Advertisement

Epigenetic Mechanisms: DNA Methylation and Histone Protein Modification

Reference work entry

Abstract

Epigenetic Regulation Allows Control of Differential Gene Expression from the Same Genome. Every somatic cell in a given organism contains the same genetic information, which is encoded in a DNA double helix. Yet there are several hundred different cell types in the human body that form four types of tissue and build organ systems that perform vastly diverse physiological functions. This diversity is achieved through developmental programming when differentiation signals and environmental cues converge to regulate temporal and spatial patterns of gene expression in a specific cell type. For example, during neurogenesis, neural progenitor cells acquire their neuronal phenotype by inducing the transcription of neuron-specific genes, whereas cells outside the nervous system maintain nonneural cell fates by permanently suppressing neuronal genes. These different patterns of gene expression in different cells of an organism come about in part through epigenetic mechanisms. Epigenetics is most commonly defined as persistent and heritable changes in gene expression that do not involve modification of DNA. However, in light of recent evidence demonstrating the dynamic nature of epigenetic modifications, especially in postmitotic neural cells, we favor a more “mechanistic” definition put forward by C. David Allis and colleagues: “The sum of the alterations to the chromatin template that collectively establish and propagate different patterns of gene expression and silencing from the same genome” (Allis CD, Jenuwein T, Reinberg D (2007) Epigenetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.). According to these authors, “chromatin ‘signatures’ can be viewed as a highly organized system of information storage that can index distinct regions of the genome and accommodate a response to environment signals that dictate gene expression programs.” Work done within the past decade has in fact demonstrated that epigenetic mechanisms are utilized by nerve cells to translate early childhood experiences into long-lasting behavioral patterns, store memories, and develop addictive behaviors after exposure to drugs of abuse. In this chapter, we will discuss various molecular events that collectively are referred to as “epigenetic regulatory mechanisms” and address the importance of these processes in nervous system development and function.

Keywords

Histone Acetylation HDAC Inhibitor Histone Variant Chromatin Remodel Complex Histone Tail 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ATF

Activating transcription factor

BAF

BRM- or BRG1-associated factor

BDNF

Brain-derived neurotrophic factor

BER

Base excision repair

BET

Bromodomain and extra terminal

BRG-1

Brahma-related gene-1

BRM

Brahma

C/EBP

CCAAT-enhancer-binding protein

CAF-1

Chromatin assembly factor 1

CARM1

Coactivator-associated arginine methyltransferase 1

CBP

CREB-binding protein

CenH3

Centromeric H3

CENP-A

Centromeric protein A

CGI

CpG islands

CHD

Chromodomain, helicase, DNA binding

ChIP

Chromatin immunoprecipitation

CNS

Central nervous system

CREB

cAMP response element-binding factor

CTCF

CCCTC-binding factor

DNMT

DNA methyltransferase

ER

Estrogen receptor

ES cells

Embryonic stem cells

EZH2

Enhancer of zeste homolog 2

FMR

Fragile X mental retardation

FXS

Fragile X syndrome

GFAP

Glial fibrillary acidic protein specific to astrocytes

GR

Glucocorticoid receptor

H2A.Bbd

H2A Barr body-deficient

HAT

Histone acetyltransferase (see also KAT)

HDAC

Histone deacetylase

HIRA

HIR histone cell cycle regulation defective homolog A

HKDM

Histone lysine demethylase

HKMT

Histone lysine methyltransferase

HP1

Heterochromatin protein-1

ICF

Immunodeficiency, centromeric instability, and facial abnormalities

ICR

Imprinting control region

IEG

Immediate-early gene

IF

Immunofluorescence

IGF

Insulin growth factor

INO80

Inositol requiring 80

ISWI

Imitation switch

JARID

Jumonji, AT rich interactive domain

JHDM

Jmjc domain-containing histone demethylase

JMJD

Jumonji-domain containing

KAT

Lysine acetyltransferase

LG-ABN

Licking, grooming and arched-back nursing

L-LTP

Late stage of long-term potentiation

LSD1

Lysine-specific demethylase 1

LSH

Lymphoid-specific helicase

LTD

Long-term depression

LTP

Long-term potentiation

MBD

Methyl-CpG-binding domain

MeCP2

Methyl-CpG-binding protein 2

mH2A

MacroH2A

MYST

MOZ, Ybf2/Sas3, Sas2, Tip60

NAc

Nucleus accumbens

NAD

Nicotinamide adenine dinucleotide

NCoR

Nuclear receptor corepressor

NGFI-A

Nerve growth factor-inducible protein A

NMDA

N-Methyl-d-aspartic acid

NR2B

NMDA receptor subunit 2B

NuRD

Nucleosome remodeling and deacetylase

NURF

Nucleosome remodeling factor

OMIM

Online-Mendelian Inheritance in Man

PCAP

p300/CBP-associated factor

PHD

Plant homeo domain

PRC

Polycomb repressive complex

PRMT

Arginine N-methyltransferase

PTM

Posttranslational modification

RC

Replication-coupled

RI

Replication-independent

SAHA

Suberoylanilide hydroxamic acid

SAM

S-adenosylmethionine

SET

Su(var)3-9, Enhancer of Zeste, Trithorax

siRNA

Small inhibitory RNA

SIRT

Sirtuins

SRC

Steroid receptor coactivator

SSRI

Selective serotonin reuptake inhibitor

SWI/SNF

Switching defective/sucrose nonfermenting

SWR1

Sick with Rat8 ts

TAFII250

TATA-binding protein (TBP)-associated factor

TSA

Trichostatin A

XCI

X chromosome inactivation

XIC

X-inactivation center

XLMR

X-linked mental retardation

Further Reading

  1. Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A (2004) Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42:947–959PubMedCrossRefGoogle Scholar
  2. Allis CD, Jenuwein T, Reinberg D (2007) Epigenetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NYGoogle Scholar
  3. Bestor TH, Ingram VM (1983) Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA. Proc Natl Acad Sci USA 80:5559–5563PubMedCrossRefGoogle Scholar
  4. Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, Allis CD (1996) Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84:843–851PubMedCrossRefGoogle Scholar
  5. Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H (2003) Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J Neurochem 85:151–159PubMedCrossRefGoogle Scholar
  6. Covington HE III, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, Fass DM, Renthal W, Rush AJ III, Wu EY, Ghose S, Krishnan V, Russo SJ, Tamminga C, Haggarty SJ, Nestler EJ (2009) Antidepressant actions of histone deacetylase inhibitors. J Neurosci 29:11451–11460PubMedCrossRefGoogle Scholar
  7. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60PubMedCrossRefGoogle Scholar
  8. Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315:1143–1147PubMedCrossRefGoogle Scholar
  9. Hardingham GE, Chawla S, Cruzalegui FH, Bading H (1999) Control of recruitment and transcription-activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22:789–798PubMedCrossRefGoogle Scholar
  10. Hebbes TR, Clayton AL, Thorne AW, Crane-Robinson C (1994) Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken beta-globin chromosomal domain. Embo J 13:1823–1830PubMedGoogle Scholar
  11. Ho L, Crabtree GR (2010) Chromatin remodelling during development. Nature 463:474–484PubMedCrossRefGoogle Scholar
  12. Hunter RG, McCarthy KJ, Milne TA, Pfaff DW, McEwen BS (2009) Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci USA 106:20912–20917PubMedCrossRefGoogle Scholar
  13. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080PubMedCrossRefGoogle Scholar
  14. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedCrossRefGoogle Scholar
  15. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324:929–930PubMedCrossRefGoogle Scholar
  16. Lessard J, Wu JI, Ranish JA, Wan M, Winslow MM, Staahl BT, Wu H, Aebersold R, Graef IA, Crabtree GR (2007) An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55:201–215PubMedCrossRefGoogle Scholar
  17. Lee S, Kim W, Ham BJ, Chen W, Bear MF, Yoon BJ (2008) Activity-dependent NR2B expression is mediated by MeCP2-dependent epigenetic regulation. Biochem Biophys Res Commun 377:930–934PubMedCrossRefGoogle Scholar
  18. Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69:905–914PubMedCrossRefGoogle Scholar
  19. Luger K et al (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389:251PubMedCrossRefGoogle Scholar
  20. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893PubMedCrossRefGoogle Scholar
  21. Maze I, Nestler EJ (2011) The epigenetic landscape of addiction. Ann N Y Acad Sci 1216:99–113PubMedCrossRefGoogle Scholar
  22. Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869PubMedCrossRefGoogle Scholar
  23. Nelson ED, Monteggia LM (2011) Epigenetics in the mature mammalian brain: effects on behavior and synaptic transmission. Neurobiol Learn Mem 96(1):53–60PubMedCrossRefGoogle Scholar
  24. Sharma RP, Gavin DP, Grayson DR (2010) CpG methylation in neurons: message, memory, or mask? Neuropsychopharmacology 35:2009–2020PubMedCrossRefGoogle Scholar
  25. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953PubMedCrossRefGoogle Scholar
  26. Stein R, Razin A, Cedar H (1982) In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc Natl Acad Sci USA 79:3418–3422PubMedCrossRefGoogle Scholar
  27. Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–411PubMedCrossRefGoogle Scholar
  28. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525PubMedCrossRefGoogle Scholar
  29. Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367PubMedCrossRefGoogle Scholar
  30. van Bokhoven H, Kramer JM (2010) Disruption of the epigenetic code: an emerging mechanism in mental retardation. Neurobiol Dis 39:3–12PubMedCrossRefGoogle Scholar
  31. Vardimon L, Kressmann A, Cedar H, Maechler M, Doerfler W (1982) Expression of a cloned adenovirus gene is inhibited by in vitro methylation. Proc Natl Acad Sci USA 79:1073–1077PubMedCrossRefGoogle Scholar
  32. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854PubMedCrossRefGoogle Scholar
  33. Wu JI, Lessard J, Olave IA, Qiu Z, Ghosh A, Graef IA, Crabtree GR (2007) Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56:94–108PubMedCrossRefGoogle Scholar
  34. Zhang TY, Meaney MJ (2010) Epigenetics and the environmental regulation of the genome and its function. Annu Rev Psychol 61:439–466, C431–433PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  1. 1.Laboratory of Neurobiology and BehaviorThe Rockefeller UniversityNew YorkUSA
  2. 2.Laboratory of Neurobiology and BehaviorThe Rockefeller UniversityNew YorkUSA

Personalised recommendations