Epigenetic Regulation in the Nervous System

Chapter 1 An Overview of the Molecular Basis of Epigenetics 1.Introduction 2.DNA Modification 3.Histone Modification 4.Non-coding RNAs 5.Non-genic DNA 6.Prion-based Epigenetic inheritance 7.Epigenome organization and higher order chromatin structures 8.Roles for epigenetic mechanisms in the nervous system 9.Epigenetic mechanisms in nervous system development 10.Neurogenesis in the adult CNS 11.Circadian rhythms 12.Persisting effects of life experience: nurturing and transgenerational effects 13.Epigenetic Mechanisms and cellular information storage 14.Human cognition and cognitive disorders

Epigenetics 3 definitions: transmission and perpetuation of information not based on DNA sequence meiotically and mitotically heritable changes in gene expression that are not coded in the DNA sequence itself epigenetics is the mechanism for stable maintenance of gene expression changes that involves physically marking DNA or its associated proteins phenotypes can be inherited by daughter cells are perpetuated past cell division using protein-based mechanisms, such as prion-like mechanism in yeast, but whether such mechanisms operate in mammalian neurons is a subject of current investigation principal criterion for the second definition is heritability<by developmental biologists and cancer researchers> allow genotypically identical cells to be phenotypically distinct(in this definition, the regulation of chromatin structure and attendant DNA chemical modification is equivalent to epigenetic regulation)

common theme: epigenetics is a mechanism for storing and perpetuating a “memory” at the cellular level. a mechanism is necessary for transferring information that concerns the differentiated state of the cell from mother cell to daughter cell the phenotype must be perpetuated through many subsequent cell divisions which dilute any non self-perpetuating chemical marks epigenetic marks are put in place(or remodeled) during cell fate determination and serve as a cellular information storage system perpetuating cellular phenotype over the lifespan<epigenesis>

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 incorrect – separate and distinct influence of genes and environment on behavior environment and experience act in part through altering gene readout in the CNS in order to achieve their effects on behavior Nature: genes Nurture: environment and experience intertwined through epigenetic molecular mechanisms----epigenetic mechanisms in the nervous system are the site where experience modifies the genome

DNA modifications DNMT3a, 3b DNMT1 DNMT1,3a, 3b express in most cells including brain, although DNMT3b is low in adult CNS De novo DNMTs place new methylation marks when specific genes are first silenced as part of cell fate determination, and Maintenance DNMTs perpetuate methylation marks after cell division DNMT3a, 3b DNMT1

CpG: ~70% is methylated methylated 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

Function In most case: suppress gene transcription The effect of methylation depend on the location of the methylated CpGs: promoter: suppression of gene transcription gene body: increase in transcriptional activity

DNA methylation-dependent gene silencing MBP: MeCP2, MBD1, MBD2, MBD4, Kaiso

Active Regulation of DNA Demethylation passive: cell division and failure to replicate DNA methylation marks active: direct chemical removal of methyl groups; embryonic development demethylation and remethylation active demethylation in mature CNS: DNMT inhibitor application or behavioral training cycling of methyl-cytosine in cultured cells DNA methylation of the parental genomes is erased in early development followed by a remethylation in later fetal development

hmC in active demethylation TET-family totipotent(全能性的)fertilized zygote and the CNS neuron art the two main cell types in which active DNA demethylation has been most demonstrated HmC most in the totipotent fertilized zygote and the CNS neuron

Histone Modifications nucleosome 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 charge b. reversible process: acetyltransferases: HATs deacetyltransferases: HDACs

HDAC Zn2+-dependent charge-relay system Class I: HDACs 1, 2, 3, 8 Class II: HDAC 4,5,6,7,9,10,11 NAD+-dependent mechanism Class III: Sirtuins

HDAC inhibitors in pharmaceutical industry potential applicability in cancer treatment; utility in neurological and psychiatric disorders TsA: Class I, II HDACs SAHA, MS275: Class I HDACs Tubacin: HDAC6 Valproate: several additional targets as lysine acetylation not only occur in histone, but also cellular proteins any behavioral effect of HDAC inhibitors might be due to alterations in acetylation of any of many intracellular targets

Histone Methylation residues methyltransferase kinds of methyl lysine KMTs mono-, di-, tri- arginine PRMTs mono-, di-

Histone Ubiquitination Ubiquitin: 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 proteasome:蛋白酶体

Histone Phosphorylation H1,H3P- chromosome condensation during mitosis H3S10P in the CNS: Rsk2;ERK;MAPK;Ipl1 H3S28 : surora kinases regulation by PP1, PP2A, DARPP32 function: gene activation DARPP32 is inhibitor of PP1

Histone Subunit Exchange histone variants H3: H3.1, H3.1, H3.3 H2: H2 A.Z, MacroH2A histone isomers role: absence of DNA methylation and transcriptional activation Chromatin remodeling enzymes: 染色质重塑酶

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 CNS 1)non-coding RNA: a. small RNAs: microRNAs, siRNAs, snRNAs multiple 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 RNAs 2)Non-genic DNA: dynamic DNA/histone changes in association with the presence of DNA repeat sequences siRNAs: small interfering RNAs snRNAs: small nuclear RNA

Prion-based Epigenetic Inheritance inactive prion active prion exogenous signal prion proteins establish a self-perpetuating biochemical reaction

Epigenetic Mechanisms in the Nervous Development deletion of the REST gene or functional inhibition of the protein in non-neuronal tissues leads to erroneous expression of neuronal genes and embryonic lethality, whereas ectopic expression of REST in the nervous system inhibits expression of neuronal gene, results in developmental dysfunction. REST is important in determining whether a cell has a neuronal phenotype.

REST-binding proteins Sin3A: most REST-dependent gene repression might be co-mediated by Sin3A REST/Sin3A is associated with HDAC1 CoREST: is important in mediating specific gene expression patterns in subtypes of cells REST/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 Sin3A: nearly identical cellular expression pattern to REST, CoREST： expression Is more restricted hSWI-SNF complex is an ATP-dependent chromatin remodeling complex

Neurogenesis in the Adult CNS there 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 Rhythms Circadian 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 SCN： 视交叉神经核

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

experientially acquired alterations in DNA methylation affect behaviors in the adult epigenetic mechanisms’ cellular memory in the CNS 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