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Nuclear Regulatory Landscape of the Circadian Clock in Mouse Liver

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Nuclear Regulatory Landscape of the Circadian Clock in Mouse Liver Nuclear regulatory landscape of the circadian clock in mouse liver Jingkui Wang1,, Daniel Mauvoisin2, Eva Martin2, Florian Atger2, Antonio Nunes Galindo2, Federico Sizzano2, Loïc Dayon2, Martin Kussmann2, Patrice Waridel3, Manfredo Quadroni3, Felix Naef1 and Frédéric Gachon2 1Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland 2Nestlé Institute of Health Sciences, Lausanne, Switzerland. 3Protein Analysis Facility, University of Lausanne, Lausanne, Switzerland. Fig. 2 Rhythmic nuclear proteins are Fig.4 Rhythmic activities of kinases Fig. 6 Rhythmic endoreplication Abstract Methods & Results mainly post-transcriptionally regulated predicted by nuclear phospho-proteome probably causes leakage of cytoplasmic Diurnal oscillations of gene expression dictated by the proteins by weakening nuclear envelope NFIA, S280 SILAC mass spectrometry analysis of mouse liver nuclei Nucleus Both Cytoplasm A CIC, S1080 A 0.8 ● 0.6 ●C B ● ● nucleus phospho 0 ● 23 1 0.5 ● ● circadian clock enable living organisms to coordinate 23 0 1 23 0 1 ● 22 2 ● 0.3 22 2 22 2 ● ● ● ● A ● ● ● ● ● F2 21 3 0.2 ● ● ● ● ● ● ● 21 3 21 3 ● 0.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 20 4 ● ● ● their physiological processes with daily environmental 20 4 20 4 −0.1 ● ● ● ● −0.3 ● ● 19 5 −0.4 19 5 19 5 ● ● ● −0.6 ● ● changes. Although such rhythms have been extensively 13 18 6 18 6 18 6 −0.7 −0.9 ● Unlabeled mice C6-Lysine 0 12 24 36 48 0 12 24 36 48 17 7 17 7 17 7 studied at the level of transcription and mRNA CHD4, S1517 NCBP1, S22 16 8 16 8 16 8 0.7 ● ● ● 0.8 15 9 15 9 15 9 0.5 ● ● ● ● ● ● 0.5 14 10 0.3 ● accumulation, comparably little is known at the proteins 0 12 24 36 45 0 12 24 14 10 14 10 ● 13 11 13 11 13 11 ● ● 12 12 12 0.1 ● ● ● 0.2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● −0.1 −0.1 ● ● ● ● ● level, though recent proteomics studies indicated that ● mRNA protein −0.3 ● mRNA protein ● −0.4 ● ● B mRNA protein ● ● ● ● −0.5 ● ● ● −0.7 ● total protein rhythms generally appeared damped 0 12 24 36 48 0 12 24 36 48 Mapk6_ST CSNK1D C Cdk1_ST D Mapkapk3_STMknk2_STDyrk2_ST ● rhythmic Fastk_ST 1.4 compared to their cognate mRNAs. In order to further Nek8_ST ● ● Every 3 hours 2 WT mice Every 12 hours 8 SILAC mice ● ● ● Csnk1a1_STNek4_ST ZT0 0.8 Map4k2_ST Cdk9_ST Mapk14_ST Prkaa2_ST ● 0.2 ● ● ● Mapk15_ST ● ● ● ●● Plk2_ST dissect how diurnal rhythms affect key functions such as Clk3_ST ● ● −0.4 ● ● ● Araf_ST ● Mapk9_ST ● Csnk1d_STVrk1_ST ●● ● −1.0 ● ● ● ● ● Limk2_ST ● Cdk18_ST ●● transcription or chromatin remodeling, we quantified the Nuclei purification and proteins extraction Nek2_ST ● Stk16_ST 0 12 24 36 48 B ● ● GSK3A Vrk3_ST ● NE Chek2_ST ● FASN ● ● Camk1d_STSnrk_ST ● 1.2 ● ● ● Gsk3a_ST ● LC ● non-rhythmic ● temporal nuclear accumulation of proteins and ● ● ● Pim2_ST 0.4 ● ● ● NR3C1 NE NE Plk3_ST ● ● −0.4 ● ACACA Pim3_ST ● ● ● ● LC ● ● LC Srpk1_ST ● −1.2 phosphoproteins from mouse liver by SILAC-based MS. WT mix (1:1) SILAC mix (1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1) Scyl2_ST ● −2.0 ● NE Srpk2_ST ● NE α NE ALB SIRT7 GSK3 β Cdk16_ST ● C Akt1_ST ● 0 12 24 36 48 LC LC ● Our analysis identified ~5000 nuclear proteins, including LC Csnk2a2_ST ● ZT18 ZT6 ● Mapk1_ST PRKAA2 Dyrk1b_ST ● ● Sik1_ST ● Map3k8_ST ● ● Dstyk_ST 2.0 Ripk3_ST Lamin A/C IF ● 1.4 ● Camkk2_ST ● ● Nek9_ST 0.8 ● ● all core-clock and clock-related proteins, over 500 of ● ● ● ● Tesk2_ST ● 0.2 ● Stk24_ST ● Cdk5_ST ● FASN ZT0 confocal ● ● ● Mapk3_ST −0.4 ● ● ●Tgfbr2_ST ● Clk1_ST ●Cdk6_ST −1.0 ● ● Cdk7_ST ●Mapk12_ST ● ● which are found to be rhythmic under a stringent mix (1:1) ●Mapkapk5_ST C ●Acvr2b_ST 0 12 24 36 48 ●Prkcb_ST ●Gsk3b_ST MAPK14 P- NE NE ●Mapk7_ST P-CDC2 ● ● CDC2 Prkx_ST ● statistical threshold (FDR <5%). These rhythmic nuclear ● ● LC Raf1_ST 1.2 LC ● ● Wee1_ST ● ● ● ●Mapk8_ST 0.4 ● ● NE ● ● ● ● proteins are mainly controlled at the post-transcriptional ● Nuak1_ST −0.4 ● Map3k13_ST ● ● CDC6 ● Rps6ka3_ST ● ● Cdk4_ST −1.2 ● LC 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Camk2d_ST ● level and are often parts of complexes showing robust A) Phase distribution for the rhythmic nuclear proteins (FDR<0.05) ZT12 0 12 24 36 48 P27 Kip1 NE NE grouped by their annotated localizations (UNIPROT) Uhmk1_ST LC LC diurnal nuclear accumulation. These rhythmic complexes Trypsin Digest B) Heat maps of the rhythmic proteins and their corresponding mRNAs. A) and B) Examples and heat maps of rhythmic nuclear phospho-proteins T-MCM2 NENE Fractionation MCM2 are notably involved in transcriptional regulation, rRNA Data is standardized by rows and gray blocks indicate missing data. with non-rhythmic nuclear proteins. LCLC Phospho-enrichment synthesis, ribosome assembly, as well as DNA damage C) Western blot of individual rhythmic proteins performed on nuclear C) Peak phases of rhythmic kinase activities predicted by the nuclear ZT 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 extract. The graphs represents the quantification of the blots and the phospho-proteins, some of which are confirmed by their nuclear protein A) FACS analyses of nuclei isolated from mouse liver around the repair. From the parallel analysis of the nuclear corresponding mass spec data. accumulations in D) clock and separated into ploidy populations by (n = 4 light dark phospho-proteome, we could infer the temporal activity MS analysis MS analysis cycles) of kinases contributing to these rhythmic B) Localization of FASN at ZT0 (confocal fluorescence) and immunofluorescence of Lamin A/C in purified liver nuclei. phosphorylations. A large fraction of the kinase activities Fig. 5 Transcription factors and C) Western blot of individual protein involved in cell cycle regulation were implicated in cell signaling and cell cycle Fig. 1 ~ 5000 nuclear proteins were Fig. 3 Subunits of nuclear protein and DNA replication. regulation. In addition, 80 transcription factors and about quantified by SILAC-based MS including complexes showed highly similar and coregulators (FDR<5%) involved in the 100 transcriptional coregulators showed clear diurnal core-clock and clock-related proteins diurnal accumulations circadian transcription oscillations in the nucleus, enlarging the extent of M NM ● Coregulator TF.nuclear SUPT6H ● Acetyl A HDAC5 A B A KDM1B CSN/CSA/DDB2 TF.both ● Deacetyl Take-home messages transcriptional and epigenetic regulations by the 3000 1.0 Coverage APPBP1−UBA3 TF.phospho ● Methyl IRF2BP1 ZFPM1 CACYBP Profilin 1 SKI Mt3−Hsp84−Ck BCCIP ● Demethyl Percent.rhythmic PAF1 Arp2/3 ●● Alpha−GDI−Hsp9 YAF2 ● ● ● ZFP128 ESCRT−II ● CXXC5 MNK1−eIF4F ● ● Ubiq SURF CRY1 SETD8 2500 0.8 HSP90−associated CCT AP2 ● ●● circadian clock and/or systemic cues. Finally, a number ● BCOR ● Deubiq ABT1 EDF1 Endocytic coat RICH1/AMOT polarity BAZ1B 20S methyltransferase ● ● AP1 KCNQ1 CLIC4 ● ● AQP2−force−generator p130CasRNA−ER PolII/associated−alpha−cSrc ●●●●●●●● Nephrin BRD2 4820 proteins quantified ● ●● WIP−WASp−actin−myosin−Iia ● Core CohensinAMPK ●● ● Emerin 2000 ● ● Bmal1−Clock−Pers NRIP1 Retromer ● CEBPG 1. SILAC nuclear proteomics in mouse liver 0.6 ● PA28 ● TP53 ZBTB33 ● ● ESR1 ● of proteins with functions in the cytoplasm are detected ● ZT0 ●● PER ●● ● MAML1 ●● ● IRF2BP2 ● ● RB1 REPIN1 ● 1500 ● NONO DIDO1 DDX17 0.4 Parvulin pre−rRNP ● NFIL3 ● - High resolution (~5000 proteins), CKII ● CRY2 AATF DNMT1−RB1−HDAC1−E2F1 RORA CIZ1 in the nucleus at a common and sharp time near the of proteins WICH ● ● ● ● MEF2D 1000 PSF−P54 ● ● IMP3−IMP4−MPP ● ● ● Exosome TCF12 nb 0.2 CPSF ● RNA PolI RORC HNF1B - ~12% highly rhythmic (FDR<5%). ● ● PHC2 WIZ night-day transition. This phenomenon is probably linked Bmal1−Clock ● ● PPARD 500 ● CoREST−HDAC ILF2 ZT6 ● NCOR/SMRT PER2 NR2F6 0.0 ZT18 - Almost all core clock and clock to the rhythmic endoreplication occurring in hepatic cells ● TFC4−CTNNB1 PER1 ● ZKSCAN3 0 ●SETDB1−HMTase ● ●HDAC1/2−associated HNF4A ● CBX2 TF IRF9 ●DNA ligase III−XRCC1 PER3 ETV3 HNF1A related genes identified and and associated to leakage of the nuclear membrane. 0 5 10 15 ●NuRD ● ESRRA SREBF1 Kinase ● Ikaros ZMYND8 ●Rev−ErbA−Ncor1−Hdac3 ● nb of quantified samples RNA KLF3 CBFA2T2 ●NCOR−SIN3 ● ● FOXA1 TBX3 quantified. Taken together, these findings provide unprecedented ● HIRA FOXK1 ZMYND8 processing NURF Coregulator ● GTF2IRD1 ZT0 ● SIN3−associated HSF1 C Phosphatase ● transcription ● APC/C PCBP1 CLOCK ZT12 ● NuA4/Tip60 HAT 2. Within these rhythmic proteins ● ● cytoskeleton ● ZNF198−PML HCFC1 ARNTL core clock ● MRE11−RAD50−NBN insights into the regulatory landscape of the diurnal liver D ARNTL CLOCK ● TRF1 TFEB ● TBL1X ● p300−CBP ● SWI/SNF ● ● TRAP/SMCC/DRIP ● stablizing loop chaperone ●Mediator/asscociated CDK8−CCNC−RNA PolII ● ● ● cell cycle ELF1 ● PHF21A ● ● ● - 81 transcription factors and more than 0.3 ● CIC ● EHMT2 nucleus. ● output regulators 0.4 ● DNA repair ● ATF1 ● ● SETDB1 ● ● NFIX IKZF1 ● ● ● proteolisis ● 0.0 ● 0.1 NR1H4 NFIA CRY1 ● ● 100 coregulators : most of them are ● protein transprot TCF7L2 ● KAT5 ● NFIL3 ● ● ● others FLI1 JMJD1C PER2 ● ● −0.3 JUNB −0.2 ZFHX3 RORC ● ● ● ● ● FOXA3 FOXP1 ATF7IP PER1 ● ● RORA ● new. CRY2 RFX1 −0.6 ● −0.5 HBP1 ●MTA2 ARNTL,CLOCK ● ● ● B PERPER Rev−ErbA−Ncor1−Hdac3 NuRD NCOR/SMRT ELF2 ● NR1D1 ●NCOR1 Cry2 2.7 ● 1.9 1.9 NR2C1 ●TBL1XR1 Per1 Nr1d1 Rbbp7 Ncor1 - Many nuclear protein complexes also ZT18 ZT6 0 6 12 18 24 0 6 12 18 24 ZFHX4 Previous work Cry1 Mta2 Tbl1xr1 ● Ncor1 2.2 Mta3 Tbl1x ERF MGA HDAC3 Per2 Hdac3 Zfpm1 Hdac3 CRTC2 PER1 PER2 Per3 Ncor1 Gatad2b 1.7 Zbtb33 E4F1 ●CABIN1 Nono Chd4 Ncor2 SP2 0.9 0.9 1.2 Smarca4 Ncor2 ●RBBP7 Wdr5 Mbd3 Trim33 MAFB NFIB ● Hdac2 Ncor1 ● HMBOX1 EMSY Mta1 0.7 Gps2 SCMH1 ● ● ● ● Smarcb1 CCNT2 N4BP2L2 display diurnal expression. 1 ● 0.2 Arid1a FOXP2 ● Mbd2 BHLHE40 TEF USF2 ● 1 −0.1 −0.1 NR3C1 TERF1 Smarcd2 AFF4 NR1D2 MLLT10 ZNF187 PPARA DBP NR1D1 ● ● Hdac1;Gm10093−0.3 ARID5B Dpf2 ●ZBTB1 ● −0.8 Actl6a KLF13 ● ● ● Smarcc2 BPTF ● Smarcc1 ● ● HLF −1.1 −1.1 Mbd3 −1.3 ● CHD6 NR1D2 0 Rbbp4 EP400 RXRA ● ● −1.8 Hnrnpc PATZ1 ● NR3C2 ● 0 Smarce1 ● KDM3A TEF ● ● ● HIRA −2.3 ● MED12 −2.1 ● ● ● −2.1 −2.8 ● ● MTA3 ● ● ● NACC1 ● 0 8 16 24 32 40 48 0 12 24 36 48 TAF2 ● ● MRGBP 0 12 24 36 48 0 12 24 36 48 TRIM24 ● ● KDM5A −1 ● Arp2/3 ● ● DAXX 3.
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