Clyde Hertzman, MD Human Early Learning Partnership University of British Columbia, Vancouver

1. Clyde Hertzman, MDHuman Early Learning PartnershipUniversity of British Columbia, Vancouver Epigenetics

2. 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’

3. Sensitive Periods in Early Brain Development Pre-school years School years High Numbers Peer social skills Symbol Sensitivity Language Habitual ways of responding Emotional control Vision Hearing Low 1 2 3 4 5 6 7 0 Years Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)

4. 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.

5. Archeology of Biological Embedding Experience/Behavior Neural Circuitry Cell/Synapse Gene Expression

6. Shallow ArcheologyCandidate Systems • HPA axis --- cortisol • ANS system --- epinephrine/ne • Prefrontal cortex • Social affiliation --- amygdala/locus cereleus • Immune function -- the ‘peripheral brain’

7. SES Differences in Prefrontal Cortex Activity by School Age

8. Deep Archeology‘Social Epigenesis’ and other processes that can influence gene expression.

9. 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

10. 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

11. The Dynamic Epigenome andModulation of Gene Expression

12. Maternal Diet Affects Epigenetic Gene Regulation in Isogenic Offspring (Avy /a) Young Mice Adult Mice Obese Lean Avy DNA Methylation High Low Avy Expression High Low High Maternal Methyl Low Randy Jirtle Duke Waterland MCB 2003

13. 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!

14. Social Environment Health RNA DNA IL6 Gene

15. Social processes Genome Social signal-transduction CNS function Peripheral neurobiology Cell signal transduction Transcription factors

16. Epigenesis at Work? • Rats – Mothers licking pups • Monkeys – Peer vs mother rearing • Humans - Suicide Brains, Dunedin Cohort

17. 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

18. 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)

19. Epigenesis at Work? • Rats – Mothers licking pups • Monkeys – Peer vs mother rearing • Humans – Various

20. 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

21. Different populations? The Wisconsin Study of Families and Work • methylation differences according to mother stress in first 18 months, not father’s stress…… butin 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’

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

23. 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

24. Thank You www.earlylearning.ubc.ca Our Funders: