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BIO SCI N156 Lecture 16: Epigenetic Control of Gene Expression &…
BIO SCI N156 Lecture 16: Epigenetic Control of Gene Expression & Neural Circuit Function
Definition
Wellington
"The branch of biology which studies the causal interactions between genes and their products, which brings the phenotype into being"
"Where nature and nurture" interface
Gene expression in LTM formation
Learning event "converted" into LTM via transcription
DNA is reeled around histones
Nucleosome is the functional unit
Doctrine: Gene activation > mRNA > Protein
Family of epigenetic mechanisms
DNA methylation
Histone PTMs
RNA-based mechanisms
Nucleosomes
Structure
Two major components
147 bp DNA double loop
8 protein histone octomer
Each individual histone has an N-terminal tail
Each tail is positively charged
Modifications to tail will alter its association with DNA
Histone code
Post-translational modifications that can occur on the tail
Methylation
Ubiquitination
Phosophorylation
Acetylation
Regulates transcription and translation machinery's access to genes
Changes to the histone code are permissive, not instructive
Enzymes that regulate histone acetylation: HDACs and HATs
Histone deacetylase (HDACs)
Removes acetyl groups from N-terminal tails
At baseline, HDACs are "peppered" on the genome
Function as the molecular break pads on memory
Histone acetyltransferase (HATs)
Adds acetyl groups to N-terminal tails
After learning event, HDACs are kicked off the chromatin and HATs are brought in to replace them
Tools for manipulating HATs & HDACs
Pharmacological inhibition of HDACs
TSA, valproic acid, RGFP966, sodium butyrate
Global genetic deletion
Transgenic animals with Cre-Lox deletion
Can provide cell-type specificity
Targeted gene deletion
Transgenic animals with targeted delivery of Cre-recombinase
Viral manipulation
Viral over expression or point mutation to endogenous enzymes
Study 1: Does deleting HDACs alter memory formation?
Design:
Delete HDAC3 in the hippocampus
Results:
Retention was enhanced in a 24-hr memory test
Study 2: Does altering HDAC function alter memory formation (con't)?
Design:
Overexposes dominant negative HDAC3 in hippocampus and lateral amygdala
Results:
Context retention in the hippocampus was enhanced
Tone retention was enhanced in the lateral amygdala
Study 3: Loss of HAT function (CBP) alters acetylation and memory formation
Design:
Delete CBP in the hippocampus
Results:
Retention was impaired in a 24-hr memory test
Study 4: Effects of global HDAC3 knockout
Results:
Impaired retention on Morris water maze, object location memory (OLM) task, and contextual fear conditioning
Design:
Significant fewer HDAC3 in hippocampus and cortex (not in striatum)
Epigenetic mechanisms in neuropsychiatric diseases/conditions
Memory declines with aging
Drug-associated and drug-seeking behavior
Acquisition and consolidation of drug memories
Drugs of abuse cause changes to the histone code throughout the reward circuitry