Epigenetic Regulation in the Nervous System

Chapter 1 An Overview of the Molecular Basis of Epigenetics

1.Introduction2.DNA Modification3.Histone Modification4.Non-coding RNAs5.Non-genic DNA6.Prion-based Epigenetic inheritance7.Epigenome organization and higher order chromatin structures8.Roles for epigenetic mechanisms in the nervous system9.Epigenetic mechanisms in nervous system development10.Neurogenesis in the adult CNS11.Circadian rhythms12.Persisting effects of life experience: nurturing and transgenerational effects13.Epigenetic Mechanisms and cellular information storage14.Human cognition and cognitive disorders

Epigenetics3 definitions:a. transmission and perpetuation of information

not based on DNA sequenceb. meiotically and mitotically heritable changes

in gene expression that are not coded in the DNA sequence itself

c. epigenetics is the mechanism for stable maintenance of gene expression changes that involves physically marking DNA or its associated proteins

common theme:epigenetics is a mechanism for storing and perpetuating a “memory” at the cellular level.

Neuroepigenetics vs Traditional Epigenetics epigenetic marks once laid down, are immutable and

inheritable across cell divisions

epigenetic molecular help drive acquired experience-dependent modifications in cognition and behavior

heritability epigenetic molecular changes can occur in cells but not necessarily be heritable

Nature vs Nurture

DNA modifications

DNMT3a, 3b DNMT1

CpG: ~70% is methylatedmethylated cytosines: <3% at 5’ end of genes 97% in intra- and intergenic and within repeat

CpG islands: unmethylated CpG, occur both near TSS and intragenically

DNMTS

FunctionIn most case: suppress gene transcription

The effect of methylation depend on the location of the methylated CpGs:promoter: suppression of gene transcriptiongene body: increase in transcriptional activity

DNA methylation-dependent gene silencing

MBP: MeCP2, MBD1, MBD2, MBD4, Kaiso

Active Regulation of DNA Demethylationpassive: cell division and failure to replicate DNA methylation marksactive: direct chemical removal of methyl groups; embryonic development demethylation and remethylation

active demethylation in mature CNS:a. DNMT inhibitor application or behavioral

trainingb. cycling of methyl-cytosine in cultured cells

hmC in active demethylation

HmC most in the totipotent fertilized zygote and the CNS neuron

TET-family

Histone Modificationsnucleosome

H2A, 2B, H3, H4

post-translational modifications of histones

human histone H3: acetylation(A), Phosphorylation(P) and methylation(M)

Acetylation

a. occurs at lysine residues, effectively neutralizes their positive chargeb. reversible process:

acetyltransferases: HATsdeacetyltransferases: HDACs

HDACZn2+-dependent charge-relay systemClass I: HDACs 1, 2, 3, 8Class II: HDAC 4,5,6,7,9,10,11

NAD+-dependent mechanismClass III: Sirtuins

HDAC inhibitors in pharmaceutical industry

potential applicability in cancer treatment;utility in neurological and psychiatric disorders

TsA: Class I, II HDACsSAHA, MS275: Class I HDACsTubacin: HDAC6Valproate: several additional targets as lysine acetylation not only occur in histone, but also cellular proteins

Histone Methylation residues methyltransferase kinds of methyl

lysine KMTs mono-, di-, tri-

arginine PRMTs mono-, di-

Histone UbiquitinationUbiquitin: 76 aa ubiquitous distribution in all cell types; high degree of conservation across species; usually as a signal for degradation by proteasome Ubiquitination: H2A, H2B, H3,H1 mono-, poly-role in the control of gene transcription in the nervous system remains poorly understood

Histone Phosphorylation

H1,H3P- chromosome condensation during mitosisH3S10P in the CNS: Rsk2;ERK;MAPK;Ipl1H3S28 : surora kinasesregulation by PP1, PP2A, DARPP32 function: gene activation

Histone Subunit Exchange

histone variantsH3: H3.1, H3.1, H3.3H2: H2 A.Z, MacroH2A

Histone Code for Regulating CNS Function

multiple histone modifications may be integrated together, driving neuronal gene expression patterns by recruiting signaling complexes and thereby remodeling the structure of chromatin.

Other Mechanisms of Epigenetic Tagging in the CNS1)non-coding RNA:

a. small RNAs: microRNAs, siRNAs, snRNAsmultiple functions within a cell, including

activation, repression, or interference with gene expression, cognitive disorders

b. long non-coding RNAs>200bp, can be spliced like mRNAs to form

active biological molecules, including small RNAs2)Non-genic DNA:

dynamic DNA/histone changes in association with the presence of DNA repeat sequences

Prion-based Epigenetic Inheritance

inactive prion

active prion

exogenoussignal

inactive prion

active prion

prion proteins establish a self-perpetuating biochemical reaction

Epigenetic Mechanisms in the Nervous Development

REST-binding proteinsSin3A: most REST-dependent gene repression might be co-mediated by Sin3AREST/Sin3A is associated with HDAC1

CoREST: is important in mediating specific gene expression patterns in subtypes of cellsREST/CoREST complex with HDAC2;associate with hSWI-SNF complex<deacetylation and DNA methylation>

REST may control dynamic, activity-dependent changes in gene expression within fully differentiated adult neurons

Neurogenesis in the Adult CNSthere is no new generation of neurons in the adult CNS

neurogenesis continue into adult in a small number of brain regions, including the hippocampal dentate gyrus

Circadian RhythmsCircadian rhythms are generated endogenously by circadian clock, which comprises intricate feedback loops of transcription and translation, and the feedback loops is to be modulated by epigenetic mechanisms.For example, H3, H4 acetylation is associated with the promoters of genes that form core molecular clock mechanism are differentially regulated;infusion of HDAC inhibitor trichostatin A into the SCN increases the expression of the clock genes mPer1 and mPer2

Persisting Effects of Life Experience: Nurturing and Transgenerational Effects

Mothers rats exhibit strong nurturing behaviors produce lasting alterations in the patterns of DNA methylation in CNS of their pups, result in decreased anxiety-like behavior and a strong maternal nurturing instinct in the adult offspring

a. experientially acquired alterations in DNA methylation affect behaviors in the adult

b. epigenetic mechanisms’ cellular memory in the CNS

c. transgenerational perpetuation of acquired epigenetic marks

Epigenetic Mechanisms and Cellular Information Storage

at the cellular level is response to transient environmental signals. is similar to behavioral memory storage in the adult nervous system.

mammalian cells: DNA methylation at specific sites that are acquired as part of the differentiation process but are self-perpetuating during DNA replication and cell division.plant: biennial plant flower

cold: activation of epigenetic(M,A)T-cells in mammalian immune system

Human Cognition and Cognitive Disorders