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 XXXXXXXXXXX Liver cell XXXXXXXXXXX Undifferentiated parent cell

What is epigenetics?

Regulation, timing and level of gene expression XXXXX XXXXXXXXXXX XXXXX Liver cell Neural cell XXXXX XXXXX Undifferentiated parent cell

What is epigenetics?

Regulation, timing and level of gene expression XXXXX XXXXXXXXXXX XXXXX Differentiation Liver cell Neural cell XXXXX XXXXX Undifferentiated parent cell

What is epigenetics?

Regulation, timing and level of gene expression XXXXXXXXXXX Liver cell Maintenance of cellular identity XXXXX Neural cell XXXXX XXXXXXXXXXX Liver cell XXXXX Neural cell XXXXX

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;

a

denosine,

g

uanine,

t

yrosine and

c

ytosine (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 • 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)

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

hyper

methlyation • Red: areas

hypo

methylation • 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

hyper

methlyation • Red: areas

hypo

methylation • 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 • 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

(2002) 297: 851-854

Arch Gen Psychiatry

(2004) 61:738-44

Science

(2003) 301: 386-389

PNAS

(2004) 101: 17316-17321

Biol. Psych.

18 (2006) 59: 673-680

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