Role of Co-Regulators in Metabolic and Transcriptional Actions of Thyroid Hormone

56:3

i astapova Co-regulators in thyroid 56:3 R73–R97 Review hormone action

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

Correspondence Inna Astapova should be addressed to I Astapova Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Email Medical School, Boston, Massachusetts, USA [email protected]

Abstract

Thyroid hormone (TH) controls a wide range of physiological processes through TH Key Words receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine ff thyroid hormone

(T3)-dependent transcription factors: on positively regulated target genes, unliganded receptors TRs mediate transcriptional repression through recruitment of co-repressor complexes, ff nuclear co-repressor f while T3 binding leads to dismissal of co-repressors and recruitment of co-activators to f steroid receptor activate transcription. Co-repressors and co-activators were proposed to play opposite co-activator ff animal models roles in the regulation of negative T3 target genes and hypothalamic–pituitary–thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. ff transcription Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR

binding have generated compelling new data regarding effects of T3, local chromatin

Journal of Molecular Endocrinology structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the Journal of Molecular function of co-regulators that may emerge from the genome-wide TR recruitment analysis. Endocrinology (2016) 56, R73–R97

Introduction

Thyroid hormone (TH) is essential for normal release of both forms of TH by the thyroid gland:

development, growth, reproduction, and regulation of predominant thyroxine (T4) and the active form tri-

metabolism and thermogenesis in mammals. Circulating iodothyronine (T3). High TH levels signal to suppress TRH TH levels are tightly controlled by a negative feedback and TSH, while a drop in circulating TH will stimulate within hypothalamic–pituitary–thyroid (HPT) axis, their synthesis and release (Chiamolera & Wondisford where thyrotrophin-releasing hormone (TRH) from the 2009, Costa-e-Sousa et al. 2012). Intracellular levels of hypothalamus stimulates production and secretion of active TH are also finely regulated by deiodinases and thyroid-stimulating hormone (TSH) by the pituitary, transmembrane transporters such as the monocarboxylate which in turn stimulates synthesis, processing, and and organic anion transporter families. Type 1 and type 2

http://jme.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-15-0246 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 09:24:34PM via free access

10.1530/JME-15-0246 Journal of Molecular Endocrinology produce threemainT ( nuclear receptor(NR)superfamily. Two different genes ligand-dependent transcriptionfactorsthatbelongtothe regulation of gene transcriptionbyTH receptors (TRs): 2013). PhysiologicaleffectsofTHarelargelymediatedby & Visser 2013, form reverseT and type35ʹ 1994, (SMRT orNCOR2)(Baniahmad of retinoic acid receptor and thyroidhormone receptor co-repressor (NCoRorNCOR1)andsilencingmediator known asNCOA1– such assteroidreceptorco-activators1– to identificationandcloningofthefirstco-activators, proteins intranscriptionalregulationbyNRsandled confirmed theimportantroleofthesereceptor-associated that interactwitheitherligand-boundorunligandedNRs Damm silence targetgenesintheabsenceofTH(Brent activation oftranscription,TRspossessthecapabilityto 2015, TH levels,aswellfunctionofHPTaxis(Bernal normal maintenanceofbothintracellularandcirculating Actions ofdeiodinasesandtransportersarecrucialfor Charalambous &Hernandez2013, 5 Hodin developmentally regulated manner (Cheng and THRB2,whichareexpressedinatissue-specific 1994, et al. chromatin structure and accessibility and ultimately lead chromatin structureandaccessibility andultimatelylead methylation, ubiquitylation, andothers,whichchange remodeling or histone modifications, such as acetylation, of complexesthatmediate ATP-dependent chromatin- importantly play a key role in recruitment and function between NRsandbasictranscriptionalmachinery, butmost as a bridge directly bind DNA. Co-regulators may serve their roleinregulationoftranscriptionandinability to diverse group of proteins, which are broadly defined by nursa.org/nursa/molecules/index.jsf) representing very receptor co-regulatorshavebeenidentified(https://www. et al. 1997, Weinberger had become apparent that in addition to T (RXR). SoonafterthecloningoffirstTRisoforms,it homodimers orheterodimerswithretinoidXreceptors regionsas response elements(TRE)intheirregulatory transcription oftargetgenesbybindingthyroidhormone ) encode the THRA and THRB subtypes and Thra andThrb)encodetheTHRATHRBsubtypes ʹ DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org -deiodinases (DIO1andDIO2)convertT Review Fonseca Chen et al. 1989).Experimentsdesignedtoisolateproteins t al.1989, et Voegel Horlein et al. 1986 , t al.1997 , et -deiodinase (DIO3)inactivatesT 3 t al.2013, et Hoftijzer andT et al. 1996).Sincethen,over300nuclear 3) and co-repressors: nuclear receptor 3) andco-repressors:nuclearreceptor 1995, et al. Koenig 3 -binding isoforms THRA1, THRB1, -binding isoformsTHRA1,THRB1, 2 ). TRs regulate Zhang &Lazar2000).TRsregulate , respectively(Arrojo 2011, et al. Chen &Evans1995, Hernandez t al.1988, et Onate 1995, et al. i

astapova © 2016SocietyforEndocrinology Gereben Schweizer & Kohrle 1995, et al. t al.2007, et Sap 3 (SRC1–3, also 3 (SRC1–3,also Printed inGreatBritain 4 intoactiveT Cavailles 3 ). 2008). et al. t al. 2010, et t al.1986, et t al.2013, et -dependent -dependent 4 et al. 1989, andT Halachmi Halachmi Torchia Heuer Heuer t al. et et al. 3 to to 3 ,

T are activated by unligandedTRandrepressed upon the regulation ofnegativeTRtargets,suchasTshb gene,which At thesametime,mechanismoftranscriptional deletion (Flamant and thefactthatathyroidmicecanberescuedbyTR sever phenotypethanmousemodelsdeficientinallTRs that neonatalhypothyroidismpresentswithmuchmore repression byunligandedTRsisunderscoredthefact & O’Malley2002).Theimportanceoftranscriptional activate transcription(Glass&Rosenfeld2000, opposing activities,suchashistoneacetylases(HATs), to by co-activators that bring enzymatic complexes with the dismissalofco-respressorsandtheirreplacement a conformationalchangeinthereceptorthatleadsto actively represstranscription.Hormonebindinginduces which modify histones and chromatin structure to complexes, importantly histone deacetylases (HDACs), recruited tounligandedTRsandbringenzymatic a positivelyregulatedtargetgene,co-repressorsare to bindtheDNAindependentofhormone.On action hasbeenproposed,whereTRsarepostulated 1998, et al. 1999, of NRs,inamutuallyexclusivemanner(Darimont to the same surface on the ligand-binding domain (LBD) sequence. Co-repressorsandco-activatorsarerecruited in theco-regulatorRIDsandsurroundingaminoacid and NRs is thought to be encoded by the differences 1999). Thespecificityofinteractionsbetweenco-regulators recruitment ofco-activators(Millard a conformational change in helix 12 of LBD that favors unliganded orantagonist-boundNR,whileligandsinduce Xu as discussedbelow. of thesyndromeresistance tothyroidhormone(RTH) also thoughttoplayarolein thephenotypicpresentation still lacking.Inappropriaterecruitment ofCoAandCoRis precise molecularmechanism underlyingtheseeffectsis play opposite functions on this type of target genes, but suggested thattheco-repressorsandco-activators may proteins (Hu&Lazar1999, 1997) andaLXXH/IIXXXI/LCoRNRboxinco-repressor Heery LXXLL motif,termedNRbox,inco-activators(Heery domains (RIDs)thatarecharacterizedbyapresenceof and NRsaremediatedbyspecificreceptor-interacting & Workman 2008).Interactionsbetweenco-regulators 2007, to activationorrepressionoftranscription(Kouzarides hormone action Co-regulators inthyroid 3 Published byBioscientifica Ltd. binding, is less clear (Darling ): generally co-repressors are recruited to al.2002):generallyco-repressorsarerecruitedto et Based on this, the bimodal switch model of TR Feng Millard Perissi et al. 1998, 2013, et al. et al. 1999, 2002, et al. Nolte Downloaded fromBioscientifica.com at09/26/202109:24:34PM Strahl & Allis 2000, Nagy et al. 1998, Watson Flamant &Samarut2003). 1989 ). It has been et al. 1999, et al. et al. 2012). 56 t al.2013, et Wang : 3 Perissi et al. 2006, Suganuma Suganuma McKenna R74 Nagy Nagy et al. et al. et al. via freeaccess

Journal of Molecular Endocrinology in vivothecontextofTRsignaling. co-repressors NCoRandSMRT, astheyarethebeststudied limit thereviewtoSRC/p160familyofco-activatorsand by dependent co-repressor(LCOR)(Song 140 (RIP140orNRIP1)(Moore 2002),andco-repressorsreceptorinteractingprotein et al. (PPARG) co-activator-1a(PGC-1aorPPARGC1A) (Wu 2001), peroxisomeproliferator-activatedreceptorgamma associated protein220(TRAP220orMED1)(Ito&Roeder in vitro), includingco-activatorsthyroidhormonereceptor- have beenshowntobindandmodulateTRactivity(atleast oftheSRCfamilyandNCoR/SMRT,discovery manycofactors genome-wide TR chromatin occupancy studies. Since the models andalsoincorporatesomeinsightsfromrecent vivo roleofco-regulatorsinTRactionobtainedfromanimal 1997, are responsiblefordirectinteractionswithNRs(Chen contains threecopiesoftheLXXLLmotif(NRbox),which Onate sensitive toproteasome-dependentturnover(Li contains anuclearlocalizationsignal,andrendersSRCs NRs, butinteractswithseveralothertranscriptionfactors, forco-activationof family members.Itisnotnecessary (b-HLH-PAS) amongthe domainisthemostconserved The N-terminalbasichelix-loop-helix-Per/ARNT/Sim 2014, contain three main functional domains (Dasgupta and overallsequencesimilarityof50 respectively), with a molecular weight around 160 closely relatedproteins:SRC1,-2,and-3(NCOA1,2and 3, The SRC/p160familyofco-activatorsconsiststhree co-regulator proteins Structural andfunctionaldomainsof Yang &Privalsky2001).Finally, twoactivation domains genes intheabsenceofhormone (Iwasaki an importantroleintheupregulation ofTRHandTSH a T isoforms throughnoncanonical NR-bindingdomainsin that SRCscanbindtheN-terminalportionofTHRB 1998, et al. show preferentialbindingtocertainNRs(McInerney co-activators orNRboxeswithinthesameco-activator NR–LXXLL motifinteractions,sothatdifferent adjacent portionoftheproteindictatespecificity of that distinctaminoacidsequencesofLXXLLmotifsand analysis andinvitro interactionstudieshavedemonstrated http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review Moore andGuy(2005)Yao (2014).However, wewill 3 In this review, we will focus on the data regarding the -independent manner, whichmaypotentially play Johnson &O’Malley2012, Heery Heery 1995).ThecentralpartoftheSRCmolecule et al. Moore t al.1997, et 2004).Ithasalsobeensuggested et al. Voegel t al.2004),andligand- et i t al.1998).Mutational et

1999, arginine arginine methyltransferase1(CARM1),andprotein (CBP)/p300 possessingHAT, co-activator-associated co-regulator complexessuchasCREB-bindingprotein for recruitmentofadditionalchromatin-modifying AD1 andAD2,locatedintheC-terminus,areresponsible expressed SMRT isoformcontainsonlyRID2andRID1. shown inlightercolortoreflectthe factthatthepredominantly of othercofactorrecruitmentareindicated byarrows.RID3ofSMRT is co-regulators andNRs,co-repressors andHDAC3areshown.Regions boxes withintheco-regulatormolecules. Interactionsbetween domains (RD),anddeacetylaseactivation domain(DAD)areindicatedby activating domains(AD),receptor-interacting domains(RID),repression mutants discussedinthisreview(C).LocationsofbHLH/PAS domain, wt NCoRandSMRT (B),andvariousgeneticallymodifiedco-repressor Schematic representationofthestructurewtSRCfamilymembers(A), Figure 1 Onate NCoR/SMRT interaction studies haveshownthattheyarenotinvolved domain alsocontainsthreeLXXLL-likemotifs;however, hormone action Co-regulators inthyroid Published byBioscientifica Ltd. C B A NCoR-DADm SRC SMRT NCoR NCoR SMRT Dasgupta SMRT 1998 , et al. N-methyl transferase1(PRMT1)(Chen -DADm GPS2 bHLH/ ∆ID ω mRID1 mRID TBL1/TBLR1 −/− RD1 2014, et al. PA Voegel S HDAC3 DAD HDAC3 HDAC3 HDAC3HDA HDAC3HDA HDAC3 HDAC3 DADm DAD DADm DAD DAD DAD DAC3 DAC3 Downloaded fromBioscientifica.com at09/26/202109:24:34PM AC AC 1998 , et al. RD2 NR Koh RIDs NR RD3 2001, et al. NR Xu &Li2003).AD1 56 p300/CBP : 3 RID3 RID3 RID3 RID3 AD1 RID2 RID1 RID3 NR NR TR Li TR RID2mR RID2m RID2 RID2 NRN 2000, et al. NR NR RID1 NR CARM1 NR R RID2 R TR NR AD2 R NR RID1 NR NRN NR RID1 RID1 TRT NR N ID1m PRMT1 R75 R t al. et NR RID1 via freeaccess Journal of Molecular Endocrinology 2011, required formaintenanceofthiscomplex(Oberoi the CoRcomplex,whileGPS2appearstobestructurally responsible forubiquitylation-dependentdismissalof complex (Oberoi or TBL1XR1),whichalltogetherformthecorerepression (TBL1 orTBL1X)anditshomolog,TBL-related1(TBLR1 pathway suppressor (GPS2) and transducin addition toHDAC3,these partners include G protein appear tobeessentialfortheirrepressivefunction.In in stoichiometricassociationwithNCoR/SMRTand and context-specific,someproteinsareregularlyfound Although co-repressorcomplexesareheterogeneous stable andreproduciblewaywithbothco-repressors. NCoR, becauseitistheproteinthatassociatesinmost responsible for the repressive activity of SMRTand al.2013).HDAC3appearstobethemainenzyme et Guenther transcriptional repression(Guenther histone tails leading to chromatin remodeling and of histonedeacetylase3(HDAC3),whichdeacetylates co-repressors responsibleforrecruitmentandactivation deacetylase activationdomain(DAD),theregionof Nagy complex (Alland through recruitmentof a multiprotein repression NCoR andSMRTmediatetranscriptionalrepression (RD1– complexes, see For comprehensive review of co-repressor structure and 1B). functionaldomains(Fig. containing conserved amino acididentity) large proteins of 270 located intheirC-terminaldomain(Fenget al.2009). 1998). Inaddition,SRCshaveweakintrinsicHAT activity in recruitmentofSRCstoDNA-boundTR(Takeshita for theretinoicacidreceptor (RAR)(Cohen avidity forTR,whileS2has demonstratedpreference RIDs (N3inNCoRandS3 SMRT)havingthehighest binding todifferentNRs,with mostN-terminalofthe acid sequencesofspecific RIDsdictatethepreferential al.1999, et NR-binding asoutlinedabove(Hu&Lazar1999, by apresenceofCoRNRbox,whichisessentialfor proteins containsthreeRIDsthatarecharacterized and t al. 2011, et in atissue-specificmanner(Faist different co-repressor isoforms, which are expressed RIDs aresubjecttoalternativesplicingthatproduces DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review NCoR andSMRTarehighlyhomologous(40% Watson 3) arelocatedwithintheN-terminalportionof Yoon t al.1997).LocatedintheN-terminusisalso et 2000, et al. 2003).TheC-terminusofco-repressor et al. Malartre Perissi t al.(2012).Threerepressiondomains et Millard 2011). BothTBL1andTBLR1 are et al. t al.1997, et t al.1999).Theexonsencoding et t al. 2004). Interestingly, amino et Ishizuka &Lazar2003, , (2013) et al. i

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in vivo. and SMRTplaynonredundantrolesintheTRactions RIDs totheTRs,ithasbeenhypothesizedthatNCoR 2000). Becauseofthesedifferencesinbindingspecific 2007). in embryonic lethality(Jepsen in embryonic as germlineknockoutofeitherco-repressorresulted and havephysiologicfunctionsbeyondNRsignaling, play nonredundant roles in mammalian development vivo rolesofco-repressorsrevealedthatNCoRandSMRT funtion ofHPTaxisandRTH'. in peripheraltissues'and'Rolesofco-regulatorsthe discussed below in the sections 'Roles of co-regulators pertinent toTHsignalingandmetabolicregulationis al.2014b).Dataobtainedfromtheseanimalmodels et by reducedreproductivefunctioninSrc2 were generated. conditional knockoutand mutantknock-inmodels animal andtheirroleinspecific NRsignaling,several physiological functionof NCoR andSMRTinadult adipogenesis (Sutanto animals revealedthatSMRTplaysanimportantrole in gland) was observed Src1gland) wasobserved responsive tosteroids(testis,uterus,andmammary hormone full physiologicalresponsetosexsteroidsandgrowth have firstprovedtheimportanceofSRCproteinsfor Mice deficientforindividualmembersofthep160family Animal modelsofco-regulator function reported inSrc3 stature andreducedfemalereproductivefunctionwere signaling andestrogenproductionresultinginshort al.2002, et found to be embryonic lethal,andanalysis ofSmrt found tobeembryonic whole-body SMRT-deficient mouse model wasalso neural stemcellstate(Jepsen normal forebraindevelopmentandmaintenanceofthe RAR andNotchsignalingpathwayareresponsiblefor protein FOXP1.Furthermore,interactionsofSMRTwith development throughitsinteractionswithaforkhead 2000). Knockout of deathbyE15.5 (Jepsen which resultinembryonic neuronal differentiationanddefinitiveerythropoiesis, Dasgupta certain functionalspecificityinvivo(recentlyreviewed These findingsestablishedthatp160co-regulatorspossess Cohen hormone action Co-regulators inthyroid Published byBioscientifica Ltd. in At thesametime,firstattemptstoelucidatein NCoR t al.2000, et 2014, et al. in vivo.Decreasedgrowthoforganshighly Xu −/− animalshavedefectsinthymocyteand −/− t al.1998).Defectivegrowthhormone et mice(Wang revealed its critical rolein heartSmrt Makowski Dasgupta & O’Malley 2014, 2010).Toet al. betterunderstand Downloaded fromBioscientifica.com at09/26/202109:24:34PM −/− andSrc2 et al. 2000, t al.2008).Adifferent et t al.2003, et 2000, et al. −/− 56 , andaccompanied : 3 −/− Xu mice(Gehin Jepsen Webb et al. 2000). Stashi R76 t al. et et al. et al. +/− via freeaccess

Journal of Molecular Endocrinology model (NCoRω 2008). Recently, Goodson receptor (LXR)isoformsweregenerated(Astapova domains andisunabletointeractwith TR and liver X NCoR∆ID, thatislackingthetwoN-terminalRID conditional alleleencodingforamutantNCoR,termed co-repressor isoforms.To thisend,micebearinga NRs aswellphysiologicalsignificanceofdifferent address theroleofco-repressorsinactionspecific makes targetingofspecificRIDanattractivestrategyto 2003, Faist different NRs(Cohen have threeC-terminalRIDs,thatpreferentiallybind ( manipulations thataffectonespecificfunction CoR proteinsmakesthemidealtargetsforgenetic 2015, knockout modelshavebeenpublished(Shimizu generated, andliver-specificadultwhole-bodySmrt knockoutallelehasalsobeen A conditionalSmrt isoforms (Nofsinger loses its ability to interactwith RAR, TR, and PPAR Li and liver-specific was describedandusedtogeneratemuscle-,adipocyte-, complete deletion of and RID2 domains, so that the resulting mutant created, where mutations were introduced into RID1 approach, theSmrt of the full-lengthNCoRω splicing site, which results in the inability to produce repressive functionsofHDAC3 (Sun nonenzymatic of HDAC3byco-repressors,which preserves HDAC3 activity, it doesnotcompletely abolish recruitment 2013). As was shown later, while this mutation eliminates generated andcharacterized (Alenghat in DADofNCoR (N-DADm)andSmrt ( repressive actionsbyrecruitingandactivatingHDAC3 et al. 2010). C), particularlyPPARsRID (Fig. 1 (Fang to NRsthatpreferablyutilizetheremainingC-terminal B. ThisleadstoanenhancedrecruitmentofSMRT Fig. 1 introduced intooneofthetwoRIDs,shownasRID2 in the mutationthatabolishesbindingtoNRswasonly Guenther i. 1C).Asoutlinedabove,bothNCoRandSMRT Fig. http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review NCoRδ t al.2011, et Presence ofdistinctfunctionaldomainsinthe A conditionalNCoRnullallelethatcanproduce As the CoRs are thought to exert much of their As theCoRsarethoughttoexertmuchoftheir t al.2009, et Malartre Sun , containing only RID2 and RID1. In a similar et al. 2013). ), mice bearing inactivating mutation 2001),micebearinginactivatingmutation et al. et al. 2004, −/− Sun ) withamutationintroducedinto Goodson NCoR knockout mice (Jo t al.2013, et mRID t al.2008).InSmrt et NCoR in atissue-specificmanner isoform,andglobalexpression t al.2001, et knock-inmousemodelwas Webb et al. (2014)reportedamouse t al.2011, et i Yamamoto et al. 2000).Thisfeature

astapova © 2016SocietyforEndocrinology et al. 2013). Cohen et al. 2008, ) were also S-DADm) werealso 2010, et al. Makowski Printed inGreatBritain ). al.2011). et t al.2000, et t al. 2015, et mRID1 You Smrt mice, Reilly t al. et t al. et et al. et al. mRID

with afocusonTHsignalingthroughtheTR(Table 1). summarize theresultsofinvivoco-regulatorstudies liver (Boergesen binding sitesundernonstimulatedconditionsinthe DNA-binding elementsshareagreatpercentage ofthe demonstrated thatevenNRswithdifferentpreferred Furthermore, recentgenome-widerecruitmentstudies Maglich 2010, 2014, SRC1 is involved in activation of transcription of key least partlyduetoimpaired hepaticgluconeogenesis,as also leadstohypoglycemia infedandfastingstates,at by likely resulting from the loss of PPARGC1A co-activation expenditure (EE)anddefectiveadaptivethermogenesis when fed high-fat diet, presumably due to reduced energy Dasgupta &O’Malley2014,Stashiet al.b). metabolic pathwaysandtissues(Dasgupta modulate expressionofmultipleenzymesindifferent as essentialregulatorsofenergyhomeostasisthey Mouse knockoutmodelsidentifiedSRCco-activators a 4nucleotidespacer(DR-4)(Brent2012, the samepreferredresponseelement:directrepeatwith NR responseelement,particularforLXRs,whichshare (squelching); andcompetitionforbindingtothesame competition fordimerizationpartnersandco-regulators same gene;regulationofTHmetabolismbyotherNRs; elements locatedinthepromoter/enhancerregionsof include: bindingofdifferentNRstospecificresponse (NR1D1), andothers.Themechanismsofinterplaymay liver receptorhomolog-1(LRH-1orNR5A2),Rev-ErbA are controlledbyvariousNRs,includingTRs,LXRs,PPARs, acid, carbohydrate,cholesterol,andbileacidmetabolism NRs. Forexampleintheliver, enzymesinvolvedinfatty and brain,thereisasignificantinterplaybetweendifferent including liver, muscle,whiteandbrownadiposetissues, pathways (Brent2012, are widely expressed and control multiple metabolic specific transcription factor. TR isoforms and co-regulators a may be difficult to attributethe physiologiceffectsto where co-regulator function has been manipulated, it of co-regulator– While effortshavebeenmadetoaddressthespecificity Roles ofco-regulators inperipheral tissues Src1 hormone action Co-regulators inthyroid Published byBioscientifica Ltd. Src1 (Picard Src1 knockoutmicedemonstrateincreasedweightgain knockoutmice Mottis Christoffolete et al. 2004, 2013, et al. et al. 2002).Atthesametime,lackofSRC1 models NR interactions,inmanyvivomodels ). Therefore, we will briefly al.2012).Therefore,wewillbriefly et Miao , 2010 et al. Cheng Downloaded fromBioscientifica.com at09/26/202109:24:34PM ). In many tissues, Obregon 2014).Inmanytissues, et al. 2015, 2010, et al. Hashimoto & Mori 2011, Qatanani 56 : 3 Dasgupta Cheng t al.2014, et et al. 2005). R77 t al. et et al. via freeaccess

Journal of Molecular Endocrinology Smrt Src2 Src1 Mouse model Table 1 NCoRΔID Smrt NCoR Src3 Liver-specific NCoRΔID DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Src1 L-NCoRΔID Review −/ −/ −/ +/− −/ −/ (Ncoa3) (Ncoa2) (Ncoa1) −/ (Ncor2) (Ncor1) Summary ofphenotypesmousemodelsdiscussedinthereviewasrelatedtoTHsignalingperipheraltissues. Embryonic lethality, impaired Embryonic lethality, defectsin Impaired metabolismoflong Improved glucoseandlipid Decreased adipocytedifferentia- Impaired circadianregulationof Diminished fatabsorptiondueto Impaired hepaticglucoserelease Lean, increasedglucosetoler Hyposensitivity toTHintheliver; Perturbed aminoacidmetabolism Impaired hepaticgluconeogenesis Obesity onhigh-fatdietdueto Obesity withhighernumberof Normalized sensitivitytoTHin Phenotype Upregulation ofLXRtargetgenes Increased expressionofhepatic Ameliorates tosomedegree Increased sensitivitytoTHin neuronal differentiation erythropoiesis, thymocyte,and forebrain development differentiation, andimpaired un heart development, chain fattyacids increased EE diet-induced obesity, and metabolism, resistanceto tion andexpressionofPPAR-γ2 genes lipid andglucosemetabolism export pump downregulation ofbilesalt elevated EE and stimulatedlipolysis, high-fat diet.Increasedbasal ance, andinsulinresistanceon rate dysregulated controlofheart adaptive thermogenesis reduced EEanddefective diet smaller adipocytesonhigh-fat the liver euthyroid conditions TR targetsinbothhypo-and TRB peripheral presentationsof increased EE some peripheraltissues, restricted neuralstemcell PV/+ andTRA1 i

astapova © 2016SocietyforEndocrinology PV/+ RTH Printed inGreatBritain - in originalpaper phenotype asdiscussed TF responsible forthe TRs RAR, possiblyTRs FOXP1, RAR,Notch PPARGC1A CEBPA ARNTL, CLOCK FXR RORA PPARG TRs CEBPA PPARRGC1A Possibly PPARG TRs TRs, LXRs hormone action Co-regulators inthyroid Published byBioscientifica Ltd. Fozatti et al. Astapova et al. Jepsen et al. Jepsen et al. Coste et al.(2008) Louet et al.(2006) Stashi et al. Chopra et al. Chopra et al. Picard et al.(2002) Sadow et al. Tannour-Louet Louet et al.(2010) Picard et al.(2002) Sutnato et al. Vella et al.(2014) References Astapova et al. et al. (2013) (2011); Fozatti (2011) (2000) (2007, 2008) (2014a) (2011) (2008) et al. (2014) (2003a); Vella et al. (2014) (2010) (2008) Downloaded fromBioscientifica.com at09/26/202109:24:34PM Unclear Unlikely: thephenotypeis Unclear Possible: TRsregulateexpres- Possible: TRregulates Possible: THregulates Unlikely: thephenotypeis Unclear Possible: THregulates Possible: TRscontrolEEand Possibly: TRsregulate original paper not theprimaryfocusof Possible TRinvolvement,if of TRco-activation be expectedincaseoflack opposite ofwhatwould gluconeogenic genes sion oflipogenicand export pump expression ofbilesalt 6-phosphatase ofglucose- expression of TRco-activation be expectedincaseoflack opposite ofwhatwould 6-phosphatase expression ofglucose- uncoupling protein 1 (UCP1). expression andactivationof and lipolysis adipogenesis, lipogenesis, 56 : 3 (Continued) R78 via freeaccess Journal of Molecular Endocrinology Smrt Liver-specific NCoR-DADm Mouse model Liver-specific Smrt Liver-specific Muscle-specific NCoRω Table 1 NCoR/Smrt-DADm Adipocyte- Liver-specific http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review Smrt L-NCoRΔID NCoR Smrt NCoR specific NCoR Hdac3 mRID1 mRID −/ −/ −/ −/ −/ −/ (Continued) −/ Premature aging,metabolic Impaired differentiation oftypeI Increased fatmass,inductionof Cumulative effect on No majorphenotype.Upregula- Increased musclemassand Pro-adipogenic: increased Increased obesity, improved Upregulation ofgenesinNADPH Hepatomegaly andsevere Phenotype Impaired TH-induced Derepression ofTRtargets Abnormal circadianbehavior Upregulation oflipogenic high-fat diet resistance, anddecreasedEEon hepatosteatosis, insulin drial function.Obesity, syndrome, reducedmitochon- distress syndromeatbirth pneumocytes andrespiratory intolerance, reducedEE adipogenic genes,glucose steatosis sequestration. Mildhepatic genes andlipidsynthesis derepression ofTRtarget acid metabolism tion ofafewgenesinretinoic oxidative metabolism exercise endurance,increased diet hepatic steatosisonhigh-fat glucose metabolism, obesity, improved PPAR-γ targets diet. Increasedexpressionof inflammation onhigh-fat decreased adiposetissue glucose metabolism, hepatosteatosis oxidation. Significant sequestration, fattyacid and lipidsynthesis, metabolism genes of carbohydrateandlipid liver steatosisDysregulation liver acid B-oxidationinthe autophagy andfatty states in hypo-andeuthyroid sensitivity fat mass,increasedinsulin metabolism genes,reduced and expressionoflipid hepatic steatosis genes intheliver, mild i

astapova © 2016SocietyforEndocrinology Printed inGreatBritain in originalpaper phenotype asdiscussed TF responsible forthe TRs, RARs,PPARs TRs, PPARG TRs, LXRs RARs MEF2, PPARD, ERRs PPARG LXRA, PPARA, ESRRA, General lackof TRs TRs Lack ofHDAC3 General lackof Rev-ErbA HDAC3 Rev-ErbA recruitment to: HDAC3 activation hormone action Co-regulators inthyroid Published byBioscientifica Ltd. Fang et al.(2010); Pei et al.(2011) Nofsinger et al. Shimizu et al. Sun et al.(2013); Yamamoto et al. Goodson et al. Li et al.(2011) References Sinha et al.(2012) You et al.(2010) Alenghat et al. Sun et al.(2013), Knutson et al. You et al.(2013) (2010) Reilly et al. (2010) (2015) (2015) Shimizu et al. (2011) (2014) (2008) Jo et al.(2015) et al. (2011) (2008), Feng Downloaded fromBioscientifica.com at09/26/202109:24:34PM Unlikely Possibly: THpromotesfatty Possibly: TRsregulate Possibly: TRsregulate original paper not theprimaryfocusof Possible TRinvolvement,if Possible: TRsregulate Very likely:TRsregulatelipid Very likely, amongotherNRs Very likely, amongotherNRs acid oxidation and lipolysis adipogenesis, lipogenesis, and lipolysis adipogenesis, lipogenesis, genes expression oflipogenic oxidation synthesis andfattyacid 56 : 3 R79 via freeaccess Journal of Molecular Endocrinology (Chopra X receptorinresponseto reducedenergyavailability bile saltexportpumpthrough interactions withfarnesoid acid absorptionfromthegut byactivatingexpressionof SRC2 alsoplaysanimportant roleinregulationoffatty human geneticvonGierke’s disease(Chopra resulting in hepatic glycogen accumulation similar to leads todecreasedexpressionofglucose-6-phosphatase, release duetothelossofco-activationRORAthat deficiency alsoresultsindiminishedhepaticglucose its interactionswithPPARG (Picard rates, andelevatedEE,atleastpartiallyduetoaloss of insulin sensitivity, higherbasalandstimulated lipolysis to diet-inducedobesity, increasedglucose tolerance and favorable metabolicphenotypecharacterizedbyresistance In contrasttoSrc1 knockoutmice, Src2 Src2 knockoutmice is bluntedintheliverofSrc1 as upregulationofpositiveTHtargetsinresponsetoT for fullTHsensitivity at least in someperipheral tissues axis (Weiss overt resistancetoTHwasapparentatthelevelofHPT metabolism intheliver(Tannour-Louet et al.2014). reported thatSrc1 isimportantfornormalaminoacid protein (CEBPA) (Louet gluconeogenic enzymesbyCCAAT/enhancer-binding (Vella intheheart regulation ofgeneexpressionwasobserved a roleinmetabolicphenotypefoundSrc1 suggesting thatabnormalTRactionmaypotentiallyplay forTHsignalinginperipheraltissues, SRC1 isnecessary signaling byvarioustranscriptionfactors,itisclearthat while metaboliceffectsofSRC1havebeenattributedto TR isoformintheheart(Sadow probably relatedtothefactthatTHRAispredominant have the most dramatic phenotypes in terms of heart rate, significant decrease of theheartrate. or combinedwiththeknockoutofeitherTRsleadsto for maintainingnormalheartrate,asitsabsencealone subtype intheabsenceofother. SRC1isalsoessential cooperatively regulatingtheseparameterswitheachTR becomes important for normal growth and weight gain, body weight,intheabsenceofeitherTHRAorTHRB,SRC1 While lackofSrc1 alonehasnoeffectonthegrowthrateor knockout miceduringTHdeprivationandtreatment. was alsoassessedincompoundThra/Src1 andThrb/Src1 DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review When THfunctionwasfirstassessedintheseanimals, t al.2014).TRisoform-specific et et al. 2011).Recently, SRC2 wasalsoidentifiedas et al. 1999).IntactSrc1 function is alsorequired t al.2010).Ithasalsobeen et −/− mice.However, normal i

2008). et al. Src1 animals. −/− mice Src2 3

white adipocyte development. SRC3 hasbeenidentifiedasacriticalregulatorof Src3 knockoutmice synthesis pathways. those involvedinglucosemetabolismandfattyacid target expressionofmanymetabolicgenes,particularly overlap with ARNTL during the light phase (ZT2), and recruitment ofSRC2intheliverwasfoundtosignificantly (ARNTL) and CLOCK (Stashi thatcontrolcircadianclock machinery rhythms:BMAL1 a co-activatorforthetwokeytranscriptionfactorsin Src3 Pparg geneexpression(Louet the loss of co-activation of CEBPA in the regulation of regulator of adipogenesis. These effects are mediated by significantly decreasedexpressionofPPARG2; amaster body weight,decreasedadiposetissuemass,and significantly derepressedin L-NCoRΔIDanimals.Thisis targets thatarerepressedin hypothyroidwtmicewere vivo interactions playarolein TR-mediatedrepressionin ( in micewithliver-specificexpressionofNCoR∆ID ( the physiologicroleofNCoR– RID3 andRID2(NCoR∆ID)havebeenusedtoaddress Mice thatexpressamutantco-repressorNcoRmissing NCoR∆ID mice of B-oxidation. fatty acids.TheseresultspointtoSRC3asakeyregulator mice can be rescued by dietscontaining only shortchain with humancasesofCACTdeficiency, Src3 knockout skeletal muscleperformance(York hyperammonemia, andimpairedneurologic,cardiac, dysregulation leading to hypoketonemia, hypoglycemia, in humans, which presents with major metabolic closely resemblesphenotypeofCACTgeneticdeficiency or SLC25A20) gene expression.The phenotype ofSrc3 regulating carnitine/acyl-carnitinetranslocase(CACT in control of long chain fatty acid metabolism by directly tissue (Coste EE due to activation of PPARGC1A in brown adipose improved glucose and lipid serum profiles, and increased adipogenic potential,andSrc3 fibroblasts (MEFs)arecharacterizedbydecreased hormone action Co-regulators inthyroid L-NCoRΔID) clearlydemonstrated that NCoR– Astapova Published byBioscientifica Ltd. −/− in hypothyroidstate.Indeed, 16%ofpositiveTH miceareresistanttodiet-inducedobesitywith et al. 2008 ). Analysisofhepaticgeneexpression 2008).SRC3hasalsobeenimplicated et al. Downloaded fromBioscientifica.com at09/26/202109:24:34PM t al.2006).Inaddition, et −/− C) 1C) TR interactions(Fig. Src3 t al. 2014a). Genomic et animalshavereduced et al. 2012).Consistent −/− 56 mouse embryonic mouse embryonic : 3 R80 TR TR −/− via freeaccess

Journal of Molecular Endocrinology positive TRtargets(Grontved implicated intheregulationofasignificantproportion genes: instead,T co-repressor complex may not occur at all TR-regulated that involvesDNAbindingbytheunligandedTRand recruitment data suggesting that active repression in agreementwithrecentgenome-widehepaticTR TH-induced autophagyinthe liver, which isanecessary al.2010).Moreover, N-DADmmicehaveadefectin et of severalpositiveTHtarget genesintheliver(You and hypothyroidN-DADm miceshowedderepression insulin resistance. Similar toNCoR ∆ID animals, euthyroid elevated EE,andprotectionfromdiet-inducedobesity metabolic phenotypecharacterizedbyreducedfatmass, and adiposetissueinN-DADmmiceleadtoafavorable metabolic genesimplicatedinlipidmetabolismliver expression patterns ofseveral Alterations intheoscillatory targets anddisruptionofnormalcircadian behavior. and activation leads to upregulation of Rev-ErbA (NR1D1) et al. 2008).EliminationofDAD-mediatedHDAC3binding mice) areviableand have no gross abnormalities (Alenghat mutation inHDAC3-activatingdomainofNcoR(N-DADm Similar toglobalNCoRΔIDmice,animalsbearinga Deacetylase activationdomainmutantmice in establishingsensitivitytoTHperipheraltissues. These findingsconfirmthatNCoRplaysanimportantrole positive TRtargetsinperipheraltissuesandthepituitary. increased EE,andeithernormalorexpressionof they grownormally, havenormalbodytemperatureand not present with typical symptoms of hypothyroidism, as levels comparedwithwtlittermates,NCoRΔIDmicedo development. Despitea30%decreaseincirculating TH that RID3andRID2arenotrequiredfornormal ratios andappearphenotypicallynormaldemonstrating (Astapova in euthyroidstate. sensitivity andresponsivenessofgeneexpressiontoTH TR targetsduringhypothyroidismanddeterminesthe NCoR plays an important role in repression of positive in theeuthyroidstate.Theseresultsdemonstratethat inL-NCoRΔIDlivers positive THtargetswasobserved importantly, significantupregulationofanumber of in negativeregulationbyTHtheliver. Evenmore L-NCoRΔID mice,showinglimited,ifany, roleofNCoR upregulated inhypothyroidwtanimals)wasaffected negative THtargets(transcriptsthatweresignificantly 2013). At the same time, expression of less than 1% of http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review Surprisingly, micewithglobalexpressionofNCoR∆ID t al.2011)are born at expected Mendelian et 3 -dependent recruitmentofTRmaybe 2015, et al. i

Interestingly, affinity ofNCoRtodifferentgroups in liver-specificNCoRknockoutmice( Jo and estrogen-relatedreceptors (ERRs),wasalsoelevated genes, whichareundertranscriptional controlofPPARs of fattyacidoxidationand mitochondrialfunction recruitment (Sun supposedly duetothecompletelossofgenomicHDAC3 which wasnotpresentintheknock-inanimalsand is to whatisseeninliver-specificHdac3knockoutmice, these micedevelopsignificanthepatosteatosis,similar to becontrolledbyLXRs,TRs,andRev-ErbA.However, and lipidsynthesissequestration,whichareknown demonstrated derepressionofgenesinvolvedinNADPH Astapova NCoR knock-inanimalmodels(Alenghat madeinmutant In agreementwithobservations Liver-specific NCoRknockout knockout mice(Sunet al.2013). HDAC3 deacetylase-dead mutants and liver-specific which wasfurtherconfirmedinexperimentsusing as itcanstillberecruitedtoDNAbyNCoRandSMRT, modestly tothetotaleffectofHDAC3protein,aslong appears thatdeacetylaseactivitycontributesrelatively to germlineknockoutsofNCoR, development(asdemonstratedbycomparison embryonic histone deacetylation, these actions are not important for forHDAC3activityandlocal SMRT DADsarenecessary Hdac3 knockout.ThissuggeststhatwhileNCoRand hepatic steatosiscomparedwithhepatocyte-specific the liver, andconsistentwiththat,amuchmilder upregulation of fewer genes involved in lipid metabolism in Abrogation ofHDAC3activityinNS-DADmmicecaused Hdac3 knockout(Feng lethal (Bhaskara severe thanHdac3knockout,whichisembryonic phenotype of global HDAC3 recruitment(You sites and reduced, but not completely abolished, genomic increased histone acetylation around HDAC3 recruitment expected, tohavealmostnodetectable HDAC3 activity, SMRT (NS-DADm)werealsogenerated,andfound,as TR isoforms. physiology throughvariousNRsincludingRev-ErbAand crucial roleintheregulationofcircadian andmetabolic demonstrate that activation of HDAC3 by NCoR playsa and B-oxidation(Sinha step inTH-mediatedincreasefattyacidmobilization hormone action Co-regulators inthyroid Published byBioscientifica Ltd. Mice carrying DADmutationsinbothNCoRand Mice carrying 2008),liver-specificNCoRknockoutmice et al. t al.2008),orevenaliver-specific et 2013). Paradoxically, expression et al. NS-DADm mice was much less t al.2011, et Downloaded fromBioscientifica.com at09/26/202109:24:34PM t al.2012).Overall,thesedata et t al.2013).Surprisingly, the et , andHdac3).Italso Smrt Knutson 56 : 3 ). al.2015). et t al.2008, et t al.2008). et R81 NCoR via freeaccess

Journal of Molecular Endocrinology removal ofSMRTalonehas no effectontheirexpression. and isnormally recruited to these genes,which is why TRs andthelipogenicpathway inthelivergeneral, NRs, exists:NCoRisclearly the principalco-repressorfor same bindingsiteonthe TRs,andpotentiallyother in therecruitmentofco-repressorscompetingfor tion intheliver. Thissuggeststhatacertain hierarchy L-NCoRΔID mice,andsignificanttriglycerideaccumula in furtherupregulationofthesegenescomparedwith in these pathways, the combination of the two results alone hasnoeffectonexpressionofgenesimplicated regulation ofsomeTHtargets.WhileSMRTknockout to regulatelipidsynthesisandsequestration,the demonstrated thatSMRTworkscoordinatelywithNCoR of ahepaticSMRTknockoutandL-NCoR∆IDexpression 2003, NRs (Cohen on preferentialinteractionsbetweenspecificRIDsand genes (Shimizu important forRARsignalingandregulationoftarget Sun the lipogenicpathwayingeneral(Shimizu in theregulationofpositiveornegativeTHtargets that Surprisingly, hepatocyte-specific deletion of Liver-specific Smrtknockout Oppenheimer Flores-Morales and fatty acid oxidation in the liver (Feng experimental paradigmsto promote bothlipidsynthesis for TRsignaling,asTHhasbeenshownindifferent could potentiallyalsohaveimportantramifications on NCoR– fasted). WhiletheeffectofS1460phosphorylation signaling dependingonphysiologicalconditions(fedvs and providesamechanismforspecificmodulationofNR of recruitmentNCoRbetweendifferentgroupsNRs allowsforaswitch insulin-dependent phosphorylation signaling is activated, for example, in the fed state. This of oxidativemetabolismgenesintheliverwheninsulin or ESRRA)withhigheraffinitytoattenuateexpression binds PPARA andestrogenrelatedreceptoralpha(ERRa NCoR synthesis. Atthesametime,phosphorylated derepresses itstargetgenesresultinginincreasedlipid binding affinityofNCoRtoLXRAandselectively atthissiteresultsindiminished S1460. Phosphorylation on protein kinaseB/Akt-mediatedphosphorylation NRs maybemanipulatedintheliverbyinsulin-induced DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review t al.2013). At thesame time, SMRTappears to be et Smrt alone,incontrasttoNCoR,playsnorole Webb TR interactionshasnotbeenstudiedyet,it et al. 2001, t al. 2000). Interestingly, the combination et et al. 1991). t al.2002, et 2015),confirmingtheinvitro data et al. Cohen Jackson-Hayes et al. 2000, i

NCoRδ all threeRIDdomains,whichrepressesadipogenesis,to with aswitchinco-repressorsplicingfromNCoRω increases sensitivitytoendogenousPPARG ligands. in agreementwiththenotionthatdeletionofNCoR tofurtherPPARG-stimulationrefractory withrosiglitazone, tissue of NCoRknockout animals, and these mice were Indeed, PPARG targetgeneswereupregulatedinadipose diminished macrophageinfiltration,andinflammation. and changesinadipocytemorphologyfunction, obesity, improvedwhole-bodyglucosetolerance, to animalstreatedwithPPARG agonists,whichincludes fed high-fat diet demonstrate phenotypic resemblance (Li CoR repressesPPARG signalingpathwayinadipocytes Adipocyte-specific deletionofNCoRhasshownthatthis knockout NCoR inadiposetissue:adipocyte-specificandω by ligand-boundTRsintheliver. NCoR norSMRTplaysaroleinthenegativeregulation Rev-ErbA. These experiments again confirmed thatneither mediated bydifferentNRsincludingTRs,LXR,and with markedlipidaccumulation.Theseeffectsarelikely full derepressionofthepathwayleadingtoaphenotype can beseen.Removalofbothco-repressorsresultsina function, andmoderateactivationofthegeneexpression When NCoRisabsent,SMRTcanonlypartiallysubstituteits liver. TheyalsosuggestthatsinceNCoRω splice variantpreventsexcessivefataccumulationinthe differentiation, whilethepresenceoffull-lengthNCoR splicing during development helpsdrivenormal adipocyte These resultsindicatethatadipocyte-specificchangeinNCoR hepatic steatosisonahigh-fatdiet(Goodson despite increasedweightgainandadiposity, aswell NCoRδ phenotype, whole-body expression of the pro-adipogenic Consistent withtheadipocyte-specificNCoRknockout to supportapro-adipogenicprogram(Goodson it playsaroleinrepression offattyacidoxidationin Muscle-specific deletionof NCoRhasdemonstratedthat Muscle-specific NCoRknockout addition toPPARG. possibly, adipose-specificNCoRknockoutanimalsin is likely to contribute to the phenotype of these and, which iscriticalforNCoR– hormone action Co-regulators inthyroid Published byBioscientifica Ltd. t al.2011).Adipocyte-specific NCoR knockoutmice et It has been shown that adipogenesis in mice is associated It hasbeenshownthatadipogenesisinmiceisassociated isoform results in protection from glucose intolerance isoform results in protection from glucose intolerance whereonlyRID2andRID1arepresent,whichappears Downloaded fromBioscientifica.com at09/26/202109:24:34PM TR interactions, TR signaling TR interactions,signaling 56 −/− : 3 is missing RID3, ismissingRID3, ). al.2014). et ). 2011). et al.

carrying carrying R82 via freeaccess

Journal of Molecular Endocrinology type 1 pneumocyte markers and normal survival. Ithas type 1pneumocytemarkers andnormalsurvival. which ledtoacomplete restoration ofexpression with antithyroid drugs propylthiouracil or methimazole, pups couldberescuedby treating thepregnantdams the adipogenicsetpoint.HypothyroidSmrt other NRs,playsanimportantroleindetermining SMRT, byrepressing signalingbyPPARG andpotentially PPARG signalingandadipogenicpotentialsuggestingthat MEFs isolatedfromSmrt to elevatedfastingglucoseandintolerance. diminished insulin-stimulatedglucosedisposalleading RER, increased basal hepatic glucose production, and adiposity withreducedbodyweight,decreasedEE,and of metabolicdisturbances:significantlyincreased genetic background.Adultanimalsdisplayanumber slightly reducedviabilityonamixedC57BL/6-Sv129 Smrt with RAR, TR, and PPAR isoforms (Nofsinger C), whichabolishitsinteractions (RID1 andRID2)(Fig. 1 liver-specific deletionortheabilityofmutantSMRT and whetherthedifferencesareduetowhole-body vs knockout(Shimizu in theliver-specificSmrt to whatwasseen absence ofhormone.Thisiscontrary plays aroleinrepressionofpositiveTRtargetsthe induced hypercholesterolemia, indicatingthatSMRT genes intheliverandimprovementofhypothyroidism- demonstrate significantderepressionofsomeTHtarget ( SMRT receptor interactingdomainmutantmice high-fat feeding,orafterenduranceexercise. increase infattyacidoxidation,suchasaging,fasting, in physiologicalconditionsthatareassociatedwithan also demonstratedthatNCoRexpressionisdecreased also knowntopromotefattyacidoxidation.Itwas related toTRactivityweremade,eventhoughTHis MEF2, PPARD, andERRisoforms,butnoobservations attributed toincreasedactivityoftranscriptionfactors leading toimprovedexercise endurance.Theseeffectswere activity andnumberoverallhigheroxidativecapacity expression inthemuscleresultshighermitochondrial the muscle(Yamamoto 99% ofSmrt remainstobeclarified. machinery still bindHDAC3andothercomponentsoftherepression respiratory distress syndrome(Pei respiratory of type1pneumocytesthatleadstopreviouslyunknown Smrt Smrt http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review Interestingly, onapureC57BL/6background, closeto mRID mRID mRID micearebornatexpectedratios,buthave mouse model bears mutations in two and mRID Smrt pupsdieduetoadefectinthedevelopment mRID1 ) mRID t al.2011).ThelackofNCoR et micedemonstrateincreased i

Krüppel-like factor2(Klf2)inneonatalSMRT downregulation ofexpressionanegativeTHtarget been determined that the lethal phenotype is due to Reilly PPARs andpotentiallysomeotherNRs(Fang in interactions mediatedbythemostC-terminalRID(RID1 that while RID1-mediated interactions are abolished, the 1C),which changes the interaction patterns, so (Fig. decreased RER.However, unlikeSmrt obesity anddevelopmentofinsulinresistance,have mice, theseanimalsaremoresusceptibletodiet-induced independent manner. by TRthroughitsinteractionswithSMRTinaligand- expression oftranscriptionfactorKLF2,whichisactivated aredependenton of neonatallungandanimalsurvival demonstratethatnormaldevelopment These observations dependent negativeregulationremainsmuchlessclear. signal. However, possible role of co-regulators in ligand- positively regulated genes in response to the hormonal for full activationof while co-activatorsarenecessary genes bothintheabsenceandpresenceofligand, attenuate expressionofpositiveTRandotherNRtarget have demonstratedthatinperipheraltissuesco-repressors & Wondisford 2009 ). Thisregulationishighly sensitive, synthesis andsecretionofboth TRHandTSH(Chiamolera in thepituitary, whileadropinserumTHwouldinduce production ofbothTRHin thehypothalamusandTSH elevated concentrationsof THnegativelyregulate system thatcontrolscirculating THlevels.Inthissystem, The HPTaxishasdevelopedasanelegantfeedback axis andRTH Role ofco-regulators inthefunction ofHPT Smrt result of increased repression through PPAR isoforms in the similarlymutatedRID,whiledifferencesare likely duetothederepressionofNRsinteractingwith of thesetwoSMRTmutantmousestrainphenotypesare display markedhepaticsteatosis.Thecommonfeatures and 5-amino-4-imidazolecarboxamideribosealso toglucose-loweringeffectsofthiazolidinediones refractory repression ofthesegenesbyPPARs. SimilartoSmrt mitochondrial function,potentiallyduetoenhanced genes intheoxidativemetabolismpathwayandreduced disease. They are also characterized by repression of accompanied byprematureagingandrelatedmetabolic hormone action Co-regulators inthyroid Published byBioscientifica Ltd. ) areenhancedleadingtoincreasedrepressionby Fig. 1 Smrt Overall, multipleanimalmodelsdiscussedabove mRID1 2010). et al. mRID1 animals. mice carry amutationonlyinRID1 micecarry Smrt mRID1 Downloaded fromBioscientifica.com at09/26/202109:24:34PM micehavedecreasedlifespan 56 mRID : 3 micetheyare 2010, et al. mRID lungs. R83 mRID via freeaccess

Journal of Molecular Endocrinology tests withlowtonormalfreeT individuals haveslightlyabnormalthyroidfunction different from classic THRB RTH. The affected very have alsobeenidentified,withclinicalpresentations & Jameson1998,Yoh et al.1997). T et al. 1997 , involved intheregulationofTHaction(Collingwood to haveimpairedinteraction with oneofthecofactors Hayashi in a dominant-negative manner (Adams Such mutantsinterferewiththefunctionofwtTHRB function-2 (AF-2)andreduceitsaffinityforthehormone. subjects withclassicRTHarelocatedintheactivation (Dumitrescu &Refetoff2013).Mostmutationsfoundin and delayedgrowthvstachycardiahyperactivity) hyperthyroidism (lack of negative feedback in HPT axis a simultaneouspresentationofsymptomshypo-and of tissue-specificexpressionTHRAvsTHRB,leadingto also variesbetweendifferenttissues,mostlikelyasaresult with somevariabilitybetweenindividuals. Thyroid status to TH is compensated for by highcirculating TH levels, families. Inmajorityofcases,peripheralhyposensitivity identified inaffectedsubjectsbelongingtomorethan450 caused by mutations in the Refetoff goiter (Beck-Peccoz&Chatterjee1994, lack ofmostusualsymptomsthyrotoxicosisandoftena accompanied byinappropriatelyelevatedornormalTSH, affinity toT 2001, dependent negativeregulationremainunclear(Abel exact molecularmechanismsunderlyingthishormone- these genesaclassicexampleofnegativeTHtargets,but encoded by nucleus ofhypothalamusandexpressionTSHsubunits, represses bothTRHgeneexpressionintheparaventricular function testinhumans.Hormone-boundTRspotently so thatcirculating TSHlevelisthemostcommonTH completely unabletobind T THRA gene led to expression of either a truncated THRA and cognitiveimpairment. Identifiedmutationsin dysplasia, markedconstipation (diarrheainonecase), with growthanddevelopmentalretardation,skeletal clear phenotypiccharacteristicsofhypothyroidism to TH,suchthathighserumlevelsoffreeT various degrees of peripheral and central hyposensitivity 2010, 3 DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review , reduced rT Recently, a fewfamilies with mutations in THRA Classic RTHisaninheritedsyndromecharacterizedby Wood Abel 1993).ThistypeofRTHismostcommonly et al. t al. 1995). Some mutant THRBs were found et Collingwood 1999, et al. CGA and et al. 1989). 3 andtranscriptionalactivity showing 3 , and normal TSHlevels,but display TSHB genes, in the pituitary, making Hollenberg et al. 1998 , THRB gene that have been 3 ormutationsdecreasing i

2001, mutations (Thra before identificationofpatientswithThragene those foundinpatientswithThrbRTHweregenerated mutationsanalogousto knock-in mousemodelscarrying 2005), reviewedinFlamantandSamarut(2003). 2001, (Reutrakul et al.2000,Weiss et al.1996). subjects withthistypeofRTHareyettobeidentified co-regulator proteinmightbeinvolved;however, human genes werealsoidentifiedsuggestingthatmutationsin of RTHintheabsencemutationsTHRBorTHRA Tylki-Szymanska classic dominantly inherited RTH (Hashimoto Ortiga-Carvalho various degreesofresistancetoTH(Ortiga-Carvalho homozygous mutation thatabolishesco-activatorbindingand high serumfreeT human RTH:elevatedserum TSHlevelsaccompaniedby RTH withphenotypicpresentation similartoclassic HPT axis(Weiss fornormalfunction ofthein vivothatSRC1isnecessary The Co-activator knockoutmodels mouse models,aresummarizedinTable 2 . presentation ofRTHobtainedusinggeneticallymodified the role of co-regulators in the function of HPT axis and to recruitco-repressorsshouldbehigher. Data regarding levels (asopposedtohighinThrbRTH),abilityofTR bigger effect,asinthepresenceofnormalcirculating TH in theThra-mediatedRTHmaypotentiallyhaveaneven drop ofcirculating TH. Lack ofco-repressorrecruitment effect onthehyperthyroidsymptomsdepending which phenotypically present as hypothyroidism, with the to TRswouldatleastpartiallyrescuesymptomsofRTH, worsen inability torecruitco-activators,suchasSrc1,would Vennstrom al.(2014)and al.2002),reviewedinvanMullem et et being similartopatientswithThraRTH(Kaneshige phenotypes,withsomeofthem and displayvarying Espiard dominant-negative features (Bochukova found in patients with RTH, such as TSH byT sensitivity to TH at thyrotrope level, as suppression of Thrb hormone action Co-regulators inthyroid Published byBioscientifica Ltd. gene mutationsinThrbgene Mouse modelscarrying Src1 knockoutmodeldemonstratedforthefirsttime T337D Liu Kaneshige -mediated RTH, loss of co-repressor binding Thrb-mediated RTH,lossofco-repressorbinding 2015, et al. , were generated and found to recapitulate , weregeneratedandfoundtorecapitulate 3 isseverelybluntedcompared withwtanimals, t al.2003, et . It has been suggested that while (2008).Ithasbeen suggested that while et al. knockout animals also demonstrate Thrb knockoutanimalsalsodemonstrate PV et al. 1999).MicedeficientinSrc1 display 4 et al. 2015, , andT t al.2000 ). MiceexpressingThrb et Thra Moran R384C 3 Quignodon . Thesemicedemonstratereduced Downloaded fromBioscientifica.com at09/26/202109:24:34PM 2014, et al. , van Mullemet al. 2012).Cases Thra L400R t al.2007, et , Thra 56 Moran : 3 P398H t al.2012, et Thrb 2013, et al. , Thra Tinnikov PV t al. et and and R84 R384C et al. et al. Thra E457A via freeaccess )

Journal of Molecular Endocrinology Postnatal Smrt NCoRΔID (NCoR1) Src1 Cga-NCoRΔID Pituitary-specific NCoR-DADm Smrt (NCoR2) Src1 Mouse model Table 2 Src2 NCoRΔID Src Postnatal NCoRΔID et al. 2002, compound severe thantheTHresistancepresentintotalThrbor axis comparabletotheThrb-nullmice,butless mice demonstrateRTHphenotypeatthelevelofHPT by thedataobtainedincompound Src1 and-2knockout of partialcompensation for Src1. Thisisalsosupported of Src1 deficiencywasfoundtolead toelevationofexpression (Xu Consistent with previous observations TH resistancepresentedasinefficientsuppressionofTSH. thyrotrope level,Src1/Thra-deficient micedemonstrate Thra knockoutmicearehypersensitivetoTHactionatthe TH action independent of of thesingleknockouts,implyingthatSRC1hasarole in Src1/Thrb micehavemoresevereTHresistancethaneither Thra-deficient mice(Sadow was alsoassessedusingcompoundSrc1/Trb gene transcriptionbydifferentTRisoformsinthepituitary T by theadministrationofsupraphysiologicaldoses appears tobedrivenbyTSH,assuppressionofTSH 1997). Theelevatedcirculating THinScr1 previouslyinvitro ( by THaswasobserved when itinteractswithagenethatisnegativelyregulated This suggeststhatSRC1behavesasaco-repressorinvivo both inbaseline‘euthyroid’andhypothyroidstate. may playaco-activatorroleinthiscase.Overall,Src1 stimulation ofTSH,suggestingthatotherco-regulators absence ofSrc1 didnotaffectthefullligand-independent http://jme.endocrinology-journals.org 3 DOI: 10.1530/JME-15-0246 Review resultsinreductionofendogenousT Src2 and-3 in pituitary, which could bea mechanism −/− −/− −/− The specificroleofSRC1inactivationTH-regulated mRID /Src2 (Ncoa2) (Ncoa1) Summary ofphenotypesmousemodelsdiscussedinthereviewasrelatedtoregulationHPTaxis. −/− −/− Weiss Thrb andThra-deficientanimals(Takeuchi −/− et al. 1999). Decreased circulatingT No phenotypeatthelevelofHPTaxis RTH similartoTRBRTH: highT Partial improvementofRTH inThrb Decreased circulatingT Phenotype Normal T Worsening ofTrb Slightly reducedT Normalized HPTfunction No effect onHPTaxis Worsening ofRTH comparedwithSrc1 Decreased circulatingT NCoRΔID animals thyroid toTSH dynamic changesinTHlevels;decreasedresponsivenessofthe during hypothyroidism dynamic changesinTHlevels Thrb. At the same time while 4 andT t al.2003b).Interestingly, et i

astapova 3 levels,elevatedTSH;normalTSHresponseto © 2016SocietyforEndocrinology PV/+ 4 onC57/BL6background andTRB 4 4 4 , T andT andT Printed inGreatBritain 4 . Notably, the 3 , andTSH.BluntedupregulationofTSH Tagami t al.1998), et - andSrc1/ E457A/E457A −/− 3 3 3 , normalTSHsimilartoglobal , normalTSH;responseto , T animals 4 , andunsuppressibleTSH PV/+ et al. RTH −/− andThra1 −/− alone

mice (Weiss to TH, TH, surpassingthatoftotalThrb and TSHconcentrations,showingdramaticresistanceto Src1 and-2resultedinmarkedincreasesofserumTH to theSrc1 homozygousknockouts.Deletionofboth Src1/Src2 micepresentedwithaRTHphenotypesimilar thyroid functiontests.Surprisingly, doubleheterozygous low circulating T axis potential roleofco-repressorsintheregulationHPT through germlinemutationwereusedtoaddressthe Mice withglobalexpressionofNCoR∆IDgenerated Co-repressor-deficient models crucial fornormalregulationofHPTaxis. clearly demonstratethatco-activatorrecruitmenttoTRsis with anincreaseinSRC2asdiscussedabove.Thesedata SRC1 aredecreasedorabrogated,whichisalsoassociated while SRC2becomesimportantonlywhenthelevels context, SRC1isclearlythepreferredco-activator for TRs, -2 intheregulationofHPTaxisbyTH.However, inthis demonstrates partial functional redundancy of SRC1 and TSH levelsandexpression. Interestingly, theseanimals as changesincirculating THproducenormalresponse in the sametime,sensitivity ofHPTaxisisnotaltered, to enhancedsensitivity TH inperipheraltissues.At However, in the pituitary, suggestive of central hypothyroidism. normal serum TSH and expression of TSH subunit mRNA hormone action Co-regulators inthyroid Published byBioscientifica Ltd. PV/+ in vivo( models Src2 NCoR∆ID mice do not appear hypothyroid due −/− 2002).WhileSrc1 et al. Astapova , Src2 4 +/− andT Pei etal.(2011) Weiss etal . (2002) References Weiss etal. (2002) Costa-e-Sousa etal.(2012) Astapova etal.(2011) Costa-e-Sousa etal.(2012) Weiss etal . (1999) You etal.(2010) Kamiya etal.(2003);Alonsoal.(2009) Vella etal.(2014) Shimizu etal.(2015) Fozatti etal.(2011);(2013) , and 2011). et al. Downloaded fromBioscientifica.com at09/26/202109:24:34PM 3 Src1 levelswithinappropriately +/− mice displayed normal −/− NCoR∆ID micehave −/− mousemodel.This 56 miceareresistant : 3 R85 via freeaccess Journal of Molecular Endocrinology concentrations were slightly reduced in in contrastwithSrc1 knockoutmice.WhileserumT hypothyroidism wasalsobluntedintheseanimals, TSH production.Remarkably, theriseofTSHduring phenotype characterizedbylowTHlevelsanddecreased driven bytheglycoproteinA-subunitpromoterledtoa usingaCrerecombinase specifically inthepituitary e-Sousa axis arenotaresultofdevelopmentaldefect(Costa- phenotype, confirmingthatthealterationsinHPT ubiquitous Crerecombinase,demonstratedanidentical NCoR∆ID wasinducedinadulthoodusinganinducible normal. Importantly, micewhereglobalexpressionof possibly hypothalamus recognize lower TH levels as and the thyroidproduceslessTH,whilepituitary which iscompensatedforbyaresetHPTaxiswhere to increasedsensitivityTHinperipheraltissues, Therefore, disruptionofNCoR– response toTSHstimulationissignificantlyattenuated. and theabilityofthyroidglandtosecreteTHin presence ofnormalserumT elevated serumTSHandsubunitexpressioninthe 2010). These mice were characterized by significantly et al. dysregulation of HPT axis was found in TR co-repressor(Shimizu recruitment existsinHPTaxis,andNCoRisthepreferred that similarlytotheliver, specificityofco-repressor or TSHsubunitexpressioninthepituitary, confirming ablation ofSMRThadnoeffectoncirculating T C57/BL6 background(Pei TH, itwashypothesizedthat RTHinSrc1 NCoR inN-CoR∆ID TH butthedisruptionofinteractionsbetweenTRand recruited competingwithco-activatorsforthebindingsite. in potentially increasingtheirabilitytorecruitothercofactors, to thefactthatwhileNCoR∆IDsimplydoesnotbindTRs is seeninNCoRΔIDmice.Thisdiscrepancypotentiallydue reset to recognize normal TH levels as low, opposite to what all conditions,suggestingthatintheseanimalsHPTaxis is deiodinase remainedmodestlybutsignificantlyelevatedin serum TSH;however, expressionofTSHand type2 pituitary circulating THlevels,produced normalresponseintermsof and TSHlevelsnormal abilitytosuppressTSHin compound knockoutmice hadnormalcirculating TH have reducedintrathyroidallevelsoffreeT Src1 by unopposedco-repressor action.Remarkably, when DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review mice NCoR does not activate HDAC3, but is still N-DADm miceNCoRdoesnotactivateHDAC3,butisstill −/− A somewhat different phenotype related to A somewhatdifferentphenotyperelatedto As werecrossedwithN-CoR∆ID animals,theresulting Src1-deficient miceareresistanttotheactionsof 2012).Moreover, expressionofNCoR∆ID et al. mice leadstoincreasedsensitivity et al. 2015). t al.2011),postnatalglobal et 4 andT i

astapova TR interactionsleads © 2016SocietyforEndocrinology 3 . Manipulations with . Manipulationswith You N-DADm mice (You −/− Smrt Printed inGreatBritain miceiscaused mRID 4 andT mice on 4 levels 3 4 ,

in of positiveTRtargetgeneswassignificantlyincreased Thrb thought toplayaroleinthedevelopmentofRTH.In Inability torecruitco-activatorsbymutantTHRBis Role ofSRCsinotherRTH models co-regulator balance. However, removalofNCoRallowstore-establishthe of Src1, highaffinitybindingofNCoRpreventsrecruitment recruitment ofco-regulators to TR:intheabsenceof Additionally, T response toT in increasedserumT mice worsenedthedegreeofresistancetoTH,resulting cholesterol levelsineitherThrb hyperplasia.LackofSrc1papillary didnotaffectserum the pathologicalprogressionofthyroidfollicularcellsto in RTHbyavarietyofdifferent mechanisms. to TRscontributesdysregulation ofHPTaxispresent demonstrate thatdisruption ofco-activatorrecruitment Src1 toAF-2(Alonso dependent repression of TSH requires recruitment of region oftheTHRAorTHRB.Atsametime,ligand- deprivation, likelythroughinteractionwithanother foractivationofHPT axisduringTH mice, isnecessary topreviousconclusionsfrom Src1contrary knockout interact withTHRBoutsideoftheAF-2domainand, target genes inthe liver, which is blunted in Src1 led todysregulatedexpressionofseveralT was restoredinNCoR∆ID growth abnormalities in Thrb leads toaworseningoftheHPTaxisdysregulationand expression of PV seen inThrb resulted inabluntedTSHrise,only50%ofwhatwas deprivation, simultaneousdisruptionofAF-2andSrc1 resistance present in Surprisingly, disruptionofSrc1 intheThrb tissues andHPT axis (Ortiga-Carvalho demonstrate profoundRTHphenotypeatperipheral abolishes recruitment of co-activators to LBD also AF-2 thatdoesnotaffectligandbindingbutcompletely andliver(Kamiyaet al.2003). the pituitary T mutation intheThrblocusthatcompletelyabolishes hormone action Co-regulators inthyroid 3 Published byBioscientifica Ltd. mice.InTrb bindingtoTHRB(Kaneshige NCoRΔID Src2 co-activatoreveninthepresenceofligand. Mice expressing PV mutantmice,amodelofRTHwithknock-in E457A Src1. Thisagainsuggestsahierarchy inthe 3 Src2 treatment,thusdemonstratingreversalof 3 PV/PV -mediated upregulationofpositiveTR mutantalone,suggestingthatSrc1 can and recruitment of animals,Src1 deficiencyintensified Src1-deficient miceVella ( 4 Thrb with E457A mutation in andTSHatbaseline.DuringTH t al. 2009).Thesedataclearly et Downloaded fromBioscientifica.com at09/26/202109:24:34PM Src1 PV/+ −/− PV/+ 2000),lackofSrc1 et al. mice but not in Thrb animals.Interestingly,

or 56 Src2 to promoters Thrb : 3 3 targetgenesin PV/PV ). al. 2005). et et al. 2014). mice,but E457A/E457A −/− mice, R86 PV/ via freeaccess

Journal of Molecular Endocrinology T in certaintissuespatientswithclassicRTH. on clinicalpresentationofhyperthyroidsymptomsseen TRB RTH.Therefore,itisunlikelytohaveapositiveeffect in correctingtheresistanceatlevelofHPTaxisseen of hypothyroidism in both types of RTH,but less effective effective intermsofcorrectingtheperipheralsymptoms RTH. ItappearsthatabolishingNCoR– contribute to clinical presentation of both THRB and THRA Thus, aberrantrecruitmentofNCoRbymutantTRsmay delayed bonedevelopment,andimpairedadipogenesis. improvement inseveregrowthretardation,infertility, Thra1 could partiallyameliorateabnormalitiesintheHPTaxisof were alsoreversed.Furthermore,expressionofNCoRΔ and repressionofanumberhepaticTRtargetgenes peripheral level, weight loss, severe thyroid hyperplasia, more similar to human RTH) (Fozzatti in thepresenceofonlyonemutantPVallele(asituation t al.2013). et found inhumanswithmutationsThragene(Fozzatti PV mutationanddisplayaphenotypesimilartothat chromatin recruitment Lessons from genome-wide analysis ofTR TR-NCoR interactionsinThrb opportunity totestthishypothesisinvivo.Theabsenceof underlying RTH.Availability ofNCoR∆IDmiceprovidedan has beenproposedtobeoneofthemolecularmechanisms Constitutive recruitmentofco-repressorsbythemutantTR Role ofco-repressors inRTH Perlman not affectedbythepresenceofTH(Baumann that TRbindingtoresponseelementsinthetargetgenes is TRs (asopposedtosexsteroidreceptors)andassumption regulation isbasedontheprimarilynuclearlocalization of The bimodalswitchmodelofTR-mediatedtranscriptional in amoderatebutsignificantdecreasecirculating T (Ayers lines usingchromatinaffinity precipitation(ChAP)-seq overexpressed TRswasassessed in neuralandhepaticcell et al. 1988,Petty1990 Zilz et al.1990). recently (Chatterjee on thegenome-widelevelhasnotbeenperformeduntil genes, acomprehensiveanalysisofTR-bindingpatterns and anumberofTREshavebeenidentifiedinsometarget preferred TR-bindingsiteshavebeenestablishedinvitro, 3 http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review , and TSH levels and TSH subunit expression, especially , andTSHlevelssubunitexpression,especially In twostudies,agenome-wide recruitmentoftagged PV/+ et al. 2014, et al. 1982, mice that carry the dominant-negative frameshift thedominant-negativeframeshift micethatcarry NCoRΔ Chatonnet Wong ID/Thra1 t al.1989 , et et al. 1995, et al. 2013).Chatonnetet al. PV/+ PV animals results /NCoR∆ID animalsresults animals also displayed animalsalsodisplayed i

the presenceofT At mostsiteswhereTRoccupancychangeddependingon while by expressionoftaggedversioneitherTRisoform, 15,723 inT TR-binding peaks (20,939 peaks in PTU-treated and immunoprecipitation (ChIP)-seq(Grontvedet al.2015). assess recruitmentofendogenousTHRB1bychromatin ii) usingamousemonoclonalTHRB-specificantibodyto precipitation andChAP-seq(Ramadoss toallowforaffinity in mouseliverbyadenoviraldelivery approaches: i)usingbiotin-taggedTHRB1overexpressed hyperthyroid conditionsinvivousingdifferent recruitment ofTHRB1intheliverunderhypo-and overlap, butalsohadagreatnumberofuniquetargets. genomic THRAandTHRBbindinghadnotonlysome neural cellsasexpected.Itwasalsodemonstratedthat consensus TR-bindingsiteforbothTHRAandTHRBin with a4nucleotidespacer(DR-$)wasestablishedasthe peaks, andadirectrepeatofNR-bindingmotifAGGTCA TRE half-sitesand classical TREswerepresent at many confirmation fornegativeregulationbyligandedTRs. negatively regulatedgenes,thusprovidingnostatistical no significantenrichmentofTRbindingwasseenat suggesting thatT in thatregion.Moreover, T all peaksidentifiedinhyperthyroidstateswerepresent 17% ofallpeaks identified in hypothyroidand 7%of within theproximalpromoters(TSSto– elements. Only2%ofT binding aremorelikelytooccuratdistalenhancer suggesting thathormone-inducedchangesinTHRB1 away fromtranscriptionstartsites(TSS)ofknowngenes, of allchangedpeaks).Thesesiteswerelocatedfarther invariant orpeaksthatweredecreasedwithT obtained frommouseENCODEproject),comparedwith less overlapwithDNasehypersensitivitypeaks(data nearby genesinthesame direction;however, some binding correlatedwithchanges intheexpressionof chromatin remodeling.Overall, thechangesinTHRB1 less accessible chromatin regions and potentially induce recruitment ofTHRB1wasaffectedbythepresenceT located withinthegenes.Interestingly, atmanysites proximity ofgenespositivelyregulatedbyT found significantenrichmentforTR-bindingsitesinthe binding inhepatocellularcarcinoma cellline.Bothstudies in neuralcelllines,whereT compared THRAandTHRBtranscriptomescistromes hormone action Co-regulators inthyroid Published byBioscientifica Ltd. Ramadoss Two otherstudieshaveinvestigated genomic Ayers 3 t al.(2014)studiedTHRBgenome-wide et -treated livers),withmostofthepeaks t al.(2013)reportedahighnumberof et 3 3 TRbindingwasincreasedbyT maypromotebindingof THRB1 to Downloaded fromBioscientifica.com at09/26/202109:24:34PM 3 -sensitive peakswerelocated 3 responsivenesswasrestored 3 -induced peaksshowed 56 : 3 t al.2013)and et 500 3 . Incontrast, 3 treatment, bp), while 3 (80% R87 via freeaccess 3 . Journal of Molecular Endocrinology T potential chromatinremodelingeventsassociatedwith seq approachwithDNaseIhypersensitivityassaytoassess mediated byindirectmechanisms. T was increased in the presence of T most representedmotifinthepeakswhereTRbinding previous reports.Surprisingly, whileDR-4wasalsothe DR-4 asthemostenrichedelement,consistentwith Motif analysisofallTHRB1-bindingsiteshasidentified THRB1 caninsomeinstancesfunctionasarepressor. binding wasstillsignificant,thusimplyingthatliganded association ofnegativelyregulatedgeneswithTHRB1 Overall, 60%ofT that these peaks may result from indirect TR binding. unique hypothyroid peaks contained TREs, suggesting those foundonlyinthepresenceofT majority of the TR-independent peaks overlapped with hypothyroid and2186inhyperthyroidconditions,where to chromatin with 864 TR-binding sites identified in genes negativelyregulatedbyT at leastoneTR-binding peak within50 suggesting thatT diminished THRB1bindinginthepresenceofT in theoppositedirection.Therefore,itispossiblethat genes wereidentifiedwheretheexpressionwasregulated genes upregulatedbyT Similar tothefindingsincelllines,significantlymore the mechanismofnegativeregulationforsomegenes. a model,whereT antibody usedinthisstudy. Theobtaineddatasuggest and/or relativelylowavidityofthemonoclonalTR the abundanceofendogenousTHRB1vsoverexpressed al.(2013),whichcouldbeduetothedifferencesin et in thisstudycomparedwiththebyRamadoss peaks decreasedwithT elevated geneexpression,DR-0wasenrichedinthe differential bindingatuniquetargetsites. mediate positiveandnegativeregulationbyemploying into thepotentialmechanismsastohowTRmay diminished gene expression. This provides an insight within theaccessiblechromatin (eitherunchangedor general, 92%ofidentified TR-binding siteswerelocalized induce robustchangesin chromatinaccessibility. In regulation byT downregulated genes(40%),suggestingthatnegative associated THRB-bindingsites(73%)ascomparedwith of T of hormone-independentTR-bindingpeaksand42% analysis foundenrichmentfortheDR-4TREin60% 3 DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review signaling.MuchfewerTR-bindingsiteswereidentified Finally, 3 -facilitated peaks.Interestingly, lessthan 20% of Grontved 3 maybelargelyindirect.However, the 3 3 -dependent repressionmay belargely 3 greatlyincreasesTHRB1recruitment -induced geneswerefoundtohave et al. (2015) 3 3 treatmentandassociatedwith treatmentwerefoundtohave 3 showlittleenrichment, i

combined THRB1 ChIP- astapova © 2016SocietyforEndocrinology 3 and associated with 3 3 kb ofTSS,while wasfoundto . Printed inGreatBritain De novomotif 3 maybe T consensus TREs.WhenT to accessiblechromatinregionscontainingstrong to T while NCoRandHDAC3occupancyisreducedinresponse change ofTRoccupancyorchromatinremodeling, able activation ofthesegenesisnotassociatedwithconsider animals thatlackinteractionbetweenTRandNCoR, are significantlyderepressedinhypothyroidL-NCoRΔID with thepreviousstudiesshowingthatGpd2andIdh3a was foundtobehormone-independent.Inagreement Idh3, whereatleastoneoftheidentifiedTR-bindingsites state. ExamplesofsuchgenesincludeGpd2, TR-binding peaks can be actively repressed by TR in that T chromatin surroundingbindingsites.Thepresence of and TR recruitment leads to dramatic remodeling of the of genes,whereallnearbyTRbindingisligand-dependent those TR-bindingsitesatalltimes.Dio1representsaclass reduced byT found withintheDNasehypersensitivesites(DHS) remodeled uponT Dio1 transcriptionintheliver. TR interactions have been reported to have little effect on with thefactthatdisruption ofNCoR–HDAC3and by TRintheabsenceofTH. Thisisagaininagreement unchanged, suggestingthat Dio1isnotdirectlyrepressed CBP, whereasNCoRandHDAC3occupancyremains DHS formeddenovouponT and presenceofT TR-bindingmotifs motifs. Onlystrong,highlyconserved accessible chromatinharboringlessstringentTR-binding context. Indeed,onlygeneswithnearbyT on thetypeofresponseelementandoverallchromatin the TR-mediatedtranscriptionalregulationmaydepend suggest thattheroleofco-activatorsandco-repressorsin upon T inaccessible chromatin,whichareremodeleddenovo absence ofT are importantdeterminantsofTRrecruitmentinthe strength oftheTRE(DR-4)andchromatinaccessibility of identified TR peaks suggests that the presence and sites, especiallyinhypothyroidconditions.Motifanalysis to howTRdiscriminatesbetweenthesetypesofbinding previously inaccessiblechromatin,leavingaquestionas open chromatinandligand-inducedTRrecruitmentto hormone-independent binding ofunliganded TR to recruited tochromatinindifferentscenarios,including dependent manner. ThisdemonstratesthatTRcanbe that TRs can induce chromatin remodeling in a ligand- hormone action Co-regulators inthyroid 3 3 Published byBioscientifica Ltd. leadstoincreasedrecruitmentofco-activator -induced TRpeakswerelocalizedintheregionswith 3 . Atthesametime,co-activatorCBPwasfoundat 3 -dependent TRrecruitment.Thesefindings 3 , whereunligandedTRpreferentiallybinds 3 treatment.Mostinterestingly, 10%of 3 3 allowforTRbindingatsiteswithin treatment),withalmostnobinding 3 Downloaded fromBioscientifica.com at09/26/202109:24:34PM isavailable,TRabletooccupy 3 treatment,suggesting 56 : 3 3 -independent Pdp2, and R88 via freeaccess

Journal of Molecular Endocrinology influenced byT found that,unexpectedly, TRrecruitmenttoDNAis potential ‘negative’TRE.Finally, thetwoinvivostudies negative THtargets,thisstudyalsoidentifiedDR-0as a responsible fortheregulationofalargepercentage of result stillsuggeststhatindirectmechanismsmaybe was muchlowerthanforpositivegenes.Whilethis with negativelyregulatedgenes,theenrichment (2013), whereTRbindingwasfoundtobeassociated at distantenhancers.InthereportbyRamadoss recruitment inthesecasesoccursalmostexclusively be largelymediatedbyindirectmechanismsorTR TSS), suggestingthatnegativeregulationbyTHmay the proximitylimitssetinstudies(10– the genesnegativelyregulatedbyTRs,atleastwithin no significantenrichmentintheTRrecruitmentto TR-binding element.Threeoutoffourreportsfound data. AllofthestudiespointtoDR-4asaconsensus of TRandco-regulatorsthroughyet unidentifiedtranscriptionfactors(TF). chromatin remodelingandbringco-activator complextoactivatetranscription.(D)NegativeTH-dependent regulationmediatedbyindirectrecruitment (B) Positivelyandnegativelyregulatedgenes,whereTRbindingtoopen chromatinisaffected by T recruited intheabsenceofhormonetoactivatetranscription,whileco-activators recruitedtotheligandedTR,mediatetranscriptionalrepression. co-activators toactivatetranscription.Onnegativelyregulatedtargets, with yetundeterminedconsensusbindingsite,co-repressorcomplexesare preferentially recruitsco-repressorcomplextorepresstranscription.Upon bindingofT model). Onapositivelyregulatedtargetgene,withconsensusDR-4TR-binding site,intheabsenceofTHRXR/TRheterodimerorTR/TRhomodimer (A) Positivelyandnegativelyregulatedgenes,whereTRisrecruitedtoan openchromatinregionindependentlyofT hypothesized basedoninvitrobindingdata,animalmodelswithalteredco-regulatorfunction,anda limited numberofChIP-PCRexperiments. Models ofTR-mediatedregulationtranscriptionbasedontheinsights obtainedfromTRChIP-seqexperiments.Possiblerolesofco-regulatorsare Figure 2 co-activators. BindingofT activate transcriptioneitherthrough ligand-independentrecruitmentofco-activatorsorby co-repressors, whichactasfunctional co-activator complexestoactivatetranscription. Onanegativelyregulatedgene,TRisrecruitedtoDR-0response elementintheabsenceofhormoneto binding site,thereisweakTRrecruitmentintheabsenceofhormone.In thepresenceofT within aregionofinaccessiblechromatin andcontainingastrongDR-4TR-bindingmotif.TRcanonlyberecruited inthepresenceofT http://jme.endocrinology-journals.org DOI: 10.1530/JME-15-0246 Review A B Negative target Positive target Negative target Positive target A fewgeneralconclusionscanbedrawnfromthese T3-independent recruitmentofTR T3-modulated recruitmentofTR CoA 3 CoA , andT CoA CoA 3 leadstodissociationofTRfromDNA anddiminishedtranscriptionofthetargetgene.(C)Apositivelyregulated genelocated RXR/TR RXR/TR DR-4 RXR/TR DR-0 ? CoR DR-4 ? RXR/TR CoR TR 3 TR ? TR -induced TRbindingorrelease TR CoR CoR i

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RXR/TR 50 CoA

DR-4 RXR/TR DR-0 DR-4 RXR/TR CoA CoA ? TR TR ? TR kb from TR CoR et al. CoR CoR CoR

but are also essential for the normal signaling by TR not only in the presence or absence of TH respectively, play aroleintheregulationoftranscriptionbyTRs overall demonstrate that co-activatorsand co-repressors Mouse modelswithdisruptedco-regulatorfunction Summary andfuture perspectives landscape (Fig. 2). the typeofTR-bindingsiteandsurroundingchromatin significantlydependingonin TRsignalingmayvary imply thattheroleofco-activatorsandco-repressors These newinsightsintodifferentscenariosofTRaction remodeling, similartootherNRs(Boergesen inaccessible chromatinregionsandinduce that uponligandbindingTRcanbindpreviously open chromatinregions,itwasalsodemonstrated majority ofTR-bindingsiteswerefoundtoresidewithin affects targetgeneexpression.Moststrikingly, while hormone action Co-regulators inthyroid C D Published byBioscientifica Ltd. 3 , aconformationalchangeoccursthatfavorsrecruitmentof Postivie regulationthroughT3-inducedrecruitmentofTR Negative regulationthroughinderectrecruitmentofTR 3 , TRstronglybindstotheresponseelementandbrings

RXR/TR CoA

DR-4 3 . OnapositivetargetgenecontainingDR-4- TR TF ? TR ? CoR Downloaded fromBioscientifica.com at09/26/202109:24:34PM 3 (basedonclassicbimodalswitch T3 T3 CoA 56 : 3 TF ? TR ?

3 RXR/TR toinitiate CoA DR-4 CoR et al. 2012). TR CoR R89 via freeaccess Journal of Molecular Endocrinology presence ofT achieved throughdiminishedrecruitmentofTRsinthe entirely newmechanism,wherenegativeregulation is 2002), 2013 , et al. assigned tothenegativelyregulated genesbyproximity distal enhancersitesandtherefore cannot be at very by TR,butTRbindinginthis caseoccurspreferentially that negativeTHtargetsmay stillberegulateddirectly negatively regulated by T found noevidencefordirectTRbindingnearthegenes recruitment data, where three out of four studies have direct regulationbyTRsremainsunclear. some degree,whethertheseeffectsaremediatedthrough function demonstrateabnormalregulationofHPTaxis to many modelswithdisruptedco-activatororco-repressor negative regulationbyTHinperipheraltissues.While so farfoundlittletonoroleforco-regulatorsinthe during neonatal period (Pei of THisactivationexpressionKlf2inthelung a role in direct transcriptional activation in the absence The onlydefinitiveinvivoproofofco-repressorsplaying paradoxically play the opposite roles on negative targets. has beenproposedthatco-activatorsandco-repressors of expression of negative TH targets remains unclear. It bind T higher percentage of the receptors that are available to TR actions. Lack of co-repressor recruitment results in a transcriptional activationvsrepressionthatunderlies in thedynamicsofcofactorrecruitmentandbalance of co-repressororco-activatorfunctionproducesashift isoforms under a range of TH concentrations. Removal knockout models,suchasSrc1 and in thecontextofTHsignaling.Infact,roleSMRT if atall,compensatefortheabsenceofNCoRandSrc1 be a ‘second-tier’co-regulator and can only minimally, co-activator forTRisoforms.SMRTandSrc2appearto NCoR andSrc1beingthepreferredco-repressor that co-regulatorspecificitydoesexistinvivo,with in therepressivemode. enhanced recruitmentofco-repressors,thus‘locking’TRs for maximaltranscriptionalactivation,butalsoleadsto of othercomponentsco-activatorcomplexnecessary time, co-activatorremovalnotonlyprecludesbinding and transcriptional response to the hormone. At the same NCoRΔ DOI: 10.1530/JME-15-0246 http://jme.endocrinology-journals.org Review This isfurthersubstantiatedbygenome-wideTR At thesametime,roleofco-regulatorsincontrol Studies usinganimalmodelshavealsoconfirmed Src2 onlybecomesapparentinthecompound 3 ID/ andco-activators,thusincreasingTRsensitivity L-NCoRΔ Src1 Grontved 3 (Ramadoss −/− ( ID/Smrt Vella 2015 ), and one suggested an et al. et al. 2014). −/− et al. 2013).Theseresultssuggest 3 ( Ayers ( Shimizu t al.2011).Moststudies et i

available (Feng genomic occupancy of some co-regulators are currently depending onthetargetgene.ChIP-seqdata co-activators andco-repressorsmayappeardifferent Therefore, itisnotsurprisingthatinvivofunctionsof considerably.and functionatthesesitesmayvary genes, andthemodeofTRco-regulatorrecruitment TR-binding sitesthatcontrolexpressionofTHtarget demonstrated thatthereisawiderepertoireofthe types ofTR-dependentRTH. display morephenotypicpresentationsthanthetwo widelyand of thesegroupspatientsarelikelytovary remain tobeidentified.Importantly, clinicalfeatures co-regulator recruitment,function,and/orexpression with disturbancesinTHsignalingduetoabnormal mutations ineitherTRisoform.However, humanpatients modulate phenotypicpresentationofRTHcausedby resistance orincreasedsensitivitytoTH,andmayalso that alterationsinco-regulatorrecruitmentcanleadto directly regulatedbyTRs. transcription factorsorregulationbyproductsofgenes recruitment ofTRtoDNAthroughtetheringother negative regulationmaybeindirect,whichincludes in ChIP-seqexperiments.Alternatively, TH-dependent different physiologicalconditions. different pathways, and how theirroles change under could helpbetterunderstand theinterplaybetween specific cell-type (e.g. LXR, PPAR, Rev-ErbA in the liver) of TRcistromewiththose otherNRprominentinthe negative regulationbyTRs.Furthermore,comparison distant enhancers,andpotentiallyshedlightonthe will helptobetterinformusaboutTR-regulated new ChIA-PET experiments for genomic TR-binding with Hi-CperformedunderdifferentTHconditions,or certain limitations.CombiningexistingTR-bindingdata transcriptional regulationbyTRs,thesemethodssuffer binding providedgreatinsightintothemechanisms of ChAP-seq andChIP-seqdataregardingchromatinTR influence genomicTRbinding.Moreover, while it becameevidentthatthyroidstatusmaygreatly in thecontextofTRsignaling,particularlynow, when help put the genome-wide co-regulator binding data and alignitwithTR-bindingsites.Suchanalysiswill thyroid conditions(hypo-,eu-,andhyperthyroid) of transcriptional activation/repression under different well as distribution of histone modifications indicative re-evaluate genomicrecruitmentofco-regulatorsas Louet hormone action Co-regulators inthyroid Published byBioscientifica Ltd. Genome-wide interrogationofTRbindingalso Mouse modelshavedefinitivelydemonstrated t al.2014).However, itwouldbeusefulto et et al. 2011, Downloaded fromBioscientifica.com at09/26/202109:24:34PM Stashi et al. 2014a 56 : 3 , Tannour- R90 via freeaccess Journal of Molecular Endocrinology Baniahmad A, Leng X, Burris TP, Leng X, Tsai SY, 1995 Baniahmad A, &O’Malley BW Tsai MJ & Arumanayagam AS Switnicki MP, Lammel J, Ayers S, Angajala A, Abel ED, Ahima RS, Boers ME, Elmquist JK &Wondisford FE 2001 Elmquist JK Boers ME, Ahima RS, Abel ED, References critical readingofthemanuscript. The authorisgratefultoDrAnthonyNHollenebrgfordiscussionsand Acknowledgements This workwassupportedbyATA ResearchGrant(2011). Funding perceived asprejudicingtheimpartialityofthisreview. 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