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, WNT! pathway! in! the! adrenal! cortex.! We! thus! evaluated! the! effect! of! Ezh2! ablation! on!
, !To! confirm! alteration! of! PKA! signalling! pathway! activity,! we! measured! PKA! activity! on! whole!adrenal!extracts.!Interestingly,!analysis!of!PKA!activity!on!whole!adrenal!extracts! showed! a! significant! decrease! in! basal! activity! in! KO! adrenals,! although! it! was! still! as! sensitive! to! cAMP! induction! as! in! wildAtype! (Fig! 4D), PACREB!accumulation!measured!by!westernAblot!on!wholeAadrenal!extracts!(Fig!4C)
, ! RTqPCR! analyses! did! not! show! any! alteration! in! the! expression! of! Mc2r! or! of! its! cofactor! Mrap! that! are! essential! to! mediate! PKA! response! to! ACTH! (Fig! S2A), PKA! pathway! activity! was! situated! upstream! of! catalytic! activity.! However
, ! Altogether,! these! data! suggested!that!EZH2!was!required!to!mount!an!optimal!response!to!PKA!in!the!adrenal! cortex! by! inhibiting! expression! of! negative! PKA! regulators,! in! particular! phosphodiesterases.! Consistent! with! this! idea,! analysis! of! publically! available! ChIP! sequencing! data! showed! enrichment! of! EZH2/H3K27me3! on! a! number! of! phosphodiesterases! regulatory! regions! in!14! different! cell! types! (Fig! S2B).! To! test! this! possibility! in! the! adrenal, ! we! evaluated! enrichment! for! H3K27me3! and! EZH2! on! the! promoters! of! Prkar1b,! Pde1b,! Pde3a! and! Pde7b! in! wildAtype! and! Ezh2! KO! adrenals
, ! This! pattern! was! further! restricted! at! 1! month! and! very! few! cells! at! the! periphery! of! the! cortex! EZH2!activity!during!embryonic!development.!To!evaluate!this,!we!analysed!adrenal! differentiation! phenotype! at! E18.5,! when! differentiation! of! zonae! glomerulosa! and! fasciculata! becomes! evident.! Indeed,! in! wildAtype! adrenals,! we! observed! a! clear! separation! of! the! expression! domains! of! DAB2! (zG)! and! AKR1B7! (zF)! (Fig! 4I,! a), showed! high! levels! of! expression! throughout! the! adrenal! gland! at! E15.5! (Fig! 4H,! a),! which! progressively! restricted! to! cortical! periphery! by! E18.5! (Fig! 4H,! b)
, !Altogether,!these!data!strongly! suggest!that!EZH2!programs!adrenal!cortex!cells!for!optimal!response!to!PKA!signalling! during! embryonic! development.! However,! although! adrenal! cortex! cell! renewal! is! a! relatively! slow! process! (12! weeks! in! female! mice, This!was!also!associated!with!decreased!expression!of!Cyp11b1!and!Akr1b7!in!RTqPCR! (Fig!4J)!and!significant!upAregulation!of!Pde1b!(Fig!4K)
, ! analysis!of!EZH2!expression!together!with!DAB2!and!AKR1B7,!showed!that!the!few!cells! that! expressed! Ezh2! in! the! adult! adrenal! were! localised! within! zG,! at! the! boundary! between! zG! and! zF! or! within! outer! zF! (Fig! 4L).! ! This! localisation! suggested! that! EZH2! may! be! reAexpressed, H3K27me3!maintenance!during!cell!divisions!associated!with!this!process.!Interestingly
, This! idea! was! further! confirmed! by! coAlocalisation! of! EZH2! with! Ki67! staining! in! the! outer!cortex!(Fig!4M).!Altogether,!our!data!show!that!EZH2
, Renewal! of! the! adrenal! cortex! is! highly! coordinated! with! zonal! cell! differentiation! to!
, ! Consistent! with! this,! H&E! staining! showed! massive! expansion! of! fibroblasticAlike! cells,! characteristic! of! the! capsular!and!subAcapsular!adrenal!compartment!where!progenitors!reside!in!the!wildA type!adrenal!(Fig!5B,!b!vs!a).!Abnormal!expansion!of!the!progenitor!compartment!was! further! suggested! by! a! large!, compared! with! wildAtype! adrenals! (Fig! 5A)
, ! can! be! recruited! to! meet! supraphysiological! demand! (6,! 18,! 19).! Interestingly,! analysis! of! microAarray! data! showed! upAregulation! of! Gata4,! Wt1! and! Gli1,' suggesting! that! supraphysiological! progenitors! may! be! accumulating! in! Ezh2! KO! adrenals! (Fig! 5C).! To! evaluate! this! hypothesis
, ! strongly! suggested! SHHAindependent! accumulation! of! GLI1Apositive! cells.! IHC! for!WT1!showed!very!weak!expression!in!the!adrenal!capsule,!as!previously!described!in! wildAtype! mice! (18).! In! contrast,! a! large! number! of! the! fibroblasticAlike! cells! that! accumulated!in!Ezh2!KO!adrenals!expressed!high!levels!of!WT1!(Fig!5D,!eAf),!which!was! associated! with! a! sevenAfold! increase! in! WT1! transcript! accumulation! (Fig! 5F).! Forced! induction!of!WT1!in!the!adrenal!cortex!has!been!shown!to!result!in!increased!expression! of! GATA4,! through! direct! WT1! binding! on' Gata4! regulatory! regions! (18).! Consistent! with! this! idea,! whereas! GATA4! was! virtually! absent! from! wildAtype! adrenals,! it! was! strongly! expressed! in! fibroblasticAlike! cells! following! Ezh2! ablation! (Fig! 5D,! gAh).! This! was! also! associated! with! an! eightAfold! increase!, RNAScope!in!situ!hybridisation!(ISH)!and!RTqPCR.!As!expected!Shh!was!detected!within! zG! in! wildAtype! adrenals! (Fig! 5D,! a).RTqPCR!(Fig!5E).!!The!normal!accumulation!of!both!Shh!and!Ptch1!(a!target!of!SHH)! (Fig! 5E)
, expression!in!the!adrenal!has!been!shown!to!result!in! aberrant!gonadalAlike!differentiation.!Consistent!with!this,!RTqPCR!analyses!showed!upA regulation! of! Pdgfra,! Foxl2! and! Lhr,! characteristic! of! gonadal! differentiation! (Fig! 5H
, Altogether,! these! data! showed! that! Ezh2! ablation! resulted! in! the! accumulation! of! cells!
, been! shown! to! accumulate! in! the! adrenal! cortex! of! mice! following! castration! (18,! 19
, Cre!is!also!active!in!the!gonad,!Sf1:Cre,Ezh2'Fl
, !d!vs!c)!within!Ezh2!KO!adrenals!at!this! stage.!By!E18.5,!GATA4'positive!cells!were!detected!throughout!the!cortex!(Fig!6A,!f!vs! e),! which! was! correlated! with! upAregulation! of! Gata4! mRNA! accumulation! in! RTqPCR! (Fig! 6B).! A! small! number! of! WT1Apositive! cells! also! appeared! at! the! periphery! of! the! gland! (Fig! 6A,! h! vs! g),! even! though! Wt1! mRNA! accumulation! was! unaltered! (Fig! 6B), !(Fig!6B),!IHC!analyses!showed!abnormal!accumulation! of!GATA4!(Fig!6A,!b!vs!a)!but!not!WT1!(Fig!6A
, positive! cells! in! response! to! Ezh2' ablation.! We! first! evaluated! the! possibility! that! this! may! be! the! result! of
, !Furthermore,!even!though! some! GATA4+! cells! displayed! Ki67! expression,! most! of! them! were! Ki67Anegative! (Fig! expression! of! both! factors! in! Ezh2! KO! adrenals! may! rely! on! a! direct! role! of! EZH2! on! their! expression.! Consistent! with! this! idea,! ChIP! qPCR! analyses! showed! enrichment!of!H3K27me3!and!EZH2!on!the!regulatory!regions!of!both!GATA4!and!WT1! and! a! significant! decrease! in! enrichment! in! Ezh2! KO! adrenals! (Fig! 6F).! This! indicated! that! EZH2/PRC2! was! directly! involved! in! repressing! Gata4! and! Wt1! expression! in! the! adrenal! cortex.! However,! whether! EZH2! exerted! this! activity! in! capsular! or! steroidogenic!cells!was!unclear, WT1+! progenitor! cells! that! reside! in! the! capsule! of! wildAtype! adrenals.! IHC! analyses! showed! that! there! was! no! overall! increase! in! the! number! of! Ki67+! cortical! cells! following!Ezh2!ablation,!both!in!IHC!and!RTqPCR!(Fig!6CAD)
, EZH2!expression!was!low!(embryonic!development,!Fig!S4A)!or!absent!(adult!adrenal
, !the! vast! majority! expressed! GFP,! indicating! that! although! they! were! SF1Anegative,! they! 16! derived! from! the! steroidogenic! lineage! (Fig! 6H).! Analysis! of! serial! sections! stained! for! WT1,!SF1!and!GFP!also!showed!that!WT1Apositive!cells,!despite!being!SF1Anegative!were! largely!derived!from!the!steroidogenic!lineage!(Fig!S4B).!!Altogether,!these!data!strongly! suggest! that! the! large! majority! of! GATA4! and! WT1Apositive! fibroblasticAlike! cells! that! accumulate! in! Ezh2! KO! adrenals! originate! from! dedifferentiation! of! engaged! steroidogenic!cells, fibroblasticAlike! GATA4Apositive! cells! in! Ezh2! KO! adrenals.! Interestingly,! most! of! these! cells!did!not!express!any!detectable!level!of!endogenous!SF1!expression.!However
, GATA4Apositive! fibroblasticAlike! cells! were! also! present! at! the! periphery! of! the! cortex,! even! though! all! spindleAshaped! cells! did! not! express! GATA4! (Fig! 6I).! ! Consistent! with! their! counterparts! in! Ezh2! KO! adrenals
, ! others! have! identified! the! molecular! signals! involved! in! zonal! differentiation,! the! mechanisms!involved!in!maintaining!global!steroidogenic!differentiation!during!adrenal! cortex!renewal!and!cell!migration!have!remained!elusive, vol.20
, ! which! synthesizes! aldosterone! and! zona! fasciculata! (zF)! in! the! inner! cortex,! which! synthesizes! corticosterone! in! rodents! and! cortisol! in! humans.! ! Our! data! show! that! Ezh2! ablation! is! associated! with! a! strong! reduction! in! zF! differentiation,! which! results! in! primary! glucocorticoid! insufficiency,! !PKA!signalling!in!the!inner!cortex!(7,!11,!21).!Interestingly,!EZH2!has! been! shown! to! directly! inhibit! WNT! signalling! in! intestinal! stem! cells! to! prevent! their! differentiation! (22)! and! in! mesenchymal! stem! cells! to! allow! their! adipogenic! differentiation! (23).! Analysis! of! WNT! pathway! status! by! microarrays! and!, Adrenal! cortex! zonal! differentiation! is! characterised! by! establishment! of! zona! glomerulosa! (zG)! in! the! outer! cortex
, ! the! capacity! to! respond! to! the! reninAangiotensin! system! in! order! to! maintain! aldosterone!homeostasis.!Indeed,!our!RTqPCR!analyses!showed!decreased!expression!of!
, the! result! of! decreased! PKA! signalling! pathway! activity! in! response! to! Ezh2! ablation.! Indeed,! our! combination! of! microarrays
, embryonic!development,!when!EZH2!is!expressed!in!all!adrenal!steroidogenic!cells!and!
, ! dividing! cells! in! the! adult! gland! through! temporary! reAexpression! of! EZH2.! To! our! knowledge
, ! a! set! of! 14! different! cell! types,! including! cancer! cell! lines,! but! also!
, Decreased!PKA!activity!in!the!adrenal,!resulting!from!mutations!of!the!genes!encoding!
, ACTH!receptor!MC2R!or!its!accessory!protein!MRAP,!is!associated!with!isolated!familial! glucocorticoid! deficiency! (FGD),! a! potentially! fatal! condition! if! left! untreated! (26,! 27
, These! mutations! only! account! for! about! 45%! of! FGD! patients.! NGS! analyses! have! identified! other! alterations! such! as! mutations! in! NNT! (28),! TXNRD2! (29),! GPX1! and!
, ! However,! for! about! 25%! of! FGD! cases! there! is! still! no! They! can! also! contribute,! albeit! at! low! frequency,! to! adrenal! cortex! replenishment! in! the! adult! (6,! 9,! 18,! 19,! 33)! and! can! be! mobilised! upon! gonadectomy,! giving! rise! to! adrenal! neoplasia! (34,! 35)! presenting! characteristics! of! adrenogonadal! cells! such! as! GATA4, replication! and! chromosome! stability! (31)! and! gain! of! function! mutations! of! the! cell! cycle! inhibitor! CDKN1C! (32)
, ! even! though! GLI1Apositive! cells! may! contribute! to! their! appearance!(19).!Here,!we!show!that!Ezh2!ablation!results!in!the!dramatic!accumulation! of!spindleAshaped!GATA4,!WT1,!GLI1!positive!and!SF1Anegative!cells!in!the!subcapsular! region! of! 2! monthAold! adrenals.! Although! we! cannot! rule! out! a! direct! contribution! of! in!response!to!Ezh2'ablation,!our!experiments!suggest!a!different!scenario:!1)!EZH2! is! expressed! at! very! low! levels! in! the! capsule! and! is! not!, /GLI1! positive! cells,! the! origin! of! spindleAshaped! cells! in! the! ageing! adrenal! cortex! is! not! as! clear
, positive! steroidogenic! cells! in! response! to! Ezh2! ablation.! Although! dedifferentiation! of!
, E18.5! respectively.! This! suggests! that! other! repressive! factors! may! be!
, ! of! multiple! differentiation! programmes! (40).! This! function! is! maintained! in! adult! hematopoietic! stem! cells! (41),! myoblasts! (42,! 43)! and! neural! stem! cells, vol.45
, ! In! marked! contrast,! our! data! show! that! EZH2! is! mostly! expressed! in! differentiated! adrenal! cortex! cells.! Its! ablation! in! these! cells! results! in! their! dedifferentiation! towards! a! progenitorAlike! state! and! is! also! associated! with! a! decreased! capacity! to! respond! to! differentiation! signals! such! as! ACTH/cAMP/PKA! signalling.! This! emphasizes! the! multiple! and! sometimes! contradictory! functions! of! EZH2!, dedifferentiation! of! astrocytes! toward! neural! stem! cells! (46)
, Ezh2!Fl/Fl!mice!were!obtained!from!the!MMRRC!repository!(strain!#015499_UNC)!and! were! initially! generated! by! Dr! Tarakhovsky! (13).! Sf1:Cre! mice! were! generated! by!
, ! mTmG! mice! were! generated! by! Muzumdar! et! al.! (14).! Unless! otherwise! stated,! all! data! on! adult! mice! were! generated! on! tissues! from! 2! monthAold! females.!For!embryonic!analyses
, ! pH! 9.0;! or! Vector! Unmasking! Solution! (H3300,! Vector! Laboratories),! depending!on!the!primary!antibody!and/or!combinations!of!antibodies!to!be!used
, CYP11B2,! unmasking! with! TrisAEDTA! was! followed! by! 5! min! incubation! in! 10%! SDS
, After! blocking! for! 1h,! slides! were! incubated! overnight! at! room! temperature,! with! primary!antibodies!at!the!indicated!concentrations!(Table!S1).!Primary!antibodies!were! detected! with! appropriate! polymers! (ImmPress! Polymer! Detection! Kit,! Vector! Laboratories).! PolymerAcoupled! HRP! activity! was! then! detected! with! either! Vectastain!
, ! All! immunohistochemical! analyses! were! conducted! on! an! automated! processor! (Intavis! InSitu! Pro! VSi)! to! ensure! homogeneity! and! reproducibility! of! detections, ! Images! were! acquired! with! a! Zeiss! Axioplan! 2,! Zeiss! ! probes! for! Shh! (#314361)! and! Gli1! (#311001)! with! the! RNAScope! 2.5HD! detection! reagentARed! system! (#322360,! Adanced! Cell!
, ! We! selected! datasets! for! which! .fastq,! peaks.bed! and! input!data!were!available!for!download, ! "H3K27me3"! and! "ChIP"! on! the! Gene! Expression! Omnibus! (GEO)! database!
, )! on! the! hg38! Human! reference! genome.! Output! files! were! converted! to! .bam! format! using! SAMtools! (version! 1.3.1).! ChIP! enrichment! for! each! of! the!marks!was!determined!using!MACS2!
, ! To! detect! potential! target! genes,! peaks! were! annotated! using! the!, TxDb.Hsapiens.UCSC
, KO! littermates! were! analyzed! using! Affymetrix! Mouse! Gene! 2.0! ST! Arrays! (Raw! and! processed!data!are!deposited!on!NCBI!GEO!platform).!Gene!expression!was!normalised! by!RMA!
, Genes! with! adjusted! p! value! (FDR)! <0.1! and! Abs(Log! 2! fold! change)! >! 1.0!
, !They!represent!genes!with!binding!of!EZH2,!SUZ12!and!H3K27me3!in!both!
, PLC5!and!mouse!ES!cells!(PRC2_CHENG_PLC5_mmES),!in!both!PLC5!and!human!ES!cells!
, ! PRC2_LEE! represents! genes! with! binding! of! SUZ12,! EED! and! H3K27me3! in! human! ES! cells! and! was! extracted! from! Lee! et! al.! (49
, PRC2_VELICHTUNA_hsES_CB_K27_EZH2! represents! genes! with! binding! of! EZH2! and!
, H3K27me3!in!both!human!ES!cells!and!germinal!center!B!cells!and!was!extracted!from!
,
, Biochem!Canada)!concentrations!were!determined!using!commercially!available!ELISA! kits,! following! manufacturer's! instructions.! Renin! activity! rate! in! plasma! was! determined! using! a! Fluorimetric! Sensolyte! 520! Mouse! Renin! Assay! Kit!
,
, !2!mM!dNTPs!and!20!units!RNAsin!(N2615,!
, ! Primer! pairs! are! listed! in! Table! S4.! For! each! experiment! and! primer! pairs,! efficiency! of! PCR! reactions! was! evaluated! by! amplification! of! serial! dilutions!of!a!mix!of!cDNAs.!Relative!gene!expression!was!obtained!by!the'##Ct'method! with! normalization! to! average! expression! of! three! housekeeping! genes,! 36b4
, PKA! activity! was! measured! using! PKA! Kinase! Activity! Assay! Kit! (ab139435,! Abcam
, ChIP)!were!performed!using!the! iDeal! ChIPAseq! kit! for! histones! (Diagenode)! according! to! manufacturer's! instructions, ! using! the! following! antibodies:! C15410195! (rabbit! polyclonal,! Diagenode)! for!
, ! 20! to! 35! mg!of!tissue!from!2!monthAold!female!WT!and!Ezh2!KO!mice!(pools!of!6!adrenals!from!3! mice,!in!triplicate)!were!first!grinded!using!a!dounce!homogenizer!and!then!crossAlinked! with!1%!formaldehyde!for!10!min.!CrossAlinking!was!stopped!by!adding!glycine!(125mM! final)! for! 5! min! at! room! temperature
, Minimal!sample!size!was!set!at!n=5!allowing!for!detection!of!40%!increases/decreases! with!"=0.05,!1A!=80%,!$=0.3!and!mean!of!control!group=1
, ! Statistical! analysis! of! normally! distributed! data! was! performed! by! twoAtailed!
, The! authors! declare! that! all! data! supporting! the! findings! of! this! study! are! available!
, Mazuel!for!animal! care,!Anipath!Clermont!for!anatomopathological!analyses
,
, for!microarray!analyses.!This!work!was!funded!through!institutional!support! from!Centre!National!de!la!Recherche!Scientifique,!Institut!National!de!la!Santé!et!de!la
,
, !The!funders!had!no!role!in!study!design,! data!collection!and!analysis
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, !CF!RTqPCR!analysis!of!accumulation!of!mRNAs!encoding!canonical!WNT! target!genes!in!2!monthAold!wildAtype!and!Ezh2!KO!adrenals.!Bars!represent!the!mean! expression! in! 7! animals! per! group! ±! SEM.! Ns,! not! significant,! **! p! <0.01.! DF! Immunohistochemical!detection!of!the!canonical!WNT!target!gene!LEF1!in!2!monthAold! wildAtype!and!Ezh2!KO!adrenals.!zF:!zona!fasciculata,!zG:!zona!glomerulosa,!Ca:!capsule.! Scalebars:!50µm.! Figure+4.+EZH2+programs+the+capacity+of+adrenal+steroidogenic+cells+to+respond+to+ PKA+ signalling.+ AF+ Gene! Set! Enrichment! Analysis! (GSEA)! of! microAarray! gene! expression! data,! using! curated! steroidogenesis! and! cholesterol! synthesis! (mevalonate! pathway)! genes! lists.! BF+ Immunohistochemical! detection! of! PanAPKA! substrates! (aAb)! and!phosphorylated!CREB!protein!together!with!GFP!(cells!of!the!steroidogenic!lineage,! cAd)!in!2!monthAold!wildAtype!and!Ezh2!KO!adrenals.!CF!WesternAblot!analysis!of!PACREB! accumulation! in! seven! 2! monthAold! wildAtype! and! Ezh2! KO! adrenals.! Graph! shows! quantification!of!PACREB!over!CREB!signal.!DF!ELISA!quantification!of!basal!and!, expression! data,! using! a! curated! WNT! pathway! regulators! and! targets! gene! list!(3).! BF! Heatmap!representing!the!median!centred!expression!of!significantly!deregulated!WNT! regulators! and! target! genes! (FDR! <0.1)! in! 2! monthAold! Ezh2! KO! compared! with! wildA type!adrenals
, ! 1! month! and! 6! months! wildA type! adrenals.! Ca:! capsule,! Co:! cortex, ! zF:! zona! fasciculata.! IF! CoAimmunostaining! for! DAB2! (zG)! and! AKR1b7! (zF)! in! E18.5! wildAtype! ! and! Ezh2! KO! adrenals.! White! arrowheads! show! cell! staining! for! both! DAB2! and! AKR1B7
, !Scalebars:!50!µm.! Figure+ 5.+ Ezh2+ ablation+ is+ associated+ with+ accumulation+ of+ cells+ with+ characteristics+ of+ adrenal+ progenitors.+ AF+ Gene! Set! Enrichment! Analysis! (GSEA)! of! microAarray!gene!expression!data,!using!a!curated!list!of!adrenal!progenitorsAassociated! genes.!BF!haematoxylinAeosin!staining!(aAb)!and!immunohistochemical!detection!of!the!, analysis! of! accumulation! of! mRNAs! encoding! zonal! differentiation! markers! (K)! and! PKA! signalling! inhibitors! (L)! in! 2! monthAold! wildAtype! and! Ezh2! KO! adrenals.! Bars! represent! the! mean! expression! in! 7! animals! per! group! ±! SEM.! LF! CoAimmunostaining! for! EZH2,! DAB2! (zG)! and! AKR1B7! (zF)! in! a! 2! monthAold! wild! type! adrenal.! M:! medulla.! Arrowheads! show! EZH2Apositive! cells.! MF! CoA immunostaining! for! EZH2! and! Ki67! in! a! 2! monthAold! wild! type! adrenal.! Arrowheads! show!cells!staining!for!both!EZH2!and!Ki67.!Stars!show!cells!only!staining!for!EZH2.!ns
, ! Ca:! capsule,! zG:! sona! glomerulosa,! zF:! zona! fasciculata! DF! RNAscope! in! situ! hybridisation! showing! expression! of! Shh! (homeostatic! progenitors,! aAb)! and! Gli1! (supraphysiological! progenitors,! cAd)! and! immunohistochemistry! for! WT1! (eAf)! and! GATA4!(gAh)!in!2!monthAold!wildAtype!and!Ezh2!KO!adrenals.!EFFF!RTqPCR!analysis!of! accumulation!of!mRNAs!encoding!key!actors!in!Hedgehog!pathway!(E)!and!markers!of! supraphysiological!progenitors!(F)!in!2!monthAold!wildAtype!and!Ezh2!KO!adrenals, Heatmap! representing! the! median! centred! expression! of! significantly! deregulated! progenitorsAassociated!genes!(FDR!<0.1)!in!2!monthAold!Ezh2!KO!compared!with!wildA type! adrenals
, !capsule,!zG:!zona!glomerulosa,! zF:!zona!fasciculata.!HF!RTqPCR!analysis!of!accumulation!of!mRNAs!encoding!markers!of! gonadalAlike! differentiation! in! 2! monthAold! wildAtype! and! Ezh2! KO! adrenals.! Bars! represent! the! mean! expression! in! 7! animals! per! group! ±! SEM
, ! capsule,! Ad:! adrenal,! Kid:! kidney.! BF! RTqPCR! analysis! of! accumulation! of! mRNAs! encoding! Wt1! and! Gata4! in! E14.5! and! E18.5! wildAtype! and! Ezh2! KO! adrenals
, Bars! represent! the! mean! expression! in! 14! (E14.5)! and! 6! (E18.5)! animals! per! group! ±! SEM.!CF+Immunohistochemical!analysis!of!Ki67!expression!in!2!monthAold!wildAtype!and!
, ! cortex.! DF! Number! of! cortical! Ki67Apositive! cells! in!
, ! capsule,! Co:! cortex.! FF+ Chromatin! immunoprecipitation!(ChIP)!of!H3K27me3!and!EZH2!on!the!regulatory!regions!of!Gata4! and!Wt1!in!2!monthAold!wildAtype!and!Ezh2!KO!adrenals.!Enrichments!were!normalised!
, ! M:! medulla.! HF! CoAimmunostaining! of! SF1! (actual! steroidogenic!cells),!GATA4!and!GFP!(cells!of!the!steroidogenic!lineage)!in!2!monthAold! wildAtype!(a,!bearing!Sf1:Cre!and!the!mTmG!reporter)!and!Ezh2!KO!(b)!
, cells! of! the!steroidogenic!lineage)!in!a!12!monthAold!wildAtype!adrenal!(bearing!Sf1:Cre!and!the! mTmG! reporter).! Right! panels! show! different! overlays! of! the! region! delineated! by! the! dashed!rectangle!to!the!left.!Scalebars!in!A
, Figure+ S1+ related+ to+ Figure+ 1.+ AF+ Immunohistochemical! detection! of! H3K27me3! together! with! GFP! expressed! from! the! mTmG! locus,! following! Sf1:CreAmediated! recombination,! in! 2! monthAold! wildAtype! (a,! Sf1:Cre,mTmG,Ezh2' +/+)! and! Ezh2! KO! female! adrenals! (b,! Sf1:Cre,mTmG,Ezh2' Fl/Fl).! Ca:! capsule,! Co:! cortex
, the!ACTH!receptor!Mc2r!and!the!accessory!protein'Mrap!in!2!monthAold!wildAtype!and!
, ! cGMP! (grey)! or! both! (green).! HeLa:! Human! cervix! cancer,! LNCaP! Abl:! Human! castration! resistant! prostate! cancer! lymph! node! metastasis! cells, ! K562:! Human! CML,! ProES:! Human! primary! fetal! liver! proerythroblasts,! DND41:! Human! T! cell! leukaemia,! h1_hesc:! Human! embryonic! stem! cells,! hepG2:! Human! hepatocellular! carcinoma,! EC:! Human! primary! epithelial! cell,! HSMM:! Human! skeletal! muscle! myoblast,! HUVEC:! Human! umbilical! vein! endothelial! cells,! NHA:! normal! Human! astrocyte! cells,! NHDFAAd:! adult! Human! dermal! fibroblasts,! NHEK:! Human! dermal! keratinocyte,! NHLF:! Human! lung! fibroblast.! CF+ !Ezh2!KO!testes!and!ovaries.! BF+Plasma!LH!
, Figure+ S4+ related+ to+ Figure+ 6.! AF! CoAimmunostaining! of! EZH2! and! GFP! (cells! of! the! steroidogenic! lineage)! in! E14.5! (AAb),! E18.5(cAd)! and! 14dpp! (eAf)! wildAtype!
, ! White! arrowheads! show! EZH2Apositive! capsular! cells.! Ca:! capsule,! Co:! cortex, ! BF! CoAimmunostaining! of! WT1! and! GFP! (aAb,! cells! of! the! ! steroidogenic!lineage)!and!WT1!and!SF1!(cAd)!in!2!monthAold!wildAtype
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