Rutten is3
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- DNMT3a, a gene involved in DNA methylation, appears to moderate stress sensitivity based on studies linking a variant of the gene to increased negative affect in response to daily stressors. - Expression of the DNMT3a protein is highest in regions of the brain associated with neurogenesis, and in newborn neurons, suggesting its role in establishing methylation patterns may be related to neuroplasticity and adaptation to stress. - Mice less susceptible to severe chronic stress had higher densities of cells with high DNMT3a expression levels in the hippocampus, indicating epigenetic mechanisms involving this gene may influence resilience to stressors.
Rutten is3
- 1. Neurobiology of resilience A role for epigenetics in linking psychological and biological aspects? Bart P.F. Rutten, M.D. PhD., July 2nd, 2014 Maastricht University Medical Centre, Maastricht, the Netherlands
- 2. Content • Resilience • Genetic moderation of sensitivity to stress by DNMT3a • DNMT3a and neuroplasticity • DNMT3a and (un)susceptibility to severe chronic stress • Conclusions
- 3. trauma Well being Psychopathology time trauma Well being Psychopathology time A B MODEL OF RESILIENCE TRAJECTORIES OF RISK & RESILIENCE Rutten et al. Acta Psych. Scan, 2014
- 4. Integrating Nurture and Nature Van Os, Kenis, Rutten. Nature 2010
- 5. DNA RNA Protein promoter exon 1 exon 2 SNP/mutation quantity quality Cell functions gene GTCATTAAACAGGT GTCATTACACAGGT
- 6. Genes related to (un)susceptibility to stress Wu, Feder, et al. Front Behav Neurosci 2013
- 7. Epigenetics & the environment ENVIRONMENT changes in phenotype and/or gene expression by mechanisms other than changes in the DNA sequence itself Maternal care during early life has persistent influence on later-life behaviour and molecules in the stress-system via the epigenetic mechanism of DNA methylation (team of Michael Meaney and others)
- 8. I. blocks transcription factors DNA Methylation ↓Gene Transcription promoter exon 1 exon 2 quantity gene methyl
- 9. DNA methylation is performed by DNA methyltransferases promoter exon 1 exon 2 gene methyl DNMT1 DNMT3a DNMT3b We determined the genetic variability in these genes 29 genetic variant in genes of DNMT1, DNMT3a and DNMT3b Pishva et al. PlosOne 2014
- 10. Stress sensitivity = increases in negative affect after unpleasant activities or events Daily Life Stress Sensitivity event High stress sensitivity Low stress sensitivity eventeventevent Pishva et al. PlosOne 2014 10 times a day 6 consecutive days at random moments multiple assessments real world, no lab in the moment, not retrospective Evaluation of the context The Experience Sampling Method (ESM)
- 11. Stress sensitivity and DNMT3a genotype a multistep replication study Pishva et al. PlosOne 2014 Cohort 1 Cohort 2 Cohort 3 However, no influence of the genetic variants on reward experience, i.e. the experience of positive affect after pleasant stimuli
- 12. Psychotic reactivity = increases in paranoid ideations after socially unpleasant events High psychotic reactivity Low psychotic reactivity social event Pishva et al. PlosOne 2014 social event social event social event Gene SNP Sample I (healthy) Sample II (twins) Sample III (Patients) Sample IV (Siblings) Sample V (Depress.) Dnmt3a rs13401241 p=0.0000 p=0.0373 - p=0.0010 -
- 13. Expression of DNMT3a in the mouse brain 1) subgranular zone dentate gyrus of the hippocampus DNMT3a protein Distinct cells are highly immunoreactive, these cells are found in: 2) subventricular zone 3) olfactory bulb 4) rostral migratory stream Hammels et al. in review
- 14. GFAP DCX Nestin, Ki-67 NeuN DNMT3a involved in neurogenesis? Establishment of methylation patterns?
- 15. High levels of DNMT3a in newborn neurons GFAP DCX Nestin, Ki-67 NeuN Dnmt3a DCXDnmt3a NeuNDnmt3a GFAP
- 16. ** p<0.01; (*) p=0.05 control susceptible resilient 0 10000 20000 30000 40000 50000 ** celldensity(cells/mm3) (*) Hammels et al. under review (same genetic background in all mice) Mice unsusceptible to severe stress have more cells with high levels of DNMT3a
- 17. Conclusions • Deep phenotyping with experience sampling methodology allows for – studying dynamics in positive and negative affect – dissection of genetic influences on emotional reactivity in daily life • A gene involved in DNA methylation (i.e. DNMT3a) moderates stress-sensitivity • DNMT3a is highly expressed in newborn neurons in the adult brain (at least in mice) • Thus, DNA methylation seems to be relevant for active adaptation to stressors
- 18. Many thanks for your attention
- 19. Acknowledgments