Post on 05-Jan-2016
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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