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Lecture 9

BIOC14Winter2013 Lecture 9 Notes.docx

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Department
Biological Sciences
Course
BIOC14H3
Professor
Patrick Mc Gowan
Semester
Winter

Description
BIOC14Winter2013 Lecture 9: Environmental Epigenetics and Transgenerational Epigenetic Inheritance The developmental program o Performationism: the idea that development unfolds without environmental input, developing from miniature versions of themselves o Gene centric view: DNA  RNA  Protein  Function ** This is not always true! o Also influenced other ideas of human developmental stages like Freud and Piaget o Jean piaget: father of developmental psych, created a developmental steps for cognitive growth, each step was a foundation for the next o Freud: predefined stages of development: no reversion o To date, very little prediction of phenotype or complex disease risk from knowledge of gene sequence  like SNPs o Genetic data alone is insufficient to explain phenotype  needs additional factors One genome, many epigenomes o Epigenetic = above the genome o Epigenetics = the study of changes in gene expression caused by mechanisms other than DNA sequence variation o 200+ cell types are generated form a virtually identical genome via epigenetic mechanism o epigenetic changes can be mitotically or meiotically heritable Epigenetic landscape o original meaning  role of gene regulation in development o current meaning  combined modifications to DNA (stochastic – random , environmenta) that give rise to phenotype o same genes but different gene expression  phenotypes differ among monozygotic twins Epigenetic regulation of gene expression o 3 components of the epigenome: o 1) histone proteins  bound to DNA and regulate accessibility of transcritption factos o 2) DNA methylation  covalently bound to DNA itself  an interface between a dynamic environment and a static genome – more DNA methylation means decreased gene expression (DNA methylation increases with age) o 3) Non-coding RNA: control the expression of other genes o epigenetic differences among monozygotic twins increases with age  goes hand in hand with the fact that DNA methylation also increases with age Classic role of DNA methylation: Transcriptional repression o DNA methylation blocks transcription factor binding  promoters, enhancers etc. o Increased DNA methylation = decreased gene expression ?  The Histone Code: Covalent modifications of the N terminal tail of histones Early life adversity and later life mental health o Suicide  a leading cause of death worldwide o Linked to but not predicted by mental disorders and adversity early in life o Genetic and non genetic factors contribute o Changes in gene expression in the brain associate with suicide The Stress Response o The HPA axis (hypothalamic pituitary adrenal axis)  negative feedback loop The stress response The stress response o Cortisol is in the blood, travels to bran stem and binds, shutting down a further stress response o Disruption in this feedback results in continued cortisol release resulting in neurotoxicity and anxiety v v v o o glucocorticoid receptors (GRs): bind glucocorticoids and inhibit the stress response o increased GRs = decreased stress response o more receptors shut down the stress response faster The HPA axis: A negative feedbackThe HPA axis: A negative feedback loop. Glucocorticoid receptors (GRs): Bind glucocorticoids and inhibit Bind glucocorticoids and inhibit the stress response. Increased GR = Decreased stress responseed GR = Decreased stress response o rats show natural variations in maternal care o Adoption studies: baby that is born biologically to a mother who s a high licker and groomer, and then adopted by low LG mom will still grow to be anxious and have the same characteristics as the adoptive mother Rats show natural variations in maternal care! LG LG GR gene expression Programming of Glucocorticoid ReceptorSTRESS RESPONSE o o high licking and grooming = high GR expression = high GRs = decreased stress response LOW LG HIGH LG n1.2 t1.0 l h0.8 e0.6 M a0.4 e0.2 * * M 0 * EMBRYO BIRTH PUP WEANING ADULT DAY 20 DAY 1 DAY 6 DAY 21 DAY 90 Age o o high LG pups have decreased DNA methylation than low LG pups EpigeneticEpigenetic regulation of the GR gene in(GR) by childhood adversity o childhood adversity: alters stress response and increases suicide risk o hippocampus from: suicides (abuse in childhood), suicides (non abused), and controls (died of causes other than suicide, like heart attack, car accident etc.) o o abused suicide victims had higher methylation and lower GR expression than non abused suicide DNA methylation of Glucocorticoid Receptor (GR) Methylation in human brain associates with childhood abuse DNA methylation of GR in human brain associates with childhood abuse 40 Control q35 Suicide Nona-bused f30 Suicide Abused n25 a20 h15 e10 M 5
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