Analysis Supplement – Biclustering Analysis of Predicted Receptor Interactome

1. Biclustering on the predicted receptor interactome

Biclustering is a data mining technique that allows simultaneous clustering of rows and columns in a matrix [1]. Given a set of m rows and n columns (i.e., an m*n matrix), biclustering algorithms generate biclusters defined as a subset of rows that exhibit similar behaviour across a subset of columns, or vice versa. On our receptor interactome, a certain bicluster module contains a subset of human proteins that exhibit similar interaction behaviour across a subset of human receptors.

We used the biclustering software toolbox BicAT [2] to bicluster the receptor interactome graph. BicAT is a graphical user interface software for the analysis of gene expression data. It provides five biclustering and two standard clustering algorithms. The algorithm we used was the Iterative Signature Algorithm (ISA) which searches for submatrices representing fixed points [3]. Our graph was first transformed from weighted graph into a binary graph (by setting all existing edges’ weight to 1). The fixed points that this algorithm looks for are the interaction edges (which take on the value ‘1’ in our input graph when using the ISA method). About 40 biclusters were detected and their sizes range from ~180 genes to ~10 genes covered.

Each derived module (bicluster) represents a list of similarly interacting partners. to possible biological pathways. We found that many of the detected biclusters relate to specific biological pathways [4]. For example, a large number of proteins in several clusters participate in apoptotic pathways, including NOTCH, TNF, TLR3 in one bicluster and TGFbR2, TNF, BMP, FAS in another bicluster are receptors of different apoptotic pathways. Some examples of ligands/molecules on the protein side inducing or inhibiting apoptosis are DAF, STAT, MAPK, PAK, AKT. In general, we observed that proteins in biclusters included both the receptor as well as ligand and signaling cascade partners. For example, in clusters including the TNF and FAS pathways, many of the proteins were ligands of the TNF pathway eg. TRAF2, TRADD, FADD. In another cluster, NOTCH and LRP5 were found on the receptor side with the protein side partners being those that participate in either the NOTCH or the Wnt/LRP pathways. The involvement of most of the molecules in a cluster in a common pathway validates the basis of the formation of these local modules.

A detailed list of modules (biclusters) is available as Table S6.1. Specific modules that are most relevant to the paper are shown below in graphical representation.

2. Visualization of specific biclusters of significance to the results presented in the paper

Biclusters can also be represented as subgraphs in the predicted receptor interactome. Below we show examples of visualized biclusters of relevance to the interactions discussed in more detail in the paper.

Visualization of the biggest bicluster: The following figure is the visualization of the biggest bicluster we detected. It includes 109 gene nodes with 1962 PPI edges between receptors and their partners. This is a very dense subgraph with closely connected Type I receptors. This bicluster includes EGFR and HCK.

Figure 1 The visualization of the biggest bicluster in the predicted receptor interactome. Green represents type I receptors. All other human gene nodes are red.

Visualization of biclusters related to rhodopsin: Rhodopsin appeared as a member in four of the biclusters detected. Since there was overlap between the proteins in these clusters, we only show the largest bicluster containing rhodopsin here (Fig. S6.2). It includes 40 nodes and 53 edges.

Figure 2 The visualization of one bicluster relating to RHO in the predicted receptor interactome. Blue represents GPCRs. All other human gene nodes are red.

Biclusters related to Chemokine ligands: There are more than ten biclusters that include chemokines. One example is shown below.

Figure 3 The visualization of a bicluster relating to chemokine genes in the predicted receptor interactome. Green refers to type I receptors and blue represents GPCRs. All other other human gene nodes (including ligands) are red.

TGF1 related bicluster: TGF1 related to two overlapping biclusters. The bigger bicluster contains 110 nodes and 288 edges, shown in Fig. S6.4.

Figure 4 The visualization of the bicluster relating to TGF1 in the predicted receptor interactome. Green refers to type I receptors. All other human gene nodes are red.

3. Detected modules from biclustering on our human membrane receptor interactome

You can download the following table in a separate file as well. (download)

Table 1 Modules from biclustering: The bicluster moduls are listed. Each module contains three lines. It starts with a line of two numbers, which means the size of their related human proteins and membrane receptor proteins. Then the following line contains the human proteins (gene name) in this module and the third line includes the related membrane receptors (gene name).

108 47

PTPN11 SPTBN1 PTPN6 HCK EPHA5 PTPRS ERBB4 NEO1 GRB14 DDR1 KDR CIT PRKD2 TYRO3 ABL1 AKT3 CSF1R TGFBR2 JAK2 PRKD3 RASA1 ARHGEF2 FGFR1 EPHA2 INSRR LCK GRB7 TEK AKT1 PTPRJ MERTK GRB10 FGFR3 EPHA4 FGD1 ABL2 PTK2B ERBB3 CRKL ERBB2 PTK7 EDD1 SHC1 MARK1 PRKD1 EGFR FGFR4 RYK ROR1 JAK1 EPHA8 PDGFRA TYK2 EPHA1 EPHB1 NTRK2 ROCK1 TGFB3 FYN DDR2 PTPRF LATS1 ADRBK2 NTRK1 FES FRK DGKD FLT1 HBEGF MET HRMT1L1 ADRBK1 SRC PTPRD CSK EPHB4 TIE1 EPHB2 ROR2 PTPRG FLT4 EPHA3 NET1 SNF1LK LYN SNF1LK2 YES1 PDGFRB TNK2 PTPRU NTRK3 AXL CBL INSR GAB1 SYK ROCK2 ALK IGF1R PTPN1 KIT PTK2 FER TRIO LATS2 PTPRC MARK2 EPHB3

MERTK FGFR3 EPHB4 PDGFRB FLT1 PTPRF ROR1 EPHB3 EPHB2 EPHA2 PTPRD IGF1R TEK PTPRS EPHA3 TYRO3 EPHA8 RYK EPHA5 EPHB6 PDGFRA EPHB1 KDR EPHA4 PTK7 PTPRG INSR PTPRU FLT4 FGFR4 EPHA1 CSF1R ERBB3 EGFR KIT DDR1 ALK NTRK2 ROR2 NTRK3 DDR2 MET PTPRJ ERBB4 FGFR1 AXL ERBB2

112 28

THBD CD83 LIFR HRMT1L2 LCP2 SPINK5 GLMN IL15 IL1R1 LILRB2 IFNA2 GNLY IFNW1 CD40LG CSF1R TNFSF10 IRAK2 IL17F MMP25 C1QG KNG1 TXNDC THBS1 IL7 IL1RAP ADM TACSTD2 CD86 LTBR IL22 SERPINA1 IL2RB LOC153561 STAT5A CD72 LY75 COL1A2 DAF PTGS2 LILRB3 IFNGR1 IL8 CD40 NOTCH1 C1QB FN1 IL7R IL10RA MAP7 WDR33 C7 IL1RN INHBA IL4R LTB4R C1QR1 IL16 CSF2RB ITGB2 IL1RL1 CD97 TNFRSF14 IFNAR2 SON HLA-DRB5 CX3CR1 LILRB1 DBNL IL2RG TIMP3 C3 CD8A TNFRSF7 HLA-DMA C1QA VWF IFNGR2 IL6ST PROS1 TXNDC4 IRF4 PLAT IL10RB ANK2 ITGB1 TCIRG1 CD1D CD14 C4A CD58 BST1 F11R LY96 C1R APOL3 CD69 IL6R SCYE1 PLAUR GNB2L1 TLR4 CTGF LAT AOAH IFNAR1 STAT1 CD164 TLR6 MCP NALP12 GRAP2 HLA-DMB

CD40 TLR3 NOTCH1 IFNAR2 LILRB3 IL6ST PROCR IFNGR2 TLR4 IL10RB IL2RG TNFRSF7 PLAUR IL6R ITGB2 ITGB1 F2RL2 IL2RB CSF1R IL1R1 C1QR1 IL4R TNFRSF14 IFNGR1 IL7R F3 IFNAR1 CD97

176 13

DAPK1 MAPK1 RHOC DAPK2 STK4 MAP2K1 WNK2 DUSP10 MAP3K3 DUSP6 MELK TRAF3 RIPK2 PRKCB1 EPHA5 PAK1 DAB2 NEK6 PRKCH STK38L TRIB1 CDK3 PLK1 STK25 PIM1 RAF1 EIF2AK2 TRAF5 TGFBR2 MAP3K5 MAPK8 ACVR1 MAPK10 CDKN3 MAP4K1 FNTA ICK MAP3K7IP1 MAP2K3 SMURF1 BRAF ERN1 DAPK3 ACVR1B RPS6KA1 MKNK2 CDK4 SRPK2 PRKG1 GOLGA5 GRK5 RPS6KA5 MAPK13 MAP2K6 AKT1 PRKAA1 VRK2 DUSP4 HIPK1 WNK1 NPR1 ARAF MAP3K12 PCTK2 CAMK4 SMURF2 CLK3 PCTK3 NPR2 MAP3K4 TRAF6 CDK6 CDC2L5 MAPKAPK3 MAPK7 CDC2L1 MAP3K2 ULK1 CDK5 PRKCZ CHUK MAP3K7 PASK RPS6KA4 ILK CSNK1D MAPK9 PTEN DAPP1 DUSP16 SGK GRK6 MAPKAPK2 MARK3 BUB1 PAK4 CCNB1 PRKCI STK17B CSNK1G3 PRKACB BUB1B GSK3B MAP2K5 PINK1 PCTK1 MAP2K4 GRK4 STK38 RPS6KB1 CAMK2D RPS6KA2 CSNK2A2 PRKCA TGFBR1 ACVR2A DYRK2 LIMK1 MAP4K4 CSNK1A1 PRKCE CLK2 TRAF4 IRAK1 PIM2 CSNK1G2 SMAD1 PFTK1 MAPKAPK5 SMAD5 ACVRL1 BMPR2 CAMK1 IRAK3 PRKCD MAPK14 PKN1 MAPK12 RIPK1 MAP4K3 SGK3 SNRPB MKNK1 BMPR1A HIPK2 CLK1 STK17A MAP4K2 PRKACA DAXX PDPK1 SNF1LK SNF1LK2 RPS6KB2 MAP3K10 PKN2 EIF3S2 RPS6KA3 CSNK1E CAMK2G STK3 STK24 CDC7 MAP4K5 CHEK1 MAPK6 DCAMKL2 TGFBRAP1 PRKCQ PAK2 PLK2 CDC42 RHOG DUSP2 CDC25B MARK2

TGFBR2 TNFRSF10A BMPR2 FAS BMPR1A TNFRSF10B TGFBR1 ACVRL1 TNFRSF11B TNFRSF25 ACVR1B ACVR1 TNFRSF21

78 17

S100B CCL24 CCR4 CCR7 CCL27 CCL16 MAPRE2 CCR5 CCL26 LSP1 IFNG CCR2 AFP CCL11 CCL19 CCL28 IL8RA CXCL2 CCL18 TNF DRD2 CXCL12 PROK2 CXCL6 TXK CCL5 TNFAIP6 ITGAL CCL23 AHSG CCL4 GNA14 LOC146909 ATP1A3 CCL20 ADA CCL13 IL8 PPBP CXCL3 XCL1 CXCL1 IGFBP1 CXCR3 CCL7 CCL1 IL16 FPRL1 CCR6 STAT3 CCL21 CD97 IL10 SAA2 CD52 MIF CSRP3 CXCL5 IL13 CCL8 CXCR4 CCL2 ARRB1 CCKAR DEFB4 GRIN1 CXCR6 CCL15 IL11 CCL17 IFNB1 CCL3 GZMK CCL25 CCR1 CXCL10 NAALADL2 CCL3L3

BDKRB2 CCR2 IL8RA CCBP2 ADORA2A IL8RB FPRL1 CCR4 FY EDG3 CXCR3 CCR5 CCR6 PRLR CCR8 CCR1 CCR3

105 11

DAPK1 ZNF207 STK4 ATF4 NFKB1 RTN3 RIPK2 TPT1 AP2M1 TNFRSF1A PBP ADAM9 CALM1 TMEM66 NOL5A TGFB1 RAF1 PSME3 TNFRSF21 FXYD5 MAP3K5 H3F3B EIF4A1 HSPCA PPP2R1A CASP10 BRAF DAPK3 CCT3 TRAF2 SLC3A2 HDLBP LDHA DEDD GPI KIAA0174 K-ALPHA-1 CTNNA1 WNK1 ACTB ATP5A1 DDX5 CRADD ADAM15 VIM LTB HNRPH1 PRKCZ PKM2 CHUK 2-Sep CFLAR IKBKG IKBKB HADHB FLJ22555 MAPKAPK2 TNFRSF10B NONO UBC ARPC5 CSNK2A1 SPOP TNFRSF11B EIF3S6IP STX12 ROCK1 PRKCA CASP7 IGFBP3 LTA PRKCE TRAF4 CASP8 VCP CIRBP YWHAE WBP2 DCTN2 DAP FADD HSPA8 CD74 RIPK1 RPL4 PIP5K2B FAS TEGT HIPK2 STK17A ENO1 HSPCB WARS FUS STK3 YARS GNB2L1 TXNIP ALDOA MALT1 SNX17 RAB7 TNFRSF10A SFRS2 TRADD

TNFRSF10A UNC5B FAS TNFRSF10B TNFRSF1A DGCR2 NGFR TNFRSF11B TFG TNFRSF25 TNFRSF21

151 7

HSPA5 ELAC2 PCDH18 VEGF CD63 NLGN1 LTBP2 DAG1 SPOCK1 PRDX4 SNTB1 FBN1 SERPINA3 DGCR2 SHMT2 PVRL1 MCAM JAG2 PCSK7 NEO1 MIB2 PTPNS1 PCDHA6 NRP2 THBS4 COL14A1 PRCP SGCE ALPL FXYD5 SYT1 ACSL4 SPG7 P4HA1 ENPP2 CTSH PECAM1 KITLG MRPS22 PTGS1 HYAL1 VGLL4 MGAT1 GAK LSAMP SIDT2 MMP12 PKD1 ROBO4 FAT TNFRSF12A SEMA3B ABCD4 SLIT2 VNN1 SYT5 NRXN3 COL4A6 PPAP2A PVR EFNB1 ITGAL LAMC2 COMP PSAP FURIN BMP5 SEMA4D PMM2 INHBB POLR3D GPNMB SEMA5A PPGB STIM1 STS MAN2B1 EI24 EDIL3 COL7A1 HYOU1 LAMA4 KAL1 ADRM1 TGFB2 GDF15 COL6A2 SYT4 SYT6 NID2 LAMC1 AMFR BMP4 SULF1 ADAM12 NCAM1 THBS3 ADAM23 TOR1A ACHE AGRN CD24 NDST1 LIPA COL16A1 EFEMP1 MMP2 SPOCK2 MGP GALC PKD2 LAMA1 ITGA4 LAMB3 SSR4 PON2 SORT1 SEMA4F LPL TMED10 SYTL3 PCDH1 NUP210 NLGN2 BMP1 GSTT1 BTD LAMB2 SPP1 FMOD BMP2 C1R SYTL2 SPINT2 GPX4 SDC4 RPLP2 NPC2 ELN ASAH1 FKBP9 SMPDL3B SERPING1 SLC8A1 SORL1 C22orf5 LARGE RARG ACADVL DCBLD2 ACE

TNFRSF12A NRXN3 NEO1 NRP2 NRXN1 ENG NRP1

51 18

S100B CCR7 MAPRE2 LSP1 IFNG CCL11 CCL19 IL8RA CXCL2 DRD2 GNA15 CXCL12 PROK2 CXCL6 CCL5 ITGAL CCL23 AHSG CCL4 IL8RB CCL20 ADA IL8 PPBP CXCL3 XCL1 CXCL1 CXCR3 FGF10 FPRL1 CCR6 STAT3 CD97 IL6 IL10 SAA2 CD52 MIF KIAA1443 CXCL5 IL13 ARRB1 CCKAR DEFB4 GRIN1 IL11 IFNB1 CCL3 CCL25 CXCL10 AGTR1

BDKRB2 IL8RA F2R LRRN6D CCBP2 ADORA2A IL8RB FPRL1 FY EDG3 CXCR3 CCR6 PRLR FPR1 C3AR1 CCR1 OPRK1 ADORA1

83 9

DAPK1 ZNF207 STK4 NFKB1 TRAF3 RIPK2 PAK1 TNFRSF1A ADAM9 NOL5A TGFB1 PIM1 RAF1 TNFRSF21 EIF2AK2 MAP3K5 TNFSF10 HSPCA BAG4 CASP10 BRAF DAPK3 TRAF2 DEDD HIPK3 AKT1 PRKAA1 WNK1 DDX5 CRADD TNFRSF25 TNFSF11 VIM CDC2L1 LTB HNRPH1 CASP8AP2 PRKCZ CHUK CFLAR IKBKG IKBKB MAPKAPK2 TNFRSF10B NONO STK17B CSNK2A1 TNFRSF11B DEDD2 ROCK1 PRKCA CASP7 IGFBP3 PRKCE TRAF4 CASP8 WBP2 PFTK1 DAP FADD HSPA8 NGFR RIPK1 MYD88 PIP5K2B FAS HIPK2 SLAMF7 STK17A UNC5B CTSS RPS6KA3 STK3 YARS TNFSF12 TAP2 TNFSF15 MALT1 RAB7 TNFRSF10A SFRS2 FASLG TRADD

TNFRSF10A UNC5B FAS TNFRSF10B TNFRSF1A NGFR TNFRSF11B TNFRSF25 TNFRSF21

123 6

CXCL9 NOV HLA-DQA1 CD83 DKK1 PRNP LEPR NFKB1 FBN1 ANGPT1 PPARD FALZ ARMC8 IL15 JAG2 NFATC3 LILRB2 RBPSUH NRP2 SERPINF1 TNFRSF19 NOTCH3 CSE1L SEMA3C TNFSF10 EDNRB CD3D SEMA4B VDR ANGPT2 NR2F2 PLXNB1 MFNG CTNNB1 CCNC IL15RA EIF2B4 MAML1 RXRA LEF1 TXNDC DNASE2 EXT1 EP300 EFNB1 ITGAL CREG1 SEMA4D PF4 DVL2 TCF12 IGFBP4 TREM1 STIM1 NRP1 ITGA11 AKAP13 SECTM1 EGLN2 SBNO1 CD40 MDK GNRH1 RELA LRP6 GSK3B TLR3 LTB4R NR2F6 DLL4 PGF CCL21 IGFBP3 POFUT1 TNFRSF14 NR2C2 GPC4 DEAF1 RORA MGP IL2RG SEMA4A CD8A NR4A2 LY6E CSF1 IFI30 DLL1 SLIT3 NGFR NR2F1 HLA-DRB1 FAS PCAF SFRP4 NR4A1 ATRN MED12 ITGB5 CD14 BST1 CNTN1 TNFRSF1B CREBBP GRN GPX4 SERPINE2 TLR4 KPNA1 LAT NPC2 PLP2 ANPEP NCK2 ARNTL DTX1 CD164 NR3C1 RARG FRAT2 STAT6 RP13-297E16.1 SMO

NOTCH2 NOTCH1 NOTCH3 NOTCH4 LILRB4 LRP5

56 12

CCL24 CCR4 CCL27 SIPA1 CCL16 CCR5 CCL26 IFNG CCR2 AFP CCL11 CCL19 CCL28 CCL18 TNF CXCL12 SRM TXK CCL5 TNFAIP6 CCL23 CCL4 GNA14 LOC146909 ATP1A3 CCL13 IGFBP1 CCL7 ZNF32 CCL1 IL16 CCR8 CCR6 CCL21 CD97 IL10 SAA2 CD52 CSRP3 CCL8 CXCR4 RPS4Y1 CCL2 ARRB1 GRIN1 CXCR6 KCNH3 CCL15 CCL17 CCL22 CCL3 GZMK CCL25 CCR1 NAALADL2 CCL3L3

CCR2 CCBP2 CCR4 FY CXCR3 CCR10 CCR5 CCR6 PRLR CCR8 CCR1 CCR3

60 11

DAPK1 EMP2 DKK1 EMP1 RYR2 LEPR FZD7 ERBB4 NEO1 MARK4 SERPINF1 THBS4 NOTCH3 TNFRSF21 EDNRB BMP7 SPG7 PLXNB1 KITLG ECM1 CHRNA5 PRKAA1 SLIT2 EMD NRCAM PPAP2A EFNB1 TGFBR3 NOTCH2 LAMA4 ROR1 NTN1 HMGCR LRP6 FZD1 AGRN PPAP2B DEDD2 EDNRA FST SPOCK2 SEMA4A APP NLGN2 FAS RTN4 STK17A ROR2 ITGA2 UNC5B TAZ FRZB GJA1 SERPINE2 CTGF IGF1R ELN ANPEP DCBLD2 SMO

NOTCH2 UNC5B NRXN3 LRP6 NOTCH4 CELSR2 DCC UNC5C HTR3A NEO1 LRP5

95 6

LGMN ABCA1 SCARB1 SNTB1 COX8A TNFRSF1A SELT PVRL1 HDDC2 VLDLR SPPL2B PLOD3 CLCN6 APOL1 MMP9 SLCO3A1 LTF MMP13 LYPLA3 ARSD F8 PLTP CALR PAPPA CTSH SEMA6A DDOST PIGK GFRA1 CALU DHCR24 ITGB1BP1 RELN MMP19 TBXAS1 ICAM1 CTSB SGSH CYP2J2 FBN2 APBB1 LMAN1 PPAP2A SDC2 CHKA PMPCB FURIN GULP1 MMP17 LRPAP1 MMP15 PLCB4 DAB1 TIMP2 SBNO1 BACE1 SERPINE1 CD82 LRP6 SULF1 ARTS-1 CYP7B1 DMPK MFHAS1 PDGFB GALC CYP3A5 APP SPPL2A LPL MMP16 TXNDC4 C4BPA APOB MANBA THY1 GSN PSMB6 RNF130 GCA APOE IGF2R STARD3 MMP14 NOMO1 CANX FDXR LDLR CPD TAP2 APOD SNX17 ADAM19 HLA-DMB RP13-297E16.1

LDLR LRP1 LRP2 LRP8 VLDLR SCARF1

130 4

HSPA5 FAT2 SPTLC1 PTGDS EIF2C3 ABCA1 EFNB2 RPN1 SCARB1 SNTB1 BACE2 FBN1 SNN SELT POMT1 VLDLR SRPX2 APOL1 NRP2 PTPRN2 SLCO3A1 BGN TGFBI MAN1A1 MRPL27 ARSD ACACA MRPS12 PLTP AGPAT3 LARS2 B3GNT3 C1S ACACB MRPS22 ATP6V0A1 EIF2B4 PTGS1 PIGK TRIP11 NT5E MRPL21 DHCR24 UGCGL2 ZNF198 PTPN9 ACP2 RQCD1 ABCD4 TBXAS1 OSMR ICAM1 SGSH LRRC17 MRPS18A PIGO NPR1 FBN2 LMAN1 MRPS5 CHKA SOS1 FURIN PMM2 LRPAP1 POLR3D PPGB PLCB4 THBS2 GLT25D2 PVRL2 KIAA0090 SERPINE1 FDX1 SULF1 C20orf155 TLR3 AGR2 NDST1 CYP51A1 HSD17B2 CYP7B1 APOC1 DMPK EIF2AK3 MMP2 LCAT MGP ECHS1 LRP8 GALC LY6E CYP3A5 MGAT2 GGTLA1 SSR4 CLU MARS ANGPTL2 TXNDC4 APOB SGNE1 ARHGAP11A MED12 KDELR2 HBXAP ALDH6A1 APOE C1R BCAP31 DGKE STARD3 AGPAT1 AP1M2 MMP14 POLG2 MRPL47 FDXR HARSL BF RPLP2 FKBP9 MAST2 APOD SNX17 LARGE CDC91L1 B4GALT1 OXCT1 RP13-297E16.1

LDLR LRP1 LRP2 LRP8

85 5

SOCS3 MYLK LIFR SMARCA2 NRG1 BRD4 ADAMTS2 CNTNAP1 ITGB3 MCAM SHB THBS4 F2R CEACAM1 SOCS2 JUP BRD3 PML CTNNB1 MLLT4 MAP2K3 CD81 BRAF CRK FRS2 ITGA8 GNA11 GRB10 WNK1 NEDD9 NPR2 EFS RIN2 ABI1 TRIM23 STAT5A COL4A5 MAP3K7 ITPR2 CAV1 PIK3R4 FGFR2 PAK4 MAP2K5 PINK1 MAP2K4 IRS1 MAP4K4 LU ERBB2IP MINK1 CASK MAPKAPK5 ID3 STAT5B HRMT1L1 USP6NL PCAF HIPK2 BIRC2 TRIM38 COL4A1 EPHB6 CNTN1 MAP3K10 PKN2 RET CSNK1E MFAP4 PALLD STK3 EPHA7 MID1 RHOB ITPR3 MAP4K5 DST ARNT DOCK1 MAPK6 PPFIA1 WEE1 SMARCA4 TSC1 STAT6

PAQR3 PVRL2 GFRA1 PTPRF EDG1

59 7

CP DKK1 SCARB1 LEPR CDH13 VLDLR SERPINF1 LRP5 NOTCH3 SEMA3C CELSR2 BCHE KIAA0152 PLXNB1 KITLG ECM1 TRPC4AP F25965 TMEM59 RELN CYP2J2 AXIN1 CHKA SERHL TGFBR3 PSAP NOTCH2 RAMP3 ITGA6 GNRH1 FDX1 LAMC1 FZD3 SULF1 LRP2 EGF ATAD2 DKK2 LRP8 CSF1 ZNRF4 DCX APP CELSR1 SFRP4 SGNE1 ROR2 LAMB2 ITGB5 MFAP5 IGF2R DGKE CTSD IL6R GRN LDLR LRP1 APOD FRAT2

LRP6 PLXNA1 LRP8 LRP5 GNRHR VLDLR TLR10

23 17

OPRD1 NPY GNAL GNAT2 GNAT1 GNA15 GNA11 SAC GNA13 GNAI3 TAC3 GNAZ ARR3 GNAS GNAI2 GRK1 FGF10 P2RY1 KRTAP4-5 GRM1 DRD1 SAG FSHB

EDNRA PTGIR NPY1R LHCGR RHO TACR2 CNR1 OPRM1 CHRM2 DRD2 FSHR FPR1 ADRA1B HTR4 C5R1 CHRM1 ADORA1

75 5

ABCA1 SCARB1 SNTB1 PCDHGC3 COX8A TNFRSF1A SELT PVRL1 HDDC2 VLDLR PLOD3 APOL1 SLCO3A1 LTF MMP13 ARSD F8 PLTP CALR SEMA6A DDOST GFRA1 CALU DHCR24 ITGB1BP1 TBXAS1 ICAM1 SGSH CYP2J2 FBN2 APBB1 PPAP2A SDC2 CHKA MAP3K4 FURIN GULP1 MMP17 LRPAP1 MMP15 PLCB4 TIMP2 SBNO1 MDK SERPINE1 CD82 SULF1 TRA1 CYP7B1 DMPK MFHAS1 PDGFB CYP3A5 APP LPL MMP16 C4BPA APOB LTBP1 MANBA THY1 GSN SPP1 GCA APOE MMP14 NOMO1 CANX PLAUR FDXR LDLR APOD SNX17 HLA-DMB RP13-297E16.1

LDLR LRP1 LRP8 SCARF1 CD44

62 6

SFRP1 DSC2 TPT1 HDDC2 CSPG2 M6PR NRP2 SERPINF1 COL14A1 TGFBI NEU1 H3F3B EIF4A1 VIL2 CALR SRPX EIF4A2 HSPCA HLA-A CALU PKD1 ZNF198 ADM RQCD1 ICAM1 ACTB SELE LMAN1 ITGB4 PTPRB SOS1 FURIN ALCAM COL1A1 EDIL3 THBS2 HYOU1 DMP1 TIMP2 SULF1 TRA1 DMPK GRSF1 MMP2 MFHAS1 RNASE4 PKD2 IL6ST CD74 TEGT SFRP4 ARHGAP11A MANBA SPP1 DGKE GNB2L1 COL5A1 IFNAR1 APOD DCBLD2 OXCT1 CD68

EMR3 LDLR LRP1 DGCR2 TFG CD44

74 5

ABCA1 SCARB1 SNTB1 PCDHGC3 COX8A TNFRSF1A SELT PVRL1 HDDC2 VLDLR PLOD3 APOL1 SLCO3A1 LTF MMP13 ARSD F8 PLTP CALR SEMA6A DDOST GFRA1 CALU DHCR24 ITGB1BP1 TBXAS1 ICAM1 SGSH CYP2J2 FBN2 APBB1 PPAP2A SDC2 CHKA MAP3K4 FURIN GULP1 MMP17 LRPAP1 MMP15 PLCB4 TIMP2 SBNO1 MDK SERPINE1 CD82 SULF1 TRA1 CYP7B1 DMPK MFHAS1 PDGFB CYP3A5 APP LPL MMP16 C4BPA APOB LTBP1 MANBA THY1 GSN SPP1 GCA APOE MMP14 NOMO1 CANX FDXR LDLR APOD SNX17 HLA-DMB RP13-297E16.1

LDLR LRP1 LRP8 SCARF1 CD44

22 16

GNA12 INHA GNAL GNAT2 GNAT1 GNA15 GNA11 GNA13 GNAI3 TAC3 GRK6 GNAZ ARR3 GNAS GNAI2 GRK1 GABRG2 TSHB KRTAP4-5 KIAA1912 SAG FSHB

NPY1R LHCGR F2R TSHR RHO TACR2 TBXA2R CNR1 OPRM1 CHRM2 FSHR ADRA1B HTR4 DRD5 C5R1 CHRM1

23 15

OPRD1 NPY GNAL GNAT2 GNAT1 GNA15 GNA11 SAC GNA13 GNAI3 TAC3 GNAZ ARR3 GNAS GNAI2 GRK1 FGF10 P2RY1 KRTAP4-5 GRM1 DRD1 SAG FSHB

EDNRA PTGIR NPY1R LHCGR RHO TACR2 CNR1 OPRM1 CHRM2 FSHR ADRA1B HTR4 C5R1 CHRM1 ADORA1

56 6

DAPK1 EMP2 EMP1 RYR2 LEPR FZD7 NEO1 MARK4 THBS4 TNFRSF21 EDNRB BMP7 ALS2CR3 SPG7 KITLG BRSK1 GCG HAND2 GIPR CHRNA5 PRKAA1 EMD NRCAM PPAP2A TGFBR3 NOTCH2 LOC115098 MYL3 LAMA4 NTN1 HMGCR KCNAB3 LRP6 FZD1 PPAP2B DEDD2 EDNRA ANGPTL3 FST SPAG11 SPOCK2 SPINT3 NLGN2 FAS RTN4 STK17A PLP1 UNC5B TAZ LOC114984 FRZB GJA1 ELN CACNG2 DCBLD2 SMO

UNC5B GLP2R UNC5C HTR3A MLNR MTNR1B

47 6

DAPK1 EMP2 EMP1 RYR2 LEPR FZD7 ERBB4 NEO1 MARK4 THBS4 TNFRSF21 EDNRB BMP7 SPG7 KITLG CHRNA5 PRKAA1 SLIT2 EMD NRCAM PPAP2A TGFBR3 NOTCH2 LAMA4 NTN1 HMGCR LRP6 FZD1 AGRN PPAP2B DEDD2 EDNRA FST SPOCK2 NLGN2 FAS RTN4 STK17A ITGA2 UNC5B TAZ FRZB GJA1 ROCK2 ELN DCBLD2 SMO

UNC5B NRXN3 CELSR2 DCC UNC5C HTR3A

25 11

HIVEP3 CD83 TRAF3 TTRAP CD40LG EXOC8 TRAF5 TNF TRAF2 TNFSF9 IL7 CD79B MS4A1 DIABLO TRAF6 TNFSF14 CD79A ZNF597 LTA TNFSF13B NRIP1 TRAF1 TRIP TNFSF8 ANKIB1

CD40 TNFRSF8 TNFRSF11A TNFRSF1B TNFRSF4 TNFRSF9 LTBR TNFRSF13B TNFRSF19 TNFRSF14 TNFRSF17

21 12

CCR7 LGALS4 ADORA1 ITGAX GAB3 TAS1R2 CD48 GUCA1B CR2 FABP5 MOV10L1 HOMER1 USP26 EXOSC9 CASR ECEL1 KLRD1 DENND1C QSCN6L1 GPR18 SIAE

GPR18 KLRK1 GUCY2F FCER2 KLRC3 DRD1 OR6A2 TAS1R3 GRM1 CCR7 GUCY2D P2RY1

109 2

ITGB1BP2 PLAU PREX1 ELF1 CLSTN1 GPR56 PROCR ITGA10 AP2M1 F3 SPINK5 NR1H2 CNTNAP1 PVRL1 PDLIM1 BAT1 CSPG2 LILRB2 STC1 MAPRE2 SF1 SLCO3A1 TGFBI ICOSLG TRIM28 STC2 ACTG1 C1QG ZYX MLLT4 KITLG CD81 TUBB CCT3 CDH3 COL11A1 ITGA8 TRAP1 ITGB1BP1 DEK CSTB DNAJB6 CXCL12 DSTN TJP1 CXCL6 PRKDC YWHAH LTBR CD151 ADAM15 CD9 VIM ITGAE FGF7 ITGA11 ITGA1 YWHAB ARHGAP5 C1QB CDH23 FSCN1 MFGE8 RAD21 ACHE YWHAZ RFXANK C1QR1 C3AR1 CD24 LGALS3BP ACTN1 MAP4K4 TNFRSF14 HMGN2 KNS2 HLA-DMA ITGA4 C1QA NME1 CD74 DSG2 FLNA EPAS1 CD58 COL4A1 F2RL2 MST1 MMRN1 F11R MFAP5 C1R DIAPH1 CCT8 VCAM1 GPX4 CANX SMAD4 LGALS8 FLNB CD36 DST MAST2 TLN1 ITGA9 MCP DOCK9 CRIM1 RP13-297E16.1

ITGB7 ITGB1

19 11

NPHS1 OR1E1 GNAT2 GNAT1 GNA11 OR7C1 GNAI3 TAC3 OR1N1 GNAZ ARR3 GNAI2 GRK1 OR1F1 IGKV1-13 OR1G1 OR1D2 SAG OR1E2

NPY1R OR1D4 RHO TACR2 OR1A1 OR7C2 OR7A17 ADRA1B HTR4 OR1A2 OR1D2

23 9

CPNE4 ATG4C ZNF566 DMRTC1 LSP1 HTR1E HTR1F CCKBR ITGAL GUCY2C CCL20 XCL1 CXCR3 HTR1D SAA2 PKN1 FLJ31222 HTR1B KIAA1443 DEFB4 F11 TBX21 CXCL10

OPN4 HTR1B HTR1F OR2C1 CCKAR FPRL1 HTR1E HTR1A CCR6

53 3

ATF4 RTN3 TPT1 AP2M1 PBP CALM1 TMEM66 NOL5A PSME3 FXYD5 H3F3B EIF4A1 HSPCA PPP2R1A CCT3 SLC3A2 HDLBP LDHA GPI KIAA0174 K-ALPHA-1 CTNNA1 ACTB ATP5A1 DDX5 PKM2 2-Sep HADHB FLJ22555 NONO UBC ARPC5 SPOP EIF3S6IP STX12 VCP CIRBP YWHAE WBP2 DCTN2 CD74 RPL4 TEGT ENO1 HSPCB WARS FUS GNB2L1 TXNIP ALDOA SNX17 RAB7 SFRS2

TNFRSF1A DGCR2 TFG

67 2

TRAM1 PLAU LGMN PROCR FBN1 F3 FOXK2 RCN2 ABCD3 IF SEMA3C 76P CALR CD59 C2 ACSL4 ATP6V0A1 GPX3 VGLL4 TMEM59 ANXA5 ACP2 FGG TFPI2 IDH3B LMAN1 EXT1 ALCAM TCF12 RNASE1 EI24 IL20RA CX3CL1 IFNGR1 SERPINE1 LAMC1 TYROBP MSRA SERPIND1 CD24 CYP51A1 SERPINH1 TRA1 GRSF1 CLU IFNGR2 PON2 LPL GSTT1 LAMP2 SPP1 CD14 C4A CD58 F2RL2 BCAP31 NCSTN HSPA4 SDC4 KATNB1 BF PTX3 SRD5A1 ASAH1 ITGA3 GPX7 APOD

ATRN GPR128

20 6

PRKCSH HLA-B CSPG2 PPY2 HLA-G HLA-E KLRC2 SYAP1 FVT1 KLRC1 AKAP13 KRTAP9-8 TIMP2 KLRC3 C1QTNF5 CD226 SLC4A10 IL10RB KLRD1 ZC3HAV1

UPK1B EMR3 KLRD1 KLRC2 KLRC1 MAS1

21 4

ABCA1 DAB2 LRP5 DLG4 ACACA PIGK CUBN PSAP LPA DAB1 SERPINE1 GPRASP1 POFUT1 LRP2BP TUFM APOB ANKRA2 STARD3 AGPAT1 EB-1 SORL1

LRP2 HTR2C IL13RA1 BAI2

14 6

IL17F IL12B NSUN3 TLR2 IL21 IL12RB2 FANCL MYH11 SON C14orf118 TLR4 MGC13017 IFNB1 NALP12

TLR1 TLR3 IL21R ADORA2A TLR6 IL12RB1

20 4

AVPR1B OR2B2 HAND2 EPB41 RP13-383K5.1 CLEC11A C14orf80 OR10C1 HB-1 OR2K2 OR2B6 PHF2 PNPLA5 PLA2G7 PAX2 POU3F1 KIAA0523 MMP27 PKLR DEFB103A

MAS1L OR2F1 OR5V1 P2RY8

13 6

NPHS1 OR1E1 TRPC4AP F25965 SERHL OR7C1 OR1N1 ATAD2 ZNRF4 DCX IGKV1-13 OR1G1 OR1E2

OR1D4 OR1A1 OR7A17 TLR10 OR1A2 OR1D2

11 7

NPHS1 OR1E1 OR2B2 OR7C1 OR1N1 OR2B6 OR1F1 IGKV1-13 OR1G1 OR1D2 OR1E2

OR1D4 OR1A1 OR5V1 OR7C2 OR7A17 OR1A2 OR1D2

9 6

NPHS1 OR1E1 OR7C1 OR1N1 OR1F1 IGKV1-13 OR1G1 OR1D2 OR1E2

OR1D4 OR1A1 OR7C2 OR7A17 OR1A2 OR1D2

9 5

C16orf50 KNDC1 SLMAP ZFY OR1F1 OR7C2 SYT7 OR7A17 OR1D2

OR1E1 OR1G1 OR7C1 OR7C2 OR1F1

15 3

ALS2CR3 MGC15631 PABPC4 BRSK1 GCG GIPR TRPS1 KCNAB3 ANGPTL3 PCGF1 KIF1A PLP1 LOC284912 LOC114984 CACNG2

GLP2R GPR20 MTNR1B

10 4

OR1N1 C16orf50 KNDC1 SLMAP ZFY OR1F1 OR7C2 SYT7 OR7A17 OR1D2

OR1E1 OR7C1 OR7C2 OR1F1

5 3

OR2B2 C14orf80 OR2K2 OR2B6 OR1F1

OR2F1 OR5V1 OR7C2

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