Table Of ContentINTERNATIONAL
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
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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
