epigenetics and the brain; the nature of nurture? anthony isles behavioural genetics group cardiff...
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Epigenetics and the brain; the nature of nurture?
Anthony Isles
Behavioural Genetics Group
Cardiff University
“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)
What is epigenetics?
• Development and differentiation
• Maintenance of cellular identity
Regulation, timing and level of gene expression
What is epigenetics?
Undifferentiated parent cell
Regulation, timing and level of gene expression
What is epigenetics?
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Liver cell
Undifferentiated parent cell
Regulation, timing and level of gene expression
What is epigenetics?
XXXXXXXXXXX
Liver cell
Undifferentiated parent cell
XXXXX XXXXX
XXXXX XXXXX
Neural cell
Regulation, timing and level of gene expression
What is epigenetics?
XXXXXXXXXXX
Liver cell
Undifferentiated parent cell
XXXXX XXXXX
XXXXX XXXXX
Neural cell
Differentiation
Regulation, timing and level of gene expression
What is epigenetics?
XXXXXXXXXXX
Liver cell
XXXXX XXXXX
Neural cell
XXXXXXXXXXX
Liver cell
XXXXX XXXXX
Neural cell
Maintenance of cellular identity
Molecular Mechanisms
• 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
• How is molecular control of gene expression exerted?
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
Epigenetic mechanisms and neurodevelopment disorders
Epigenetics important in cell differentiation and maintenance
• Rett syndrome
• Rubinstein-Taybi syndrome
• Angelman/Prader-Willi
Aberrant DNA-methylation (MECP2)
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)
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
• Identical twins have identical DNA
• Global differences in epigenetic status
between twins increases with age
Fraga et al. (2005) PNAS 102, 10604-10609
Environment and epigenetics- encoding life events
Increased differences in methlyation
• Green: areas of hypermethlyation
• Red: areas hypomethylation
• Yellow: equal levels of methylation
• Identical twins have identical DNA
• Global differences in epigenetic status
between twins increases with age
Fraga et al. (2005) PNAS 102, 10604-10609
Environment and epigenetics- encoding life events
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
• Female rats show varying levels of maternal care
→ Characterised by levels of licking and
grooming of the pups
• Maternal care previously has long term non-
genomic, 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
Nature neuroscience 2004 7:847-54
Environment and epigenetics- programming of by early life events
• Altered DNA methylation
• Altered recruitment of histones
Environment and epigenetics- programming of by early life events
McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)
• Childhood abuse leads to long term altered expression of Glucorticoid receptor (GR) expression
Environment and epigenetics- programming of by early life events
McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)
• Childhood abuse leads to long term altered expression of Glucorticoid receptor (GR) expression
• Corresponding changes in methylation of the neuron specific GR promoter, NR3C1
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…
PNAS (2004) 101: 17316-17321
Science (2002) 297: 851-854
Science (2003) 301: 386-389
Biol. Psych. 18 (2006) 59: 673-680
Arch Gen Psychiatry (2004) 61:738-44
Low expressing MAO-A gene variant interacts with childhood maltreatment
Effects of 5-HTT gene variant on depression moderated by care
Environment and epigenetics- where genes and environment meet
• 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
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– DNA methylation