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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).

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Epigenetics and the brain the nature of nurture

Epigenetics and the brain; the nature of nurture?

Anthony Isles

Behavioural Genetics Group

Cardiff University


What is epigenetics
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 epigenetics1
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 epigenetics2
What is epigenetics?

Regulation, timing and level of gene expression

Undifferentiated parent cell


What is epigenetics3

XXXXXXXXXXX

What is epigenetics?

Regulation, timing and level of gene expression

Liver cell

XXXXXXXXXXX

Undifferentiated parent cell


What is epigenetics4

XXXXXXXXXXX

XXXXX

XXXXX

What is epigenetics?

Regulation, timing and level of gene expression

XXXXX

XXXXX

Liver cell

Neural cell

Undifferentiated parent cell


What is epigenetics5

XXXXXXXXXXX

XXXXX

XXXXX

What is epigenetics?

Regulation, timing and level of gene expression

XXXXX

XXXXX

Differentiation

Liver cell

Neural cell

Undifferentiated parent cell


What is epigenetics6

XXXXXXXXXXX

XXXXXXXXXXX

XXXXX

XXXXX

XXXXX

XXXXX

Neural cell

Neural cell

Liver cell

What is epigenetics?

Regulation, timing and level of gene expression

Liver cell

Maintenance of cellular identity


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


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
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 & Nestler2007 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 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

  • Altered DNA methylation

  • Altered recruitment of histones

Nature neuroscience 2004 7:847-54


Environment and epigenetics- programming of by early life events

McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)


  • Corresponding changes in methylation of the neuron specific GR promoter, NR3C1

Environment and epigenetics- programming of by early life events

McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)


Environment and epigenetics Glucorticoid receptor (GR) expression- 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 Glucorticoid receptor (GR) expression- 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…


Science Glucorticoid receptor (GR) expression (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

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


Molecular Mechanisms Glucorticoid receptor (GR) expression– 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 2005;102:9341-9346


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