Epigenetics and the brain; the nature of nurture?

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Epigenetics and the brain the nature of nurture?

• Anthony Isles
• Behavioural Genetics Group
• Cardiff University

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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)

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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

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What is epigenetics?

• Regulation, timing and level of gene expression

Undifferentiated parent cell
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What is epigenetics?

• Regulation, timing and level of gene expression

Liver cell
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Undifferentiated parent cell
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What is epigenetics?

• Regulation, timing and level of gene expression

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XXXXX
Liver cell
Neural cell
Undifferentiated parent cell
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What is epigenetics?

• Regulation, timing and level of gene expression

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XXXXX
Differentiation
Liver cell
Neural cell
Undifferentiated parent cell
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What is epigenetics?

• Regulation, timing and level of gene expression

Liver cell
Maintenance of cellular identity
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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

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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

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Molecular Mechanisms histone modifications
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Molecular Mechanisms histone modifications

• Modifications of residues in the histone tails
• gt40 possible modifications
• Modification alter 3-D structure and make DNA
  more, or less, accessible
• Acetylation found in regions of increased gene
  expression

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Molecular Mechanisms histone modifications

• Modifications of residues in the histone tails
• gt40 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
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The relevance of epigenetics to brain function
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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)

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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)

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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

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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
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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
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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
  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 7847-54
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Environment and epigenetics- programming of by
early life events

• Altered DNA methylation
• Altered recruitment of histones

Nature neuroscience 2004 7847-54
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Environment and epigenetics- programming of by
early life events
McGowan et al. Nature Neuroscience 12, 342 - 348
(2009)
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Environment and epigenetics- programming of by
early life events
McGowan et al. Nature Neuroscience 12, 342 - 348
(2009)
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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

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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

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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
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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              

Methylation of the reelin promoter in
Schizophrenia
Grayson D. R. et.al. PNAS 20051029341-9346