Chromatin-remodeling
enzymes
in
control
of
Schwann
cell
development,
maintenance
and
plasticity
Claire
Jacob
Generegulationisessentialforcellulardifferentiationand
plasticity.Schwanncells(SCs),themyelinatinggliaofthe
peripheralnervoussystem(PNS),developfromneuralcrest
cellstomaturemyelinatingSCsandcanatearlydevelopmental
stagedifferentiateintovariouscelltypes.AfteraPNSlesion,
SCscanalsoconvertintorepaircellsthatguideandstimulate
axonalregrowth,andremyelinateregeneratedaxons.What
controlstheirdevelopmentandversatilenature?Severalrecent
studieshighlightthekeyrolesofchromatinmodifiersinthese
processes,allowingSCstoregulatetheirgeneexpression
profileandtherebyacquireorchangetheiridentityandquickly
reacttotheirenvironment.
Address
DepartmentofBiology,UniversityofFribourg,CheminduMuse´e10,
1700Fribourg,Switzerland
Correspondingauthor:Jacob,Claire(claire.jacob@unifr.ch)
Introduction
SCsoriginatefromneuralcrestcellsthatalsogiveriseto othercelltypesincludingsensoryneurons,chondrocytes, melanocytes, smooth-muscle cells [1,2].After specifica-tion in SC precursors, thelineage further differentiates into immature SCs that encircle bundles of axons of different calibers. Next, big caliber axons are sorted in a one-to-one relationship with SCs by a process called radial sorting which leads to the promyelinating stage. The last step of maturation is the myelination process where SCs build a thick myelin sheath rich in lipids aroundaxons(Figure1).Meanwhile,smallcaliberaxons remainin bundlesassociatedwith non-myelinatingSCs and persist as Remak bundles in adult nerves [3,4]. Myelin provides axonal insulation and fast conduction ofelectricsignalsalongaxons;itsformationand mainte-nancearethuscriticalforneuronalfunctions.Bycontrast, myelin is detrimental for axonal regrowth after lesion,
becauseitcontains growthinhibitoryproteins [5]. How-ever, SCsreactquickly to anaxonal lesionby dediffer-entiating,digestingtheirown myelin—aprocesscalled myelinophagy[6]—andconvertingintorepaircells[7,8] thatfosteraxonalregrowthandguideaxonsbacktotheir former target [9,10]. SCs then remyelinate regenerated axons(Figure2).ThisremarkableSCplasticityallowsthe PNStofunctionallyregenerateafter lesion.
Thisreviewisfocusedonthemechanismsof SC devel-opment, maintenance and plasticity after lesion con-trolled by chromatin-remodeling enzymes. Chromatin remodeling regulates the accessibility of genes for the transcriptional machinery, and thereby gene activation and repression. Changes of chromatin architecture are controlled by ATP-dependent nucleosome remodeling andbycovalentmodifications, eitheronDNAby meth-ylationoronhistonesbyvariouspost-translational mod-ificationsincludingacetylation,methylation, phosphory-lation, ubiquitination, SUMOylation, ADP-ribosylation. Althoughourknowledgeonthesemechanismsisstillvery sparse, recent findings on the functions of chromatin-remodeling enzymeshavesignificantlycontributed to a betterunderstandingof theircriticalfunctionsin SCs.
Chromatin-remodeling
factors
controlling
SC
development,
maintenance
and
plasticity
after
lesion
Nucleosome-remodeling complexes,DNA methylation/ demethylation, histone acetylation/deacetylation and methylation/demethylation enzymes have been shown tohold keyfunctionsinSCs(Figures1 and2).
Nucleosome-remodelingcomplexes
Nucleosome-remodelingcomplexesuseATPto destabi-lize the interaction between DNA and histones. This local chromatin destabilization results in nucleosome sliding and repositioning that can also leadto adjacent nucleosomeejectionorinsertion.Thesechangesof chro-matinstructuremodifyDNAaccessibility,andcanleadto either transcriptional activation or repression. Nucleo-some-remodeling complexesareclassified intodifferent families, based ontheir composition and activity: SWI/ SNF, ISWI, INO80/SWR1 and NuRDcomplexes [11]. Amongthose,theSWI/SNF andthe NuRDcomplexes are known to regulate aspects of SC development and plasticity after lesion (Figures 1 and 2). Two subtypes BAFandPBAFofSWI/SNFcomplexesareknown;they owe their enzymatic activity to their ATPase subunit BRM or BrG1 [12]. The NuRD complex comprises
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Published in "Current Opinion in Neurobiology 47 (): 24–30, 2017"
which should be cited to refer to this work.
CHD3orCHD4asATPasesubunit,andhasinaddition deacetylase activityby therecruitment of HDAC1 and HDAC2[13].
DNAmethyltransferases(DNMTs)
DNMTstransfer amethyl group from amethyl donor, generally S-adenosylmethionine (SAMe) to the carbon 5 of cytosines located within CpG dinucleotides [14]. Most CpGs in mammalian genomes are maintained
methylatedacrossgenerationsbyDNMT1.Bycontrast, CpG islands in promoters and enhancers often remain unmethylated through active DNMTs exclusion. This usuallyrequiresrecruitmentofatranscriptionfactorand otherpartnerssuchashistoneH3lysine4(H3K4) methyl-transferases(HMTs),aTET dioxygenaseand a thymi-dine DNA glycosylase that erase/prevent methylation. Promoter silencing can however occur through de novo methylationatCpGislandsbyDNMT3AorDNMT3B,
Figure1
Current Opinion in Neurobiology
Chromatin-remodelingenzymesandassociatedmechanismsregulatingSCdevelopmentandmaintenance.Activatingmechanismsaredepicted
aboveandinactivatingmechanismsunderneathSCstages.Thetablelistsmousemutantsandtheirphenotypesusedtoidentifythese
mechanisms.
Figure2
Current Opinion in Neurobiology
Chromatin-remodelingmechanismsregulatingSCplasticityafterlesion.Activatingmechanismsaredepictedaboveandinactivatingmechanisms
underneathregenerationstages.Thetablelistsmousemutantsandtheirphenotypesusedtoidentifythesemechanisms.
andisusuallyprecededbyrepressiveH3K9methylation marks.Interestingly,inthecaseofverylowavailabilityof methyldonor,DNMT3A/BcannotmethylateCpGs,but in contrasthavebeenreportedto activelyparticipatein DNAdemethylation[15].
Histoneacetylationanddeacetylationenzymes
Histoneacetyltransferases (HATs) addacetyl groups to lysines of histone tails, which loosens the attraction between histones and DNA and results in chromatin decompactionthatfacilitatestheaccessforthe transcrip-tional machinery. By contrast, HDACs remove these acetylgroups,whichleadstoamorecondensedchromatin thatrestrictsDNAaccess[16].HATsarethuscommonly thought to act as transcriptional co-activators, whereas HDACs as transcriptional co-repressors. However, sev-eralstudieshaveshownthatHDACscanalsoparticipate in transcriptionalactivation[17–19].HATsandHDACs cannotbindDNAdirectlyandthusneedaDNA-binding partner to modify histones. In addition, these enzymes can acetylate and deacetylate and thereby control the activityofnon-histonetargetsincludingseveral transcrip-tion factors[20]; they are thus very powerful transcrip-tional regulators. Eighteen known mammalian HDACs aresubdividedintofourclasses,basedontheirstructure [21].HDAC1andHDAC2,twohighlyhomologousclassI HDACs thatcanusuallycompensateeachother’s func-tions, havebeenextensivelystudied inSCs.
Histonemethylationanddemethylationenzymes HMTs catalyzetheaddition of methylgroups to target residues,whereashistonedemethylases(HDMs)remove thesemethylgroups.Histonescanbemethylatedonthe threebasicresidues K,arginine(R)andhistidine(His), althoughHismethylationisrare.Activatingmethylation marksarelocatedonH3K4,H3K36,H3K79,H3R17and H3R26, and repressive methylation marks on H3K9, H3K27, H4K20 and H3R8, whereas methylation of H3R2andH4R3leadseithertotranscriptionalactivation or repression, depending on the exact location of the methylgroup. Thereareseveral familiesof HMTsand KHDMs,buttheexistenceofRHDMsisnotclear[22].
Functions
of
chromatin-remodeling
enzymes
in
SC
development
and
maintenance
of
PNS
integrity
SC development from specification of the lineage to terminaldifferentiationintomyelinatingcellsand main-tenanceofmyelinationrequiretranscriptionalactivation ofgenes thatinducelineagedifferentiationand acquisi-tionandmaintenanceofcellstageidentity.HDAC1and HDAC2 (HDAC1/2) and theBAF complex hold major functions in theseprocesses. For differentiation to pro-ceed,inactivatinginhibitorymechanismsofSC differen-tiation is also necessary. In addition, preventing over-myelination is required for stable myelination and optimal nerveconduction. TheNuRD complexas well
asDNAandhistone methylationregulatethese mecha-nisms. Current knowledge on this topic is discussed belowandsummarized inFigure 1.
HDAC1/2controlSClineagespecification
ThetranscriptionfactorSox10isessentialforSClineage specification and the entire SC developmental process [23].However,Sox10isexpressedinallneuralcrestcells. Thus, additional mechanisms direct Sox10-dependent specification into the SC lineage. Indeed, ablation of HDAC1/2inneuralcrestcellsbycrossingHdac1/2floxed mice with mice expressing the Cre recombinase (Cre) undercontroloftheWnt1promoter(Wnt1-Cre)prevents peripheralgliaspecification[24].WeshowthatHDAC1/2 andSox10 interactto activatethepromoterof theearly lineagemarkerMyelinproteinzero(P0[25])andof Pax3, another key transcription factor for SC specification [26,27]. In turn, Pax3 and Sox10 activate the Sox10 MCS4enhancer(alsocalledU3[28,29])tomaintainhigh levelsofSox10,whichinducesexpressionofP0andFatty acidbindingprotein7(Fabp7),anotherearlyperipheralglia marker[30].
HDAC1/2regulateradialsorting,SCsurvival,induction andmaintenanceofmyelination
HDAC1/2havealsoessentialfunctionsatlater develop-mentalstagesandinthemaintenanceofintegrityinadult nerves.AblationofHDAC1/2inSCprecursors(by cross-ingHdac1/2floxedmicewithmiceexpressingCreunder controloftheDhhpromoter)leadstoradialsortingdelay and virtualabsence of myelin, followedby massiveSC apoptosis[31]. Weshowedthat HDAC1/2maintainSC survivalbylimitingactive-beta-catenin(ABC)levelsand thattheyinteractwithSox10toactivatetheSox10andP0 promotersandtheKrox20MSE(myelinatingSCelement [32]), a critical enhancer for expression of the major transcription factor of SC myelination Krox20 [33]. In adult SCs, ablation of HDAC1/2 (using the tamoxifen-inducible CreERT2 under control of theP0 promoter) leads to disruption of paranodal and nodal structures, followed by moderate demyelination due to 50% loss of P0 expression, presumablycaused by impairment of Sox10-mediatedactivationoftheP0promoter[34].Chen et al. [35] also showedthat HDAC1/2 interact with the transcriptionfactorNFkBtoactivatetheSox10promoter in SCs during developmental myelination. However in vivoNFkBinactivationleadsto minoreffectson myeli-nation[36],thereforethismechanismmayhaveaminor controloverinvivomyelination.
TheBAFcomplexATPaseBrG1isrequiredforradial sortingandmyelination
AblationofBrG1inSCprecursors(usingfloxedBrg1and Dhh-Cremouselines)preventsradialsortingand myelina-tion[37,38].Limpertandcolleagues(2013)showthatBrG1 interactswithNFkB toactivatetheSox10 promoterand suggestthatthismechanismcontrolsBrG1-dependentSC
myelination[37].However, giventhe minoreffect ofin vivoNFkBinactivationonmyelination[36],BrG1 inter-actionwithNFkBislikelytohaveminorfunctionsonSC myelination.Furthermore,whileSox10levelsare moder-ately[37]ornot[38]affectedintheabsenceofBrG1inSCs, Oct6,Krox20andP0arevirtuallyabsent.Indeed,theBAF complex is recruited by Sox10 to the Oct6 SCE (SC enhancer[39]),theKrox20MSEandtheP0promoterto induce Oct6, Krox20 and P0 expression [38–40], and therebycontrolsthemyelinationprocess.
TheNuRDcomplexregulatesradialsortingand myelination
As mentioned earlier, Krox20 is a major transcription factor of SC myelination, which is absolutely required fortheactivationofmyelingenesandtheproductionof peripheralmyelin[33].Interestingly,Krox20canalsoact asatranscriptionalrepressor.Indeed,Krox20caninteract withthetranscriptionalrepressorsNAB1/2,whichrecruit theNuRDcomplextosilenceexpressionofinhibitorsof myelinationincludingId2,Id4andcJunatalate myelina-tionstage [41–43]. Consistently, ablationof theNuRD complexATPaseCHD4in immatureSCs(usingfloxed Chd4andP0-Cremouselines)leadstoincreased expres-sionofinhibitorsofmyelinationandtohypomyelination [43]. Ablation of CHD4 also leads to delayed radial sorting [43]. At this earlier developmental stage, the NuRD complex may allow radial sorting by silencing the transcription of Sox2, Hey2 and Ednrb [44,45], otherinhibitorsof SC differentiation,together withthe transcriptionfactorZeb2.Indeed,Zeb2hasbeen shown torecruittheNuRDcomplexinSCs[44]andablation ofZeb2inSCprecursors(usingfloxedZeb2andDhh-Cre mouse lines) leads to upregulation of Sox2, Hey2 and Ednrb and prevents radial sorting and myelination [44,45].However,ablationofZeb2results inamore severephenotypeascomparedtoablationofCHD4[43], suggestingthatZeb2 actsalso through CHD4-indepen-dent mechanisms. Alternatively, the different levels of phenotypeseveritybetweenZeb2andChd4mutantmice could bedue to the differentCre mouse lines used to generatethesemutants.
DNAdemethylationadjustsmyelinthickness
DNAdemethylationofselectedgenesappearsnecessary for appropriate developmental myelination. Indeed, DNAdemethylationatpromotersandenhancersof mye-lingenes(Mbp,Pmp22,Prx,Cnp),transcriptional regula-torsofmyelination(Lgi4,Nab1,Nfatc1)andlipid metab-olismgenes(Scap,Srebf1,Hmgcr,Mvk,Pmvk,Dgat1,Lipe, Scd1, Abca2and Elovl7) correlates with upregulation of these genes during myelination [46]. Simultaneously, expression of DNMTs decreases and expression of Gadd45a(growtharrestandDNAdamage45a),Gadd45b, and Apobec1 (apolipoprotein B mRNA editing enzyme catalyticsubunit1),whichpromoteDNAdemethylation [47],increases[46].TheprincipalmethyldonorSAMe
isconvertedintoS-adenosylhomocysteineand N-methyl-glycinebyGlycine N-methyltransferase(GNMT,[48]). Ablation of GNMT impairs this conversion and thus increasestheavailabilityofSAMe,whichresultsinathin myelin phenotype in constitutive Gnmt mutant mice [46,48]. These data provide further evidence that DNA demethylation of myelin-related genes allows SCs to build myelin sheaths of appropriate thickness duringdevelopment.
Involvementofrepressivehistonemethylationmarksin regulatingmyelination
Other repressive mechanisms mediated by H3K27me3 marksongenepromotershavebeenreportedduringthe myelinationprocess.Nessandcolleagues(2016)identify Nuc-ErbB3,anuclearvariantofErbB3,asa DNA-bind-ingproteinthatpromotesH3K27me3atgenepromoters presumablyby activatingthe HMT EZH2. This study reports that loss of Nuc-ErbB3 (constitutive mouse mutant)leads to developmentalhypermyelination [49]. Consistently,ablationofthePRC2subunitEedin imma-tureSCs(usingfloxedEedandP0-Cremouselines),that leads to inactivation of the PRC2 complex (mediating H3K27me3through itsHMT EZH2), results in hyper-myelination in adults [50]. This is due to impaired repression of Igfbp2 that maintains the activation of Akt-dependent myelination [50]. However, no defect in developmental myelination occurs in Eed mutants [50]. A thirdstudy conducted in SC culturesproposes thatlossofEZH2leadsincontrasttotheinhibitionofthe myelination process through impaired inactivation of p75kip2 transcription that promotes expression of the inhibitorofmyelinationHes5[51].Theseinconsistencies needto beresolvedwith additionalinvivostudies.
Functions
of
chromatin-remodeling
enzymes
in
SCs
after
lesion
RegenerativepropertiesofthePNSafterlesionaretoa large extent due to the plasticity of SCs that first de-differentiateandconvertintorepaircellsin responseto injurytofosterandguideaxonalregrowth,andsecond re-differentiatetoremyelinateregeneratedaxons[3,5,7,10]. These different key steps of the regeneration process involvethedynamicregulationof manygenesand thus thetimedactionofseveraltranscriptionfactors,whichare known to promote either SC de-differentiation or re-differentiationafterlesion.Incomparison,ourknowledge onthefunctionsof chromatin-remodeling enzymesand their coordinated action with transcription factors after lesion is just emerging with recently published studies thatarediscussedbelowand illustratedinFigure 2. HATs,HDACs,HMTsandHDMscontroltheconversion intorepaircells,theircellcycleandfunctionsafter lesion
Inadultnerves,injury-inducedgenesaresilencedbythe PRC2complex,whichaddsrepressiveH3K27me3marks
attheirpromoter[52].Uponinjury,thesegenesare de-repressed by H3K27 demethylation and activated by H3K4 methylation at promoter regions and by H3K27 acetylation at enhancers, the latter correlating with recruitment of the transcription factor cJun [52,53], a majorinducerofSCconversionintorepaircells[54].This mechanismallowstheexpressionofinjury-inducedgenes includingShhandtheneurotrophicfactorGdnf[52],and thuspromotesaxonalregrowth afterlesion.
De-differentiatedSCsre-enterthecellcycleafterinjury. TopreventSCoverproliferationthatcouldleadtotumor formation,theArf/Ink4locusisde-repressedbytheHDM JMJD3 that demethylates H3K27 at the promoter of p19Arfandp16Ink4aandpotentiallyalsoatthep15Ink4b promoter. These tumor-supressor proteins then inacti-vateSCproliferation[55].
EventhoughtheconversionofSCsintorepaircellsafter lesion isefficient, it isinteresting to point outthatthis process is not optimal and can be improved. Indeed, shortly after injury, HDAC2 is upregulated in SCsand mediatestheassemblyofaproteincomplexwiththetwo H3K9 HDMsKDM3A and JMJD2C andthe transcrip-tionfactorSox10,whichisrecruitedto theOct6SCEto demethylateH3K9andinduceOct6transcription.Inturn, Oct6slowsdowntheupregulationofcJun[56]. Consis-tently, ablation of HDAC1/2 in adult SCs (using the tamoxifen-inducible P0-CreERT2 mouse line) or a short-termtreatmentwiththeHDAC1/2inhibitor Moce-tinostatdelaysOct6upregulationafterlesionandleadsto higher and earliercJun upregulation, earlier conversion intorepaircellsandfasteraxonalregrowth[56]. HDAC1/2andtheNuRDcomplexpromoteremyelination afterlesion
At the remyelination stage, the same protein complex assembled by HDAC2after lesion (described above) is recruitedto theKrox20MSEtodemethylateH3K9and activateKrox20transcription[56].Krox20theninduces remyelination.IntheabsenceofHDAC1/2inadultSCs, Krox20 expression is strongly reduced. This results in impairedremyelination[56],indicatingthatHDAC1/2 are necessaryfortheremyelination process afterlesion. Ofnote,ashort-termHDAC1/2inhibitortreatmentafter lesion (during the 3 days following lesion) does not interfere with the remyelination process, but leads to fasterfunctionalrecoveryduetofasterandmoreefficient axonalregeneration,asmentionedabove[56],thereby identifyinganoveltreatmenttoacceleratePNS regener-ationafterlesion.
Toenableremyelinationafterlesion,itisalsonecessary to downregulateinhibitorsof myelinationsuchas Sox2, Hey2andId2.SimilartoitsfunctionindevelopingSCs, the transcription factorZeb2 represses the promoter of thesegenes in conjunctionwith theNuRDcomplex to
silencetheirexpressionandtherebyallowremyelination [44,45].
Conclusion
Insummary,eachstepof SCdevelopment,the mainte-nance of integrity in adult nerves and theregeneration process afteraPNS lesionare controlledby chromatin-remodelingenzymesthateithermodifyhistones,DNAor remodel nucleosomes. The recent studies discussed in this review show that several chromatin-remodeling enzymes or events act in sync to regulate one cellular process.Itappearsalsoincreasinglyobviousthat chroma-tin-remodelingenzymesare often targeted to aspecific setof genesthroughtheirinteraction withtranscription factors,andtherebyactasco-factorsofthesetranscription factorstoenabletheregulationof theirtargetgenes. Althoughrecentfindingshaveimprovedour understand-ing of chromatin-remodeling enzymes functions in SC development, maintenance and plasticity, a lot more work—preferentiallycarriedoutinvivo—is necessary to fully understand their functions and mechanisms of action, resolve inconsistencies, and potentially use and controlthemindiseasecontexts.Inparticular,itwillbeof majorimportanceinfuturestudiestoanalyzethe coordi-natedactionof differenttypesof chromatin-remodeling enzymes, and elucidate their mode of activation and recruitmentto specific targetgenes. Mass spectrometry combinedwithchromatinimmunoprecipitationanalyses will certainly reveal instrumental to identify dynamic protein complex formation and recruitment to specific loci depending on the developmental or regeneration stage.
Conflict
of
interest
statement
Nothingdeclared.
Acknowledgements
ResearchintheJacoblabissupportedbytheSwissNationalScience
Foundation(grantnumbers:PP00P3_163759and31003A_173072),the
InternationalFoundationforResearchinParaplegia/OPO-Stiftung(grant
number:IRP-P147),theNovartisFoundation(grantnumber:15C191),and
theForschungspoolofFribourgUniversity.
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ThisstudyshowsthatHDAC2assemblesaproteincomplexwiththetwo
H3K9HDMsKDM3AandJMJD2CandwithSox10tode-repressand
activate Oct6 transcriptionearlyaftera PNSlesion. Thiscomplexis
subsequentlyrecruitedtotheKrox20MSEtode-repressandactivate
Krox20transcriptionattheremyelinationstage.Theauthorsdemonstrate
that inactivating this mechanism accelerates cJun upregulation, the
conversionintorepaircellsandaxonalregrowth,butimpairs
remyelina-tion.However,short-terminactivationusinganHDAC1/2inhibitor
accel-eratesregenerationandfunctionalrecoverywithoutimpairing
remyelina-tion,therebyidentifyinganoveltreatmenttoimprovePNSregeneration
afterlesion.
