Epigenetics PDF
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INTERNATIONAL REVIEW OF NEUROBIOLOGY VOLUME115 SERIES EDITORS R. ADRON HARRIS WaggonerCenterforAlcohol andDrugAddictionResearch The University of Texas at Austin Austin, Texas, USA PETER JENNER Division of Pharmacology and Therapeutics GKT School of Biomedical Sciences King's College, London, UK EDITORIAL BOARD ERICAAMODT HUDAAKIL PHILIPPEASCHER MATTHEWJ.DURING DONARDS.DWYER DAVIDFINK MARTINGIURFA BARRYHALLIWELL PAULGREENGARD JONKAAS NOBUHATTORI LEAHKRUBITZER DARCYKELLEY KEVINMCNAUGHT BEAULOTTO JOSE(cid:1)A.OBESO MICAELAMORELLI CATHYJ.PRICE JUDITHPRATT SOLOMONH.SNYDER EVANSNYDER STEPHENG.WAXMAN JOHNWADDINGTON AcademicPressisanimprintofElsevier 225WymanStreet,Waltham,MA02451,USA 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 32JamestownRoad,LondonNW17BY,UK TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK Firstedition2014 Copyright©2014,ElsevierInc.AllRightsReserved Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorageand retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek permission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. 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ISBN:978-0-12-801311-3 ISSN:0074-7742 ForinformationonallAcademicPresspublications visitourwebsiteatstore.elsevier.com PrintedandboundinUSA CONTRIBUTORS TiffaniD.M.Berkel DepartmentofPsychiatry,UniversityofIllinoisatChicago,andJesseBrownVeteransAffairs MedicalCenter,Chicago,Illinois,USA SumanaChakravarty ChemicalBiology,CSIR-IndianInstituteofChemicalTechnology(IICT),Hyderabad, India KarisettyBhanuChandra ChemicalBiology,CSIR-IndianInstituteofChemicalTechnology(IICT),Hyderabad, India EdwinH.Cook InstituteforJuvenileResearch,DepartmentofPsychiatry,UniversityofIllinoisatChicago, Chicago,Illinois,USA ChristinaFloreani DepartmentofPsychiatry,UniversityofIllinoisatChicago,andJesseBrownVeteransAffairs MedicalCenter,Chicago,Illinois,USA DavidP.Gavin DepartmentofPsychiatry,UniversityofIllinoisatChicago,andJesseBrownVeteransAffairs MedicalCenter,Chicago,Illinois,USA DennisR.Grayson ThePsychiatricInstitute,DepartmentofPsychiatry,UniversityofIllinoisatChicago, Chicago,Illinois,USA AlessandroGuidotti ThePsychiatricInstitute,DepartmentofPsychiatry,UniversityofIllinoisatChicago, Chicago,Illinois,USA NitinKhandelwal EpigeneticsandNeuropsychiatricDisordersLaboratory,CSIR-CentreforCellularand MolecularBiology,Hyderabad,India HarishR.Krishnan DepartmentofPsychiatry,UniversityofIllinoisatChicago,andJesseBrownVeteransAffairs MedicalCenter,Chicago,Illinois,USA ArvindKumar EpigeneticsandNeuropsychiatricDisordersLaboratory,CSIR-CentreforCellularand MolecularBiology,Hyderabad,India Chiao-LingLo DepartmentofAnatomyandCellBiology,StarkNeuroscienceResearchInstitute, IndianaAlcoholResearchCenter,IndianaUniversitySchoolofMedicine,andDepartment ofPsychology,IndianaUniversityPurdueUniversityatIndianapolis,Indianapolis, Indiana,USA ix x Contributors SwatiMaitra ChemicalBiology,CSIR-IndianInstituteofChemicalTechnology(IICT),Hyderabad, India RajeshC.Miranda DepartmentofNeuroscienceandExperimentalTherapeuticsandWomen’sHealthin NeuroscienceProgram,A&MHealthScienceCenter,CollegeofMedicine,Bryan, Texas,USA SubhashC.Pandey DepartmentsofPsychiatry,andAnatomyandCellBiology,UniversityofIllinoisatChicago, andJesseBrownVeteransAffairsMedicalCenter,Chicago,Illinois,USA SalilSauravPathak EpigeneticsandNeuropsychiatricDisordersLaboratory,CSIR-CentreforCellularand MolecularBiology,Hyderabad,India NadiaRachdaoui RutgersEndocrineResearchProgram,DepartmentofAnimalSciences,RutgersUniversity, NewBrunswick,NewJersey,USA AmulJ.Sakharkar DepartmentofPsychiatry,UniversityofIllinoisatChicago,andJesseBrownVeteransAffairs MedicalCenter,Chicago,Illinois,USA DipakK.Sarkar RutgersEndocrineResearchProgram,DepartmentofAnimalSciences,RutgersUniversity, NewBrunswick,NewJersey,USA TaraL.Teppen DepartmentofPsychiatry,UniversityofIllinoisatChicago,andJesseBrownVeteransAffairs MedicalCenter,Chicago,Illinois,USA FengC.Zhou DepartmentofAnatomyandCellBiology,StarkNeuroscienceResearchInstitute, IndianaAlcoholResearchCenter,IndianaUniversitySchoolofMedicine,andDepartment ofPsychology,IndianaUniversityPurdueUniversityatIndianapolis,Indianapolis, Indiana,USA AdrianZhubi ThePsychiatricInstitute,DepartmentofPsychiatry,UniversityofIllinoisatChicago, Chicago,Illinois,USA PREFACE Epigenetics isan emergingareain neuroscienceresearchthatappearsto be crucial in regulating the pathophysiology of brain disorders. Chromatin architecture is regulated by chemical modifications to DNA and histones. DNA and histone methylation, as well as other histone modifications such asacetylationandphosphorylation,havebeenshowntoregulategenetran- scription. These epigenetic modifications cause short- and long-term changes in gene function without producing changes in DNA sequence. The epigenome can be effected before and after birth by several environ- mental factors, and this modified epigenome can play an important role intheetiologyofmanybraindiseasesandassociatedbehavioralphenotypes. Recently, it has been recognized that changes in epigenetic processes prior to birth can produce profound effects on brain development and thereby regulate several neurodevelopmental disorders. The first chapter on “Environmental alterations of epigenetics prior to the birth” by Lo and Zhou has provided attractive evidence of how aversive environmental exposure,including alcohol drinking of parents,might producechanges in epigeneticprocesses(DNAmethylation,histonemodification,andnoncod- ing RNA) and predispose offspring to neurodevelopmental disease. This chapterwillprovidereadersabetterunderstandingoftheprenatalepigenetic modificationsduetoenvironmentalfactorsandrelatedneurodevelopmental deficits and development of neuropsychiatric disorders later in life. Transgenerational epigenetic inheritance has emerged as a fascinating mechanismfortheinheritanceofbraindisorders.Itappearsthatepigenetic changesproducedbyenvironmentalfactorssuchasalcoholexposureinthe germline during embryonic development can be transmitted across several generations and contribute significantly to the inheritance of brain disease. Thesecondchapteron“Transgenerationalepigeneticsandbraindisorders” byRachdaouiandSarkarhasdiscussedrecentfindingsontransgenerational epigenetic inheritance. Readers of this chapter will learn the epigenetic mechanismsinvolvedintheheritabilityofalcohol-inducedneurobehavioral disorders such as fetal alcohol spectrum disorders. Alcoholismingeneralisacomplexpsychiatricdisorderandisdictatedby positiveandnegativeaffectivestates.Thethirdchapteron“Theepigenetic landscapeofalcoholism”byKrishnanetal.discussesevidencethatchroma- tin remodeling causes changes in gene expression in specific brain regions xi xii Preface contributing to the pathophysiology not only to alcoholism but also to comorbidanxietydisordersrepresentingthe“darksideofaddiction.”Here, evidence is presented to show that pharmacologically manipulating epige- netictargetsmayhavegreattherapeuticpotentialintreatingalcoholismwith or without comorbid anxiety disorders. Another environmental factor which has been shown to modulate chromatin architecture is stress. In the fourth chapter entitled “Epigenetic regulatory mechanisms in stress-induced behavior,” Chakravarty et al. discussvariousepigeneticregulatorymechanismsinthebrainunderstressful situations. The review will give readers an overview of epigenetic dys- regulation of neuropsychiatric diseases such as depression. Epigeneticmodificationsappeartoplayaroleintheetiologyofschizo- phrenia.Inthefifthchapteron“Epigeneticsofschizophrenia:anopenand shut case,” Gavin and Floreani discuss several epigenetic studies, some of whichsuggestthatschizophreniaischaracterizedbyoverlyrestrictivechro- matin.However,recentstudiesindicatethattheepigeneticmechanismsreg- ulatingthepathophysiologyofschizophreniamaybemorecomplex.They provideevidencebasedonrecentstudiesinthefieldthatitisplausiblethat drugs which further restrict chromatin may be efficacious in treating schizophrenia. Autism spectrum disorder (ASD) is a neurodevelopmental disorder and recentevidencesuggeststheinvolvementofepigeneticmechanismsinpath- ophysiology of ASD. The sixth chapter on “Epigenetic mechanisms in autismspectrumdisorder”byZhubietal.coversrecentprogressinthefield regardingtheimpactofepigeneticmechanismsontranscriptionalprograms in the brain and their role in the pathophysiology of ASD. MicroRNAs (miRNAs) are a class of small nonprotein-coding RNAs that have been shown to regulate gene expression and represent another layerofcomplexityinwhichepigeneticsregulatesthegenome.Theseventh chapterentitled“MicroRNAsandethanoltoxicity”byMirandaprovidesa discussiononrecentfindingsthatclearlysuggestthatmiRNAsareanimpor- tant component of the epigenetic machinery that modulate gene networks during pre- and postnatal ethanol exposure. All chapters in this volume of the International Review of Neurobiology have attempted to summarize the recent progress and trends underlying epigeneticmechanismsofbraindisorders.Oneoftheenvironmentalfactors, alcohol,caninteractwiththeepigenomeatseverallevelsandhastheability tomodulatebrainstructureandfunction,therebyexertingprofoundeffects on endophenotypes. Epigenetic mechanisms, as discussed above, play an Preface xiii importantroleinthepathophysiologyofdepression,stress,anxiety,schizo- phrenia,andautism.Takentogether,theevidencepresentedhereindicates thatpharmacologicalagentswhichmodulatetheepigenomesuchashistone deacetylaseandDNAmethyltransferaseinhibitorshavepotentialtherapeu- ticvalueintreatingvariousbraindisorders.Inthefuture,studiesthatextend thesepreclinicalepigeneticfindingsintohumansacrossallbraindiseasesdis- cussed here, offer the hope that one day we may be able to target the epigenome to treat these brain disorders, including alcoholism. SUBHASH C. PANDEY Departments of Psychiatry, and Anatomy and Cell Biology, University of Illinois at Chicago, and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA CHAPTER ONE Environmental Alterations of Epigenetics Prior to the Birth Chiao-Ling Lo, Feng C. Zhou1 DepartmentofAnatomyandCellBiology,StarkNeuroscienceResearchInstitute,IndianaAlcoholResearch Center,IndianaUniversitySchoolofMedicine,andDepartmentofPsychology,IndianaUniversityPurdue UniversityatIndianapolis,Indianapolis,Indiana,USA 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 2. ManifestationofEnvironmentalFactors 4 2.1 Substancesofabuse 4 2.2 Dietandnutrition 13 2.3 Prescriptivemedicine 14 2.4 Environmentaltoxinsandpollutants 15 2.5 Stressandaversivelifeexperience 18 3. MechanismsofEnvironmentallyInducedEpigeneticChanges 19 3.1 OnDNAmethylation 19 3.2 Onhistonemodification 23 3.3 OnmiRNAandothernoncodingRNA 23 3.4 Ontransposableelements 24 4. EffectofEpigeneticAlterationsonNeurodevelopment 25 4.1 Epigeneticfunctionalconcerns 25 4.2 Intrinsicepigeneticprogram 26 4.3 Alcoholdrinking,epigeneticsphenotypes,andFASDs 30 Acknowledgments 34 References 34 Abstract Theetiologyofmanybraindiseasesremainsallusivetodateafterintensiveinvestigation of genomic background and symptomatology from the day of birth. Emerging evidencesindicatethatathirdfactor,epigeneticspriortothebirth,canexertprofound influence on the development and functioning of the brain and over many neurodevelopmental syndromes. This chapter reviews how aversive environmental exposure to parents might predispose or increase vulnerability of offspring to neu- rodevelopmental deficit through alteration of epigenetics. These epigenetic altering environmentalfactorswillbediscussedinthecategoryofaddictiveagents,nutrition ordiet,prescriptivemedicine,environmentalpollutant,andstress.Epigeneticalterations induced by these aversive environmental factors cover all aspects of epigenetics InternationalReviewofNeurobiology,Volume115 #2014ElsevierInc. 1 ISSN0074-7742 Allrightsreserved. http://dx.doi.org/10.1016/B978-0-12-801311-3.00001-9 2 Chiao-LingLoandFengC.Zhou including DNA methylation, histone modification, noncoding RNA, and chromatin modification.Next,themechanismshowtheseenvironmentalinputsinfluenceepige- neticswillbediscussed.Finally,howenvironmentallyalteredepigenetic marksaffect neurodevelopment is exemplified by the alcohol-induced fetal alcohol syndrome. It ishopedthatathoroughunderstandingofthenatureofprenatalepigeneticinputswill enable researchers with a clear vision to better unravel neurodevelopmental deficit, late-onsetneuropsychiatricdiseases,oridiosyncraticmentaldisorders. 1. INTRODUCTION Recent progress on epigenetics begins to provide unprecedented insighthowtheformationofournervoussystemisaffectedbytheenviron- mental inputs in life history dated long before birth, or even generations Figure1.1 Theaversiveenvironmentexposure(e.g.,alcohol,nicotine,airpollution)can berecordedintheformofepigeneticsthroughoutancestral(includingparental),pre- natal,andpostnatalstages.Thesealteredepigenetics(epimutation)onthetopofDNA orhistonecanbeaccumulatedovertimebutcanalsobeerasedtwiceinalifetimedur- ingzygoticstageandgermlinematuration.Thepersistingepimutationwhenreacheda critical threshold may alter gene transcription to affect the neural development. Dependingonstageoflife,theearlieronsetmayaffectneuraldifferentiationandbrain formation.Thecontinuousincrementofepimutationorlastinginfluenceofepigenetic changesmayfurtheraffectsynaptogenesisandneuraltranscription,andtogetheraffect thebrainfunctionandneuropsychiatricdiseaseatgiventimeofthelife. EnvironmentalAlterationsofEpigeneticsPriortotheBirth 3 back(Fig.1.1).Theseenvironmentalmemoriesarerecordedchemicallyin theformofepigeneticcodes,depositedonthetopofDNAorhistones(for review,seeJaenisch&Bird,2003;Portela&Esteller,2010).Evolutionarily, to avoid endless accumulation of epigenetic marks with each new cycle of life,duringformationofzygotesandgermline,mostofthesememoriesare erased,butnotentirely(Saitou,Kagiwada,&Kurimoto,2012).Epigenetic codesintheformofDNAmethylation,histonetailmodification,orchro- matinconformationcancriticallyaffectgenetranscriptionby,e.g.,altering the 3D DNA conformation to dictate transcription factor binding. Thus, dependingonhowmuchalteredepigeneticcodesareretainedwithinagen- eration or several generations, this epigenetic memory may affect brain development or functioning through misregulation of gene transcription. There are three categorical stages of life history when epigenetics are registered—ancestral (including parents), prenatal, and postnatal stages. Among these stages, prenatal epigenetic registration is the most eminent andprofoundinfluenceontheformationorfine-tuningofthenervoussys- tem during development. Thus, environmental inputs prior to the birth havebeenreportedtoimposeepigeneticentries,manyofwhicharecarried throughoutthelifeofsomaticcells,includingthoseinthebrain.Thisreview focuses on epigenetic influences by various types of environmental factors specifically at prenatal stage. From a clinical point of view, this review advocates that many contributing factors and mechanisms of neu- rodevelopmentaldeficit, including late-onset mental or psychiatric diseases (e.g., autism or schizophrenia),may have been seeded before birth beyond the default of the parental genetics. Section 2 is devoted to eminent environmental factors including sub- stancesofabuse,prescriptionmedications,pollutants,diets,andstresswhich arefoundtoaltertheepigeneticsofoffspringofexposedparents;thenature and types of epigenetics altered in the cells and organs will be reviewed. Section3elucidateshowenvironmentalfactorsmightchemicallyalterepi- genetics,thusleadingtoabetterunderstandingofhowotherenvironmental factorsmightexertyettobefoundinfluence.Section4elaboratesthatepi- genetics evolved during neurodevelopment as an intrinsic program. Envi- ronmental factors, by altering epigenetics at individual genes or via the epigenetic program of differentiating neuroprogenitor cells, may alter the courseofneurodevelopment.Thiswillbedemonstratedusingalcoholexpo- sureduringpregnancy(fetalalcoholsyndrome)asamodel.Thefetalalcohol syndrome is taken as an example, because it has a systemic influence of epigenetics in every form and which has been found potentially trans- generational. Further, alcohol is one of the most abused environmental
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