Epigenetics

Clyde Hertzman, MDHuman Early Learning Partnership

University of British Columbia, Vancouver

The Challenge of the Gradient

• ubiquitous in wealthy and majority world countries by income, education, or occupation

• cuts across a wide range of disease processes

• not explained by traditional risk factors

• replicates itself on new conditions as they emerge

• occurs among males and females

• ‘flattens up’

• begins life as gradient in ‘developmental health’

Sensitive Periods in Early Brain Development

Vision

0 1 2 3 7654

High

Low

Years

Habitual ways of respondingEmotional

control

Symbol

Peer social skillsNumbers

Hearing

Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)

Pre-school years School years

Language

Biological embedding occurs when

• experience gets under the skin and alters human biodevelopment;

• systematic differences in experience in different social environments lead to different biodevelopmental states;

• the differences are stable and long-term;they influence health, well-being, learning, and/or behaviour over the life course.

Hypothesis: Biological embedding

Archeology of Biological EmbeddingArcheology of Biological EmbeddingArcheology of Biological EmbeddingArcheology of Biological Embedding

Experience/BehaviorExperience/BehaviorExperience/BehaviorExperience/Behavior

Gene ExpressionGene ExpressionGene ExpressionGene Expression

Cell/SynapseCell/SynapseCell/SynapseCell/Synapse

Neural CircuitryNeural CircuitryNeural CircuitryNeural Circuitry

Shallow Archeology

Candidate Systems• HPA axis --- cortisol

• ANS system --- epinephrine/ne

• Prefrontal cortex

• Social affiliation --- amygdala/locus cereleus

• Immune function -- the ‘peripheral brain’

SES Differences in Prefrontal Cortex Activity by School Age

Deep Archeology

‘Social Epigenesis’ and other processes that can influence

gene expression.

Epigenetics

Alterations to the DNA, other than changes to the genes themselves, that:

• are passed on with cell division

• can change normal gene expression

• can be caused by (early) experience

Most well-studied epigenetic mechanism = methylation of

cytosine on the DNA

If methylation occurs in an active stretch of DNA, especially

a promoter region, gene expression will likely change

The Dynamic Epigenome andThe Dynamic Epigenome andModulation of Gene ExpressionModulation of Gene ExpressionThe Dynamic Epigenome andThe Dynamic Epigenome and

Modulation of Gene ExpressionModulation of Gene Expression

Maternal Diet Affects Epigenetic Gene Regulation in Isogenic Offspring (Avy /a)

Avy Expression

Avy DNA Methylation

High

HighLow

Low

Maternal Methyl

HighLow

Randy Jirtle DukeWaterland MCB 2003

Young Mice Adult Mice

Obese Lean

What’s new about this?

It does not only occur during basic fetal development, when cells are specializing……it can

continue after birth and be influenced by the broader

environment!

Social Environment

Gene

Health

IL6

RNA

DNA

Genome

Socialprocesses

CNSfunction

Peripheralneurobiology

Cell signal transduction

Transcriptionfactors

Social signal-transduction

Epigenesis at Work?

• Rats – Mothers licking pups

• Monkeys – Peer vs mother rearing

• Humans - Suicide Brains, Dunedin Cohort

The ‘Meaney-Szyf Paradigm’ I

• rat pups from high and low licking/suckling mothers cross-fostered to remove genetic effect

• differential qualities of nurturance occurs during sensitive period of brain development

• differential nurturance leads to epigenetic modification of key DNA regulatory loci through methylation

The ‘Meaney-Szyf Paradigm’ II

• epigenetic modification leads to lifelong change in HPA axis response to stress

• this change affects learning and behaviour across the rat life course

• inter-generational transmission (high licked female pups become high licking mothers, and vice versa)

Epigenesis at Work?

• Rats – Mothers licking pups

• Monkeys – Peer vs mother rearing

• Humans – Various

1958 cohort, WBC’s, age 45

• 1252 loci differentially methylated according to childhood SES (smaller signatures for adult SES and social mobility)

• 794 loci differentially methylated by maternal smoking

• >1000 loci differentially methylated by retrospective reports of abuse in childhood

Different populations?

The Wisconsin Study of Families and Work

• methylation differences according to mother stress in first 18 months, not father’s stress…… but in pre-school age, father’s stress, not mother’s, influences DNA methylation

The BC GECKO Study: ‘On and Off-diagonal children’ in ‘On and Off-diagonal neighbourhoods’

Common FocusCommon Focus

Developmental neurogenomics: how developmental environments and epigenetic variation work together to produce social disparities in child health and development

Developmental neurogenomics: how developmental environments and epigenetic variation work together to produce social disparities in child health and development

BC capacity

• Kobor lab -- social epigenetics facility; multiple funding sources

• 450,000 CpG island capacity; covering all genes

• emerging as reference facility for Canada, US, and global studies

www.earlylearning.ubc.cwww.earlylearning.ubc.caa

Thank YouThank You

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