Epigenetics and Clinical Interventions: Implications and Strategies (79 characters)

1. EPIGENETICS AND IMPLICATIONS FOR CLINICAL INTERVENTIONS AND PREVENTION STRATEGIES. ACBS 2015 Josephine Loftus Centre Hospitalier Princesse Grace Monaco (jloftus@chpg.mc)

2. • At the launch of the Human Genome Project: • « We used to think that our fate was in the stars. Now we know that , in large measure, our fate is in our genes. » • Watson (Jaroff, 1989)

3. • « The gene------- may have no fixity at all; its existence is both transitory and contingent, depending cticially on the functional dynamics of the entire organism » • (Keller, 2000)

4. • Epigenetics (« above the genes »): the study of how the environment infuences gene expression • Epigenetic mechanisms can shape gene expression over a few minutes, an hour, a lifetime and can even shape gene expression in the next generation. • • • DNA methylation Histone modification Interfering RNA •

5. How do environmental influences get under the skin and embed themselves in the genome? • Behaviour shapes gene expression through epigenetic mechanisms and gene expression shapes behaviour • Certain environments can turn on or off specific genes • Epigenetic status can be changed by: Nutrition, chemical substances, medication, Through behavioural programming and early experience (maltreatment, parental stress)

6. ANIMAL STUDIES: How can specific behaviours affect gene expression? • Preconception :parental olfactory experience in mice influences behavior and neural structure in subsequent generations through hypomethylation of an olfactory receptors. (Dias and Ressler, 2014) • Prenatal stress: Male offspring: exhibited behaviours associated with depression following exposure to stress ((Muller and Bale, 2008) • Hypomethylation of corticotrophin releasing hormone (CRH) Hypermethylation of the glucocorticoid receptor gene • Increased activation of HPA axis • decreased receptivity and negative feedback to cortisone • Offspring’s capapcity to regulate the HPA axis diminished

7. POST NATAL: Maternal nurturing: • Rodent offpsring of mothers with high levels of licking and grooming (LG) and arched back nursing (ABN) are less anxious as adults, do better in spatial learning and memory tasks, • • Low LG and ABN pups:over active stress response , nervous, fearful More methylation <transcription < glucocorticoid receptors> cortisone • Other epigenetic mechanisms: methylation of oestrogen receptor genes (Champagne, 2006) increased methylation of gene for brain derived neurotophic factor (BDNF, a neural growth factor) Sweat et al, 2012 •

8. Separation in infancy • Mice: separated from mother for 3 days • Higher corticosterone levels • Increased arginine vasopressin (potentiates CRH and increases HPA activity) • Hypomethylated DNA in the regulatory region of the AVP gene • Early life stress: enhanced performance in stress related memory tasks. Correlation with reduced histone methylation of a BDNF promoter. Beneficial effects lost in middle age (Suri et al 2012)

9. Humans: epigenetic impact of the environment • Depressive mothers in the third trimester of pregnancy: hypermethylated GR promoters and higher cortisol responses in 3 month old babies (Oberlander et al, (2008) • Infants born by CS : increased DNA methylation in the first 3-5 days • More methylated and fewer expressed genes in institutionalised children ((Naumova et al (2012) • Methylated genes : the control of immune response , cellular signalling systems, the biosynthesis of hormones, neurotransmitters , the control of receptor activity including that of the HPA system

10. Childhood stress exposure and DNA methylation in adolescence.(Essex et al,2013) • 1)Maternal stress during infancy : increased methylation • 2) Develomental time frames: • Maternal stressors in infancy more potently predictive • Paternal stressors during the preschool years more predictive • 3) Paternal stress stongly associated with epigenetic modifications in girls • Mothers’ more related to those of both sexes • Maternal PTSD : increased risk for PTSD in offspring (Yehuda et al, 2008)-effect greater if parental PTSD present

11. Clinical consequences • Adverse environment • Fewer plasticity related genes expressed • Potential to learn and adapt decreased • Memory affected` • Less flexibility, more rigid and stereotyped responses • Increased psychopathology ((schizoprenia, depression, addiciton, anxiety disorder, bipolar disorder) and • Increased risk of medical illnesses

12. Post-mortem brain studies • Level of DNA methylation in the neuron-specific GR receptor (NR3C1) promoter sites was signigicantly higher in the hippocampi of abused suicide victims compared with non- abused and control subjects. • Labonte et al (2012) • Male victims of severe child abuse (25 vs 16 controls) fewer genes actively transcribed • Genes related to plasticity- learning and adaptive mechanisms: in the top 5 hypermethylated

13. Interventions • PSYCHOTHERAPY: enriched environment • Enhance neural plasticity, learning , memory, flexibility • RODENTS: enriched environment ; less methylation: mitigate the effects of prenatal distress or separation • BDNF- gene: very responsive to the environment • NUTRITION: • MEDICATION: Down regulation of BDNF: reversed by chronic imipramine treatment • SOCIAL CONTEXT

14. PTSD veterans and exposure psychotherapy (pilot study-Yehuda et al, 2013) • Responders vs non-responders (16) • Decreased methylating of gene regulating GR receptivity in responders • Intensive DBT and Borderline Peronsality Disorder( Perroud et al 2011) Responders: decrease in methylation status (BDNF) Non-responders: increase in methylation status

15. Prevention in vulnerable high risk populations (What do we already know?) • Studies of children of parents with bipolar disorder • Birth complications: low birth weight, increased risk of prematurity, microcephaly, hyperglycaemia and caeserian section • (Boden et al, 2012, Lee et al, 2010) • Children of parents with bipolar disorder: 70% psychopathology (externalising and agressive behaviours, anxiety, depressive symptoms, addiction) • Risk factors: familial stress; environment; social factors

16. Prevention • Preconception: nutrition (vitamin B12 and folate), social problems • Prenatally: anxiety, depression, nutrition support • Post-natal: attachment, support • Childhood and adolescence

17. TARGETED INTERVENTIONS (Vallarino et al,in press) 10 high risk studies (RCT and case series) Children of BP parents • Main interventions : family, cognitive behavioural and interpersonal therapies, MBCT,not all studies finished. • 40% of participants in the studies with high risk participants were already receiving psychotropics • Results mixed: improved functioning; less conversion to BP on follow-up, diminished anxiety and mood symptoms

18. Questions asked by Vallarino et al • Will individuals at high risk of bipolar disorder who are asymptomatic engage with or require a therapy? • Which interventions should be offered? • Should the goal be on health promotion (such as sleep hygiene) ? • Transdiagnostic approaches better than order specific approaches?

19. ACT for prevention • Transdiagnostic • Processes not symptoms • More acceptable • Flexible • Well-being

20. CONCLUSION • An appreciation of epigenetics inspires compassion for those of us who come into the world vigilant and defensive, our epigenetic legacy anticipating a harsh world, a dangerous place to live, yet it also inspires hope, for even the most epigenetically defensive stance is , by its very nature,responsive to the novelty of benign and benevolent environments (Haley Peckham, 2013),

21. • THANK YOU FOR YOUR ATTENTION