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CONTRIBUTORS
W.F.CarsonIV
UniversityofMichiganMedicalSchool,AnnArbor,MI,UnitedStates
W.Chen
StateKeyLaboratoryforConservationandUtilizationofSubtropicalAgro-Bioresources,
CollegeofLifeSciences,SouthChinaAgriculturalUniversity,Guangzhou,China
O.Fogel
Universit(cid:1)eParisDescartes,Ho^pitalCochin—AssistancePublique—Ho^pitauxdeParis,
EULARCentreofExcellence,Paris;LaboratoryforEpigeneticsandEnvironment,Centre
NationaldeG(cid:1)enotypage,CEA-InstitutdeG(cid:1)enomique,Evry,France
A.F.Holloway
SchoolofMedicine,UniversityofTasmania,Hobart,TAS,Australia
S.L.Kunkel
UniversityofMichiganMedicalSchool,AnnArbor,MI,UnitedStates
Y.Liu
StateKeyLaboratoryforConservationandUtilizationofSubtropicalAgro-Bioresources,
CollegeofLifeSciences,SouthChinaAgriculturalUniversity,Guangzhou,China
Y.Luo
FacultyofMedicalTechnology,TeikyoUniversity,Itabashi,Japan
T.Nakaoka
DivisionofPharmacotherapeutics,KeioUniversityFacultyofPharmacy,Minato-ku,Japan
D.S.Pisetsky
DukeUniversityMedicalCenter,VAMedicalCenter,Durham,NC,UnitedStates
J.S.Rawlings
FurmanUniversity,Greenville,SC,UnitedStates
C.Richard-Miceli
Universit(cid:1)eParisDescartes,Ho^pitalCochin—AssistancePublique—Ho^pitauxdeParis,
EULARCentreofExcellence;ImmunoregulationUnit,Unit(cid:1)eMixtePasteur/APHP,
InstitutPasteur,Paris,France
H.Saito
DivisionofPharmacotherapeutics,KeioUniversityFacultyofPharmacy,Minato-ku,Japan
Y.Saito
DivisionofPharmacotherapeutics,KeioUniversityFacultyofPharmacy,Minato-ku,Japan
J.L.Schultze
Genomics&Immunoregulation,LIMES-Institute,UniversityofBonn;SingleCell
GenomicsandEpigenomicsUnit,GermanCenterforNeurodegenerativeDiseases,
UniversityofBonn,Bonn,Germany
ix
x Contributors
K.Suzuki
FacultyofMedicalTechnology,TeikyoUniversity,Itabashi,Japan
J.Tost
LaboratoryforEpigeneticsandEnvironment,CentreNationaldeG(cid:1)enotypage,CEA-Institut
deG(cid:1)enomique,Evry,France
A.M.Woodworth
SchoolofMedicine,UniversityofTasmania,Hobart,TAS,Australia
Q.Zhang
StateKeyLaboratoryforConservationandUtilizationofSubtropicalAgro-Bioresources,
CollegeofLifeSciences;KeyLaboratoryofPlantFunctionalGenomicsandBiotechnology
ofGuangdongProvincialHigherEducationInstitutions,CollegeofLifeSciences,South
ChinaAgriculturalUniversity,Guangzhou,China
Q.Zhu
StateKeyLaboratoryforConservationandUtilizationofSubtropicalAgro-Bioresources,
CollegeofLifeSciences,SouthChinaAgriculturalUniversity,Guangzhou,China
PREFACE
Theimmunesystemisexquisitelypoisedtoidentify,respondto,anderad-
icate pathogens from the body, as well as to produce a more rapid and
augmented response to a subsequent encounter with the pathogen. These
cellularresponsesrelyonthehighlycoordinatedandrapidactivationofgene
expressionprogramsaswellastheabilityofthecelltoretainamemoryofthe
initialgeneresponse.Itisnowclearthatchromatinstructureandepigenetic
mechanismsplayacritical rolein determiningthese gene responses,andin
facttheimmunesystemhasprovedaninstructivemodelforinvestigatingthe
multifaceted mechanisms through which the chromatin landscape contrib-
utestogeneexpressionprograms.Thesemechanismsincludemodifications
to theDNAandhistone proteins,thepositioning, compositionandremo-
deling of nucleosomes, as well as the formation of higher order chromatin
structures (Woodworth & Holloway, 2017).
This thematic volume of the Advances in Protein Chemistry and Structural
Biology is dedicated to the role of different chromatin-remodeling mecha-
nisms in controlling immune responses in mammals and plants. Chapter 1
explores in detail the interplay between activation of monocytes and
macrophages, the transcriptional consequences, and the epigenetic regula-
tion,sofarmainlystudiedonthelevelofchromatinlandscapesandhistone
modifications. Chromatin remodeling is an important mechanism during
cellulardifferentiationofmonocytesandmacrophagesfromadultstemcells
and during embryogenesis. However, changes in the chromatin landscape
arealsoassociatedwithdifferentialgeneexpressionofmonocytesandtissue
macrophagesunderhomeostaticconditions,mainlyduetotheintegrationof
dominant local signals from the microenvironment. Furthermore, even
stress signal-induced changes in gene expression are guided by significant
remodeling of the chromatin. While the current multidimensional model
of macrophage activation is mainly based on global transcriptional analysis,
Chapter 1 proposes that specific epigenetic differences are also part of this
model.Furthermore,epigeneticregulationinmonocytesandmacrophages
has been reviewed as a new field for therapeutic intervention in acute and
chronicinflammatorydiseasesassociatedwithdysfunctionalmonocytesand
macrophages. Understanding this sophisticated epigenetic regulatory net-
work in monocytes and macrophages will open up new avenues toward
xi
xii Preface
tissue- and disease-specific therapeutic strategies in many of the chronic
inflammatory diseases our societies are currently facing.
Chapter 2 focuses on the role of epigenetic alterations specifically in
T lymphocytes (T cells) development and function. T cells comprise a
critical component of the immune system charged with diverse functions
during an immune response. As a function of maturation in the thymus,
Tcellsbecomequiescentandremainsountiltheyparticipateinanimmune
responseintheperiphery.RecentworkindicatesthatthecontrolofTcell
proliferationismediated,atleastinpart,bychromatinarchitecture.Quies-
cent T cells possess a condensed chromatin, whereas proliferating T cells
have a more open chromatin configuration. The structural maintenance
ofchromosome(SMC)complexes,whichincludeCohesinandCondensin,
have long been known to play roles in modulating chromatin architecture
duringcelldivision;however,theyarenowknowntohaveadditionalroles
duringinterphasebiology.Theserolesincludethelarge-scalereorganization
of chromatin as well as the regulation of specific gene loci. This review
focuses particularly on the roles that SMC complexes play in T cell devel-
opment and function.
Itisnowestablishedthatepigeneticmechanismsalsoprovideaninstru-
ment by which cells can retain memory of the initial transcriptional
response, “priming” the genome so that it can respond more quickly to
subsequentexposuretothesamesignal.Chapter3usestheimmunesystem
as a model to demonstrate the complex interplay between transcription
factors and the chromatin landscape required to orchestrate precise gene
responsestoexternalstimuliandfurthertodemonstratehowtheseinterac-
tions can establish memory of past transcriptional events. Authors focus on
the multilayered mechanisms that contribute to epigenetic and transcrip-
tionalmemoryintheimmunesystem,keepinginmindthatthelessonsthat
wehavelearntfromtheimmunesystemareinformingourunderstandingof
other biological systems and also disease processes.
Chapter 4 in this volume focuses on the role of chromatin remodeling,
particularlyremodelingthatinvolveshistoneacetylation,intheconstitutive
andinducibleregulationofmajorhistocompatibilitycomplex(MHC)class
IIgeneexpression.MHCclassIImoleculesareessentialforprocessingand
presenting exogenous pathogen antigens to activate CD4+ T cells. Given
their central role in adaptive immune responses, MHC class II genes are
tightlyregulatedinatissue-andactivation-specificmanner.Theregulation
of MHC class II gene expression involves various transcription factors that
interactwithconservedproximalcis-actingregulatorypromoterelements,as
Preface xiii
wellasMHCclassIItransactivatorthatinteractswithavarietyofchromatin-
remodeling machineries. Recent studies also identified distal regulatory
elementswithinMHCclassIIgenelocusthatprovideenormousinsightinto
thelong-rangecoordinationofMHCclassIIgeneexpression.Novelther-
apeuticmodalitiesthatcanmodifyMHCclassIIgenesattheepigeneticlevel
are also discussed in this chapter.
Chapter 5 considers the remodeling processes that affect chromatin
during cell death and their immunological consequences. Chromatin
remodelingisusuallyconceptualizedasanintranuclear(andcertainlyintra-
cellular) event. However, remodeling can have a broader context and
involve extensive and far-reaching molecular movement. Indeed,
depending on the cell process, chromatin can translocate entirely from
theinsidetotheoutsideofthecell.Outsidethecell,thefunctionalactivities
of chromatin can undergo a dramatic transformation since components of
chromatin can, when present in the extracellular space, display powerful
immunological activities. With the breakdown of cells, many intracellular
components—both large and small—can enter the extracellular space to
serve as signaling elements to drive inflammation and to counteract events
challenging the host. Chromatin and its components show such mobility
andimmuneactivity.Asthesetranslocationeventsofchromatincanbereg-
ulatedandmediatedbyenzymes,theycanbeconsideredafacetofchromatin
remodeling and repurposing albeit in the setting of cell death.
Next three chapters review the role of epigenetic changes in different
diseases.Thenumberofpeoplediagnosedwithinflammatorydiseaseshas
increasednoteworthyinthelast40yearsandthisfast-growingnumberhas
beenimpossibletoexplainbyMendelianinheritanceonly.Amongthem,
spondyloarthritis, inflammatory bowel diseases, and psoriasis are the most
frequent chronic inflammatory diseases, resulting from a combination of
geneticpredispositionandenvironmentalfactors.Forexample,inankylos-
ing spondyloarthritis, only 25% of heritability can be explained by
currently known risk loci, suggesting that 75% of the disease risk remains
unknown.Thislackofknowledgeiscalledthemissingheritability.Among
otherhypotheses,theepigenomemightholdatleastparttotheanswerof
this missing heritability. Chapter 6 reviews in detail the reported changes
in patterns of DNA methylation and posttranslational histone modifica-
tionsinchronicinflammatorydiseases,highlightingpotentialconnections
between disease-associated pathophysiological changes such as the
dysbiosis of the microbiome or genetic variations associated with disease
susceptibility and the epigenome. It also discusses important parameters
xiv Preface
of meaningful epigenetic studies such as the use of well-defined, disease-
relevantcellpopulationsandeludesonthepotentialfutureofengineering
oftheepigenomeininflammatory diseases.Chapter 7 focusesontherole
of histone modifications in governing immune responses in severe sepsis,
with an emphasis on specific leukocyte subsets and the histone modifica-
tions observed in these cells during chronic stages of sepsis. Additionally,
theexpressionandfunctionofchromatinmodifyingenzymesarediscussed
in the context of severe sepsis, as potential mediators of epigenetic
regulationofgeneexpressioninsepsisresponses.Insummary,thisreview
argues for the use of chromatin modifications and chromatin-modifying
enzyme expression in leukocytes as potential biomarkers of immunosup-
pressioninpatientswithseveresepsis.Chapter8reviewsanewmolecular
mechanism underlying the antitumor effect of DNA methylation inhibi-
tors that involves induction of an antiviral immune response. This new
mechanism was recently proposed: induction of interferon-responsive
genes via double-stranded RNAs derived from ERVs. The available data
indicate that DNA demethylation suppresses the proliferation of cancer-
initiating cells by inducing an antiviral response including activation of
interferon-responsive genes.
Intheabsenceofacirculatorysystemandmobileimmunecellsthatver-
tebrateshave,plantsrelyonamultilayeredinnateimmunesystemtoachieve
highlyspecific,adaptiveimmunityandestablishimmunememory.Increas-
ing evidence indicates a critical role of chromatin remodeling in the
establishment of long-lasting, even transgenerational immune memory in
plants, as DNA methylation, histone deacetylation, and methylation prime
the promoters of immune-related genes required for disease defense. The
role of chromatin remodeling in plant immunity is discussed in Chapter 9
in this thematic volume of the Advances in Protein Chemistry and Structural
Biology with particular emphasis on the links between Snf2-mediated
ATP-dependent chromosome remodeling and plant immunity, and the
mechanisms that might support its involvement in disease resistance.
Nonetheless,chromatin-remodelingfactorsremainarelativelyunderex-
ploited group of proteins for therapeutic interventions on immune system
responses. A number of recent advances in technology and biomedical
knowledgesuggestthattheseproteinsarepromisingtargetsforfuturether-
apeuticdevelopment.Therefore,theaimofthisvolumeistopromotefur-
therresearchinthisveryexcitingandcentralfieldforthemolecularcontrol
of immune responses to environmental factors. Advancing our knowledge
Preface xv
onthisfundamentaltopicwouldallowfurtherdesignoftherapeuticstrate-
giestocontrolimmunesystemmisbehavior,forexample,inchronicinflam-
matory disorders, sepsis, cancer, etc.
DR. ROSSEN DONEV
Biomed Consult
United Kingdom
REFERENCE
Woodworth,A.M.,&Holloway,A.F.(2017).Theroleofepigeneticregulationintran-
scriptional memory in the immune system. Advances in Protein Chemistry & Structural
Biology,106,43–69.
CHAPTER ONE
Chromatin Remodeling in
Monocyte and Macrophage
Activation
J.L. Schultze1
Genomics&Immunoregulation,LIMES-Institute,UniversityofBonn,Bonn,Germany
SingleCellGenomicsandEpigenomicsUnit,GermanCenterforNeurodegenerativeDiseases,
UniversityofBonn,Bonn,Germany
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 2
2. TheMultidimensionalModelofMonocyteandMacrophageActivation 2
3. EpigeneticsofTissueMacrophagesinHomeostasis 5
4. EpigeneticRegulationDuringStressSignal-InducedActivation 7
5. EvidenceforEpigeneticRegulationDuringTrainedImmunityandTolerance 8
6. Conclusion 10
Acknowledgments 11
References 11
Abstract
Increasingevidencecollectedduringthelastyearssupportstheideathatmonocyteand
macrophage activation is not only associated with transcriptional changes but also
changesinthechromatinlandscape.Moreover,theintroductionofamultidimensional
modelofmacrophageactivationallowsamoreprecisedescriptionofmonocytesand
macrophagesunderhomeostaticandpathophysiologicalconditions.Monocytesand
macrophagesaremastersofintegratingmicroenvironmentalsignals,therebyreshaping
theirchromatin landscape andas a consequence their transcriptional andfunctional
programs.Albeitthesecellssharealargenumberofepigeneticlandmarks,theirchro-
matinissignificantlyshapedbyenvironmentalsignals.Thechromatinlandscapeofany
giventissuemacrophageisaratherspecificfingerprintofthesecells,whichisdirectly
linked to tissue-specific functions of these cells. Moreover, chromatin remodeling in
response to stress signals also seems to be an important mechanism of these cells
toincreasetheirreadinessforfuturestressors.Understandingthissophisticatedepige-
neticregulatorynetworkinmonocytesandmacrophageswillopenupnewavenues
towardtissue-anddisease-specifictherapeuticstrategiesinmanyofthechronicinflam-
matorydiseasesoursocietiesarecurrentlyfacing.
AdvancesinProteinChemistryandStructuralBiology,Volume106 #2017ElsevierInc. 1
ISSN1876-1623 Allrightsreserved.
http://dx.doi.org/10.1016/bs.apcsb.2016.09.001
2 J.L.Schultze
1. INTRODUCTION
Monocytesandmacrophagesarecentraltotissuehomeostasis,butthey
arealsoimportantcellsduringhostdefenseagainstviruses,bacteria,andother
pathogens(Wynn,Chawla,&Pollard,2013).Moreover,theyareinvolvedin
chronic inflammatory diseases including atherosclerosis, diabetes, cancer,
neurodegenerative diseases, obesity, and skin diseases (De Felice &
Ferreira, 2014; Heneka, Kummer, & Latz, 2014; Tall & Yvan-Charvet,
2015; Viola & Soehnlein, 2015). Changes in function of monocytes and
macrophageshavebeenassociatedwithcellularactivationasaconsequence
of transcriptional regulation (Mosser, 2003; Mosser & Edwards, 2008;
Murray&Wynn,2011;Sica&Mantovani,2012).Duringacuteinfections,
suchtranscriptionalactivationisseenasbeingbeneficialandrequiredtoover-
comeinfections(Wynnetal.,2013),whileactivationincontextofchronic
inflammatoryresponsesisoftenjudgedasadysfunctionalstate(Pollard,2009;
Qian&Pollard,2010;Wynnetal.,2013).About15yearsago,asimplistic
modeldescribingbothpro-andantiinflammatoryactivationastwoopposite
activation conditions was ascribed to macrophages (Mantovani, Sozzani,
Locati, Allavena, & Sica, 2002; Mantovani, Vecchi, & Allavena, 2014;
Sica&Mantovani,2012).Enormousprogresshasbeenmadesince,particu-
larlybyapplyinghigh-contenttranscriptome,butalsoepigenomeapproaches
to monocyte and macrophage biology, thereby extending the previous
bipolar model of macrophage activation to a multidimensional model
(Ginhoux, Schultze, Murray, Ochandi, & Biswas, 2016; Schultze, 2015;
Schultze, Freeman, Hume, & Latz, 2015; Schultze & Schmidt, 2015;
Xue et al., 2014). In fact, macrophages are also specifically activated under
homeostatic conditions (Gosselin et al., 2014; Lavin et al., 2014) and their
transcriptional programs are further changed in response to physiological
and nonphysiological stress signals (Ghisletti et al., 2010; Heinz et al.,
2010;Ostunietal.,2013;Xueetal.,2014).Here,Iwilldescribetheinterplay
between activation of monocytes and macrophages, the transcriptional
consequences,andtheepigeneticregulation,sofarmainlystudiedonthelevel
ofchromatinlandscapesandhistonemodifications.
2. THE MULTIDIMENSIONAL MODEL OF MONOCYTE
AND MACROPHAGE ACTIVATION
The application of transcriptome and epigenome analysis to mono-
cytes and tissue macrophages has challenged our view on how we define
