Epigenetics
Clyde Hertzman, MD
Human 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
Pre-school years
High
School years
Numbers
Peer social skills
Symbol
Language
Habitual ways of responding
Emotional control
Vision
Hearing
Low
0
1
2
3
4
Years
5
6
7
Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)
Hypothesis: Biological
embedding
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.
Archeology of Biological Embedding
Experience/Behavior
Neural Circuitry
Cell/Synapse
Gene Expression
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
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 and
Modulation of Gene Expression
Maternal Diet Affects Epigenetic Gene
Regulation in Isogenic Offspring (Avy /a)
Young Mice
Adult Mice
Obese
Low
High Avy DNA Methylation
High
Low
Low
High Maternal Methyl
Lean
Avy Expression
Randy Jirtle Duke
Waterland MCB 2003
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
Health
RNA
IL6
Gene
DNA
Social signal-transduction
Social
processes
CNS
function
Peripheral
neurobiology
Cell signal
transduction
Transcription
factors
Genome
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 Focus
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
Thank You
www.earlylearning.ubc.ca
Our Funders: