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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:
