local amplification
ChIP-seq

Contd…
Genome
“Depth”: the number of
mapped sequence tags
“Coverage”: how much of the genome the reads can be mapped to

ChIP-seq vs. ChIP-chip
Mikkelsen et al., 2007

Chromatin Condensation Spermatogenesis
Kruhlak M J et al. J. Biol. Chem. 2001.

Epigenetics and complex diseases
• Epigenetics is the reflect of
– Environmental factors
– Stochastic events
– Aging
• It is less stable than DNA variations but it is stable enough
to explain chronic diseases. It may add to or reverse the
effect of DNA variations explaining uncomplete
penetrances.
• It may explain
– Altered sex ratio in complex diseases
– Incomplete concordance in monozygotic twins
– Cancers Ptak et al. 2008

Representative Clinical Conditions
Suggested to Have Epigenetic Origins
• Type 2 DM and Metabolic Syndrome
• Coronary artery disease
• Autoimmune Diseases
• Cancer
• Allergic Disorders
• Depression
• Neurologic: Alzheimer’s, PD, ALS,
Autism

Methylation in human disease
• ICF- rare recessive disease
– Immunodeficiency
– Facial anomalies
– Mental retardation and developmental delay
– Chromosomal instability (1, 9 & 16)
• Due to mutations in DNMT3b (de novo methyl transferase)
• Specific areas of hypomethylation
– Instability sites on chromosomes 1, 9 & 16
– Satellite DNAs 2 & 3
– DNA repeat D4Z4
– X chromosome
• Loss of methylation results in either relief from transcriptional
silencing or an upregulation of normally silenced genes

Epigenetic Biology of Cancer Cells: DNA
• The coexistence of gene-specific promoter
hypermethylation and global genomic DNA
hypomethylation is an epigenetic characteristic of cancer
cells.
• Genes regulated via methylation mechanisms include
tumor suppressors, cell cycle regulators, DNA repair
enzymes and regulators of apoptosis, among others.
• Global genomic DNA hypomethylation is a feature of
malignancy because there is a loss in the methylation of
repetitive sequences of the genome. This has been linked to
the chromosomal instability of cancer cells

Epigenetic Biology of Cancer Cells: Histones
• Loss of the monoacetylated Lys16 and trimethylated Lys20
residues of histone H4 appears in the early phase of cell
transformation and increases with tumor progression.
• Histone modifications may or may not be associated with
promoter hypermethylation.
• The tumor suppressor gene CDKN2/p16 is silenced via
aberrant methylation in breast cancer (33%), prostate
cancer (60%), renal cancer (23%), and colon cancer (92%).

DNA methylation in cancer
• Hypermethylation of promoter regions is most well
catergorised epigenetic change to occur in tumours
– Seen in virtually every tumour type
– Associated with inappropriate silencing
– Is at least as common as disruption of TSGs
eg BRCA1 – associated with familial breast cancer- evidence that 10-15% non
familial cases have tumours with hypermethylation of BRCA1

DNA methylation in cancer
• Also hypomethylation – may result in enhanced genomic
instability; activation of oncogenes
• Expression profile of DNMTs also observed in tumours
– DNMT1, 3a, 3b all increase with progression of cancer
– Expression profile varies depending on cancer type
• Methylated CpG may also undergo spontaneous
deamination; C>T and result in germline mutation
– ~50% inactivating point mutations in TP53 are C>T
mutations

DNA Methylation and Gene Silencing
in Cancer Cells
1 32 4
1 2 3 4
X
CGCG CG CG CG MCG MCG
Normal
Cancer
CG CG CGMCGMCGMCG MCG
C: cytosine
mC: methylcytosine
CpG island

Normal Cancer
Region-Specific
Hypermethylation
Global
Hypomethylation
+
Progressive Alterations in DNA
Methylation in Cancer

CpG Island Methylation: A Stable, Heritable and
Positively Detectable Signal
Normal
Epithelia
Dysplasia Carcinoma
in situ
Carcinoma
Metastasis
1
2
3
4
5

Normal
Epithelia
Dysplasia Carcinoma
in situ
Carcinoma
Metastasis
1
2
3
4
5
CpG Island Methylation: A Stable, Heritable and
Positively Detectable Signal

DNA Methylation Influences Cancer Processes
DNA
Repair
Hormonal
Regulation
Carcinogen
Metabolism
Apoptosis
Differentiation
Cell Cycle
DNA
Methylation

Hormones, Growth Factors and
Epigenetics
Epigenetic drugs can restore the expression of estrogen, progesterone,
androgen and retinoic acid receptors.

Rett syndrome
• Affects X chromosome
• Usually presents in females only
• Normal development until 6-18months then
• Gradual loss of speech, purposeful hand use
• Develop microcephaly, ataxia, autism
• Due to mutations in the MeCP2 gene (methyl binding
domain protein)
• Again hypomethylation occurs at specific sites
• Target genes not yet identified

Fragile X syndrome
 is most commonly caused by a CGG trinucleotide repeat
expansion in the 5’ region of the FMR1 gene.
 Unaffected individuals have 6-50 CGG repeats.
 >200 CGG repeats is seen in
individuals with fragile X.
 >200 CGG repeats is correlated with
hypermethylation at CpG
dinucleotides and silencing of the
FMR1 gene.

Epigenetics and inflammation
• Th1/Th2 ratio:
– Methylation between IL-4 and IL-13 (5q21) reduces
expression of Th2
– Th2 polarization increases methylation and decreases
histone deacetylation of g-IFN promoter
• IL-4/IL-13:
– Demethylation + histone modification
– Allowing GABA and STAT6 fixations
– Lead to IL-4 synthesis that induces IL-13 and IL-15
• FOXP3:
– CpG motifs in promoter : methylted in naif and activated
LT4 but demethylated in Treg.
Lee. Immunity 2002
Jones EMBO J 2006

Epigenetics in lupus
Thabet J Autoimmunol 12

Epigenetics in diabetes
Keating J Cardiovasc Transl res 2012

Model proposing a role for epigenetic mechanisms in the pathogenesis of type 2 diabetes.
Ling C , and Groop L Diabetes 2009;58:2718-2725
Copyright © 2014 American Diabetes Association, Inc.

A conceptual model linking epigenomics to cardiovascular disease and cardiovascular risk
factors.
Baccarelli A et al. Circ Cardiovasc Genet. 2010;3:567-573
Copyright © American Heart Association, Inc. All rights reserved.

Epigenetic mechanisms can lead to the inhibition of protective genes and activation of
pathologic genes associated with renal disease.
Reddy M A , and Natarajan R JASN 2011;22:2182-2185
©2011 by American Society of Nephrology

Different carbohydrates produce unique
genomic responses!
High Glycemic Carbs Low Glycemic Carbs
62 genes regulating Same genes turned off;
Inflammation, stress, Genes regulating same
insulin sensitivity production turned off.
Immune responses
Kalle et al. Am J Clin Nutr;2007:851:1417-27

Therapies Targeting Epigenetic Errors
• In contrast to mutations, epigenetic changes can be reversed.
• Are there therapies that influence epigenetic patterns?
– Yes
 Vorinostat (trade name Zolinza)
approved by FDA for cutaneous T cell
lymphoma in 2006.
 Vorinostat is a histone deacetylase
inhibitor.
 ⬆ acetylation = ⬆gene expression.
X

Combination Therapy
• Phase III Clinical Trial
– Vorinostat plus cytarabine
and idarubicin.
– 85% remission rate after
initial treatment.

Position effects
• Change in the level of gene expression brought about by a
change in the position of the gene relative to its normal
environment
– Chromosomal rearrangement may separate promoter and
transcription unit from an essential distant regulatory element
» Leading to reduction or absence of expression
– Rearrangement may dissociate transcription unit from an element that
serves to silence expression
» Leading to inappropriate activation of the gene
– Rearrangement may place gene with an enhancer from a second gene
» Leading to inappropriate expression of the gene

Examples of disorders caused by
position effects mechanisms
• Burkitts lymphoma - translocation event that places the cMYC gene
under the control of an immunoglobulin enhancer
• Holoprosencephaly – caused by mutations in/deletions in the sonic
hedgehog (SHH) gene. Can also be due to chromosomal rearrangements
that involve translocations 15-25kb upstream of gene
• Aniridia – caused by mutations in/deletions of the PAX6 gene. Can also
be due to chromosomal rearrangements that involve breakpoints
downstream of gene
– suggests that the rearrangement separates the PAX6 gene from an
essential regulatory element

Position effects
• Proximity of genes to centromeres, telomeres or
heterochromatic regions can suppress expression
– Facioscapularhumeral muscular dystrophy (FSHD)
• Maps to 4q35 (close to telomere)
• Shown to be associated with deletion of copies of a repeat unit
(D4Z4) from the subtelomeric region
• 95% patients with FSHD have contraction of repeat units
(1-10 vs control up to 100)

FSHD
4qA
4qB
Allelic variants 4qA/B – equal in population
But FSHD allele is always of 4qA type
D4Z4 repeat blocks
6.2kb beta satellite repeat
Actual disease mechanism is unclear – no specific gene identified as causative
but considered that the D4Z4 units form boundary between the heterochromatic
and euchromatic region
•upon contraction the local chromatin relaxes and allows transcription of
genes normally under repression,
or
•upon contraction, the boundary between regions is abolished allowing
heterochromatinisation and subsequent downregulation of genes in region
upstream genes

Paramutation
• A meiotically heritable change in expression of one allele invoked by another allele
• Initially observed and extensively studied in maize and other plants (pigment
genes) but recent evidence suggests it may be more widespread
• Usually results in a decrease in expression
• Paramutagenic alleles – have ability to induce change in allelic partner
• Paramutable alleles – can be induced to alter by paramutagenic allele
• Neutral alleles – can neither change or invoke change
• Possible human example – the insulin minisatellite which is associated with
protection against diabetes
– Paternally inherited class I alleles do not predispose to disease when have been allelic to
class III allele in father.

Transvection
• Another trans sensing mechanism ie involves the interaction
of homologous alleles
• Observed in Drosophila eg spreading of DNA methylation
through successive generations
• Modifications can occur across homologs
• No known examples in human genome

Protein conformation
• Observed in prions
– infectious agents implicated in scrapie, BSE and Creuzfeldt-Jakob disease
– have little or no associated DNA
– consist primarily of single protein (PrP) which is host encoded and is present at low
levels in disease free individuals
– Exists as two stable conformers (wild type and abnormal infectious type)
– Infectious nature of disease believed to derive from capacity of abnormal protein (PrPsc)
to interact with wild type protein and convert it to abnormal type
• Observed in yeast
– Similar scenario where protein conformer alters a second
– Results in inheritance of altered form in daughter cells to produce new strain
with different metabolic phenotype

Imprinting
• Most autosomal alleles expressed from both alleles – maternal and paternal origin
• Subset of genes are “imprinted” ie expressed from only the mother’s or father’s allele
• Alleles identical in each case but regulated differently
• Involves several different mechanisms
– Differential DNA methylation
– Allele specific RNA transcription
– Anti sense transcripts
– Histone modification
– Differences in replication timing
• Example of disorders involving imprinting
– Prader Willi syndrome
– Angelman syndrome
– Beckwith Wiedemann
• Discussed later

X- inactivation
• Method of ensuring dosage compensation
• In mammals dosage is equalised between sexes by
inactivating 1 X chromosome in female cells
– Requirement for counting the X chromosomes
– Choosing which to inactivate
– Inactivation process
• Occurs under control of X inactivation centre (XIC)
– Region of ~1Mb which contains several control elements and at least 4
genes
– Two of these genes are
• Xist – encodes a large non coding RNA
• Tsix – encodes an RNA which is synthesised antisense to Xist; regulates activity of
Xist

X- inactivation
– Both Xs are expressing Xist and Tsix at low levels prior to X inactivation
– Prior to inactivation the two X chromosomes “communicate” at the XIC -
decision is made as to which chromosome will be inactivated
– Selected inactive chromosome adopts a heterochromatic form which
upregulates the expression of Xist - coats the inactive X chromosome
– Process also involves methylation of the inactive X chromosome and
modification of the histones
• Modification allows silencing of most of the X chromosome
genes and thereby dosage compensation

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

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

HDAC inhibitors induce replication-independent active demethylation
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decom pr essor
decom pr essor
decom pr essor
decom pr essor
decom pr essor
CH3
CH3
CH3
demethylase
X
TSA
HAT binding
decom pr essor
decom pr essor
decom pr essor
decom pr essor
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decom pr essor
CH3
Ac
Ac
Ac
Ac
Ac
Ac
Ac
demethylase
CH3
CH3
((++)) TTSSAA
- M H- M H - M H- M H
EcoRIEcoRI
controlcontrol
MM
UU
(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).

N
CH
CN
O
HNH
CH3
C
DNA
C
N
CH
CHN
HNH
O
DNA
dMTase
DNMT
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)
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YUV420 codec decompressor
are needed to see this picture.

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
MeanC-Methylation
0
0.2
0.4
0.6
0.8
1.0
1.2 GR (17) 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 LG Low LG
NGFI-A
CH3CH3
Ac Ac
Demethylase
HDAC TSA

demethylase
DNMT
SAM
X
SAM
NGFIA binding NGFIA binding
X
Detich et al. J Biol. Chem. 278, 20812-20820 (2003).
SAM inhibits replication independent demethylation
NGFI-A
CH3CH3
Ac Ac
Is it possible to reverse the effects of maternal care on DNA methylation
and behavior in the adult rat?

0
10
20
30
40
50
60
70
80
90
100
110
Low LG-ABN High LG-ABN
Maternal care
Timespentininnerfield(min)
Vehicle TSA Methionine
(a) (b)
0
50
100
150
200
250
300
350
400
Low LG-ABN High LG-ABN
Maternal care
Totalnumberofsquarescrossed
Vehicle TSA Methionine
*
**
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
Demethylase
MBD2?
DNMT

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

Epigenetics role in diseases

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