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Lecture 9

BIOC14H3 Lecture Notes - Lecture 9: Glucocorticoid, Non-Coding Rna, Epigenome


Department
Biological Sciences
Course Code
BIOC14H3
Professor
Patrick Mc Gowan
Lecture
9

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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

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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
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
Programming of gene expression by maternal behavior in rats
o in rats, maternal care consists mainly of licking and grooming (LG)
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
o
o high licking and grooming = high GR expression = high GRs = decreased stress response
o
The stress response
The HPA axis: A negative feedback loop.
Glucocorticoid receptors (GRs): Bind glucocorticoids and inhibit
the stress response. Increased GR = Decreased stress response
The stress response
v v
v v
The HPA axis: A negative feedback loop.
Glucocorticoid receptors (GRs): Bind glucocorticoids and inhibit
the stress response. Increased GR = Decreased stress response
Rats show natural variations in maternal care!
GR gene expression
STRESS RESPONSE
LG LG
Programming of Glucocorticoid Receptor
DNA methylation in rats
LOW LG
HIGH LG
Mean Methylation
0
0.2
0.4
0.6
0.8
1.0
1.2
EMBRYO
DAY 20
BIRTH
DAY 1
ADULT
DAY 90
WEANING
DAY 21
PUP
DAY 6
Age
* * *
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