Epigenetics and the brain;
the nature of nurture?
Anthony Isles
Behavioural Genetics Group
Cardiff University
What is epigenetics?
“The transmission and perpetuation of information through
cell division that is not based on the sequence of the
DNA” (after Conrad H. Waddington c. 1942)
What is epigenetics?
“The transmission and perpetuation of information through
cell division that is not based on the sequence of the
DNA” (after Conrad H. Waddington c. 1942)
• Development and differentiation
• Maintenance of cellular identity
What is epigenetics?
Regulation, timing and level of gene expression
Undifferentiated parent cell
What is epigenetics?
Regulation, timing and level of gene expression
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Liver cell
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Undifferentiated parent cell
What is epigenetics?
Regulation, timing and level of gene expression
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Liver cell
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Neural cell
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Undifferentiated parent cell
What is epigenetics?
Regulation, timing and level of gene expression
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Differentiation
Liver cell
Neural cell
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Undifferentiated parent cell
What is epigenetics?
Regulation, timing and level of gene expression
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Liver cell
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Liver cell
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Neural cell
Maintenance of
cellular identity
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Neural cell
Molecular Mechanisms
• How is molecular control of gene expression exerted?
• DNA code remains unchanged
• Epigenetics are another layer of information laid on top of
the DNA code
• Two main mechanisms:
→ DNA methylation
→ Histone (chromatin) modification
Molecular Mechanisms
– DNA methylation
• DNA sequence made up of 4 chemical bases; adenosine,
guanine, tyrosine and cytosine (A,G,T,C)
• One base, cytosine is epigenetically modified by DNA
methylation
• Encoded DNA information (i.e. ‘C’) remains the same
• Epigenetic code has changed…
• DNA methylation generally = suppression of gene activity
Molecular Mechanisms
– histone modifications
• Histones; proteins around which
DNA is bound
• Histones are the main component
of chromatin
• Chromatin compacts and provides
stability and structure to the DNA
Molecular Mechanisms
– histone modifications
• Modifications of residues in the histone
‘tails’
• >40 possible modifications
• Modification alter 3-D structure and make
DNA more, or less, accessible
• Acetylation found in regions of increased
gene expression
Molecular Mechanisms
– histone modifications
• Modifications of residues in the histone
‘tails’
• >40 possible modifications
• Modification alter 3-D structure and make
DNA more, or less, accessible
• Acetylation found in regions of increased
gene expression
DNA-methylation and chromatin interact – differential recruitment of histones
The relevance of epigenetics
to brain function
Epigenetic mechanisms and
neurodevelopment disorders
Epigenetics important in cell differentiation and maintenance
Aberrant DNA-methylation (MECP2)
• Rett syndrome
• Rubinstein-Taybi syndrome
• Angelman/Prader-Willi
Lack of Chromatin Binding Protein
• Loss of Histone acetly-transferase
Mutations in tightly regulated genes
• Paternally/maternally imprinted genes on 15q11-q13
• Also caused by loss of epigenetic control mechanism (i.e. no DNA loss)
Environment and epigenetics
The transmission and perpetuation of information through
meiosis and/or mitosis that is not based on the sequence
of the DNA (after Conrad H. Waddington c. 1942)
Environment and epigenetics
The transmission and perpetuation of information through
meiosis and/or mitosis that is not based on the sequence
of the DNA (after Conrad H. Waddington c. 1942)
“…complex 'epigenetic' mechanisms, which regulate gene
activity without altering the DNA code, have long-lasting
effects within mature neurons.”
Tsankova, Renthal, Kumar & Nestler 2007 Nature Neuroscience Reviews 8: 355-367
Environment and epigenetics
- encoding life events
• Identical twins have identical DNA
• Global differences in epigenetic status
between twins increases with age
Increased differences in methlyation
• Green: areas of hypermethlyation
• Red: areas hypomethylation
• Yellow: equal levels of methylation
Fraga et al. (2005) PNAS 102, 10604-10609
Environment and epigenetics
- encoding life events
• Identical twins have identical DNA
• Global differences in epigenetic status
between twins increases with age
Increased differences in methlyation
• Green: areas of hypermethlyation
• Red: areas hypomethylation
• Yellow: equal levels of methylation
Different life events give rise to different
patterns of epigenetic marks
Fraga et al. (2005) PNAS 102, 10604-10609
Environment and epigenetics
- programming of by early life events
• Female rats show varying levels of maternal care
→ Characterised by levels of licking and
grooming of the pups
• Maternal care previously has long term nongenomic, effects on the offspring
→ Altered reactivity to stress
→ Altered expression of hippocampal GR
→ High licking and grooming in mother leads to
high licking and grooming in offspring (and
vice versa)
Nature neuroscience 2004 7:847-54
Environment and epigenetics
- programming of by early life events
• Altered DNA methylation
• Altered recruitment of histones
Nature neuroscience 2004 7:847-54
Environment and epigenetics
- programming of by early life events
• Childhood abuse leads to long term
altered expression of Glucorticoid
receptor (GR) expression
McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)
Environment and epigenetics
- programming of by early life events
• Childhood abuse leads to long term
altered expression of Glucorticoid
receptor (GR) expression
• Corresponding changes in
methylation of the neuron
specific GR promoter,
NR3C1
McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)
Environment and epigenetics
- where genes and environment meet
• Genome variation can effect gene function in several ways
→ Changes in encoded product (amino acid sequence)
→ Changes in regulatory regions that effect expression
Environment and epigenetics
- where genes and environment meet
• Genome variation can effect gene function in several ways
→ Changes in encoded product (amino acid sequence)
→ Changes in regulatory regions that effect expression
• Epigenetics influence gene expression
• Epigenetic change may interact with genetic variation
• Provides the molecular link between genes and
environment…
Environment and epigenetics
- where genes and environment meet
Low expressing MAO-A gene
variant interacts with childhood
maltreatment
Effects of 5-HTT gene variant on
depression moderated by care
Science (2003) 301: 386-389
Science (2002) 297: 851-854
PNAS (2004) 101: 17316-17321
Arch Gen Psychiatry (2004) 61:738-44
Biol. Psych. 18 (2006) 59: 673-680
Methylation of the reelin promoter in Schizophrenia
Molecular Mechanisms
– DNA methylation
• DNA methylation usually
correlates with decreased
gene expression
• Generally occurs in regulatory
regions of genes - promoters
and enhancers - not in the
coding regions
Grayson D. R. et.al. PNAS 2005;102:9341-9346