Figure S17 Figure S16

Gene Set Databases TF-TF module enrichmentsaGOslimPos (ChIP+KO+ATAC TRN) response to interferon gamma type i interferon signaling pathway 10 response to virus amino acid transport 8 brown fat cell differentiation glycogen metabolic process GO cytokine production 6 leukocyte migration mapk cascade single organismal cell cell adhesion 4 t cell differentiation myeloid leukocyte differentiation immune response regulating cell surface receptor signaling pathway 2 response to transforming growth factor beta transforming growth factor beta receptor signaling pathway PathwayCommonsPos 0 Amino acid and oligopeptide SLC transporters

CIC 9 Amino acid transport across the plasma membrane SP4 SP9 REL MAF IRF9 IRF7 IRF2 IRF1 IRF4 ERG E2F4 E2F1 ELF1 VAX2 KLF7 ZEB1 JDP2 ETV4 DPF1 ATF2 THRA PEG3 RXRA RORC RORA AHRR DDIT3 HIF3A HIF1A

Transport of inorganic cations/anions and amino acids/oligopeptides STAT3 FOSL2 KLF10 STAT2 STAT4 STAT1 TRP73 TRP53 PHF20 NR1D2 NR1D1 FOXO1 SCRT1 NFKB2 NFKB1 CREB1 PRRX1 MYT1L SMAD3 RUNX1 ZFP365 ZFP750 ZFP367 ZFP960 DMRT1 ZFP534 HOXB1 ZBTB32 KDM5B HMGA2 ATR signaling pathway ZBTB7B PLSCR1 PLAGL1 BCL11B ANKZF1 PLAGL2 ZFP385A ZFP280B 8 Direct p53 effectors BHLHE41 p53 pathway Alpha9 beta1 integrin signaling events 7 Beta1 integrin cell surface interactions C030039L03RIK Integrin family cell surface interactions 6 Proteoglycan syndecan-mediated signaling events HIF-1-alpha transcription factor network Pathway Hypoxic and oxygen homeostasis regulation of HIF-1-alpha 5 CXCR4-mediated signaling events IL2 signaling events mediated by PI3K 4 Commons TCR signaling in naïve CD8+ T cells IL2-mediated signaling events IL12-mediated signaling events 3 IL23-mediated signaling events Calcineurin-regulated NFAT-dependent transcription in lymphocytes 2 IL27-mediated signaling events Immune System Interferon Signaling 1 Interferon alpha/beta signaling Phosphorylation of CD3 and TCR zeta chains KeggPos 0 Chemokine signaling pathway

CIC 6 SP4 SP9 REL MAF IRF9 IRF7 IRF2 IRF1 IRF4 ERG

T cell receptor signaling pathway E2F4 E2F1 ELF1 VAX2 KLF7 ZEB1 JDP2 ETV4 DPF1 ATF2 THRA PEG3 RXRA RORC RORA AHRR DDIT3 HIF3A HIF1A STAT3 FOSL2 KLF10 STAT2 STAT4 STAT1 TRP73 TRP53 PHF20

Osteoclast differentiation NR1D2 NR1D1 FOXO1 SCRT1 NFKB2 NFKB1 CREB1 PRRX1 MYT1L SMAD3 RUNX1 ZFP365 ZFP750 ZFP367 ZFP960 DMRT1 ZFP534 HOXB1 ZBTB32 KDM5B HMGA2 ZBTB7B PLSCR1 PLAGL1 BCL11B ANKZF1 PLAGL2 ZFP385A ZFP280B Cell adhesion molecules (CAMs) BHLHE41 5 Measles Intestinal immune network for IgA production

Cytokine-cytokine receptor interaction C030039L03RIK 4 Jak-STAT signaling pathway Rheumatoid arthritis Alanine, aspartate and glutamate metabolism 3 KEGG p53 signaling pathway Mismatch repair Pathways in cancer 2 Renal cell carcinoma Galactose metabolism Glycolysis / Gluconeogenesis 1 Starch and sucrose metabolism Insulin signaling pathway MAPPPos 0 Adipogenesis CIC SP4 SP9 REL MAF IRF9 IRF7 IRF2 IRF1 IRF4 ERG

Adipogenesis genes E2F4 E2F1 ELF1

VAX2 KLF7 ZEB1 JDP2 ETV4 DPF1 ATF2 5 THRA PEG3 RXRA RORC RORA AHRR DDIT3 HIF3A HIF1A STAT3 FOSL2 KLF10 STAT2 STAT4 STAT1 TRP73 TRP53 PHF20

EGFR1 Signaling Pathway NR1D2 NR1D1 FOXO1 SCRT1 NFKB2 NFKB1 CREB1 PRRX1 MYT1L SMAD3 RUNX1 ZFP365 ZFP750 ZFP367 ZFP960 DMRT1 ZFP534 HOXB1 ZBTB32 KDM5B HMGA2 ZBTB7B PLSCR1 PLAGL1 BCL11B ANKZF1 PLAGL2

IL-3 Signaling Pathway ZFP385A ZFP280B

BHLHE41 4 WikiPathways Insulin Signaling PodNet 3

XPodNet - protein-protein interactions in the podocyte expanded by STRING C030039L03RIK IL-6 signaling Pathway 2 White fat cell differentiation TGF Beta Signaling Pathway 1 Glycolysis and Gluconeogenesis Signatures MSigDBPos 0 11 ELVIDGE HIF1A AND HIF2A TARGETS DN CIC SP4 SP9 REL MAF IRF9 IRF7 IRF2 IRF1 IRF4 ERG

ELVIDGE HIF1A TARGETS DN E2F4 E2F1 ELF1 VAX2 KLF7 ZEB1 JDP2 ETV4 DPF1 ATF2 THRA PEG3 RXRA RORC RORA AHRR DDIT3 HIF3A HIF1A STAT3 FOSL2 KLF10 STAT2 STAT4 STAT1 TRP73 TRP53 PHF20

ELVIDGE HYPOXIA BY DMOG UP NR1D2 NR1D1 FOXO1 SCRT1 NFKB2 NFKB1 CREB1 PRRX1 MYT1L SMAD3 RUNX1 ZFP365 ZFP750 ZFP367 ZFP960 DMRT1 ZFP534 HOXB1 ZBTB32 KDM5B HMGA2 ZBTB7B PLSCR1 PLAGL1 BCL11B ANKZF1 PLAGL2 10 QI HYPOXIA ZFP385A ZFP280B BHLHE41 MARTORIATI MDM4 TARGETS FETAL LIVER UP MARTORIATI MDM4 TARGETS NEUROEPITHELIUM UP

GOBERT OLIGODENDROCYTE DIFFERENTIATION UP C030039L03RIK 9 PYEON HPV POSITIVE TUMORS UP KRIGE AMINO ACID DEPRIVATION ZHAN MULTIPLE MYELOMA CD1 VS CD2 UP WANG RESPONSE TO GSK3 INHIBITOR SB216763 DN 8 BROWNE INTERFERON RESPONSIVE GENES LEE DIFFERENTIATING T LYMPHOCYTE GRAESSMANN APOPTOSIS BY SERUM DEPRIVATION UP 7 KRIGE RESPONSE TO TOSEDOSTAT 24HR UP CLASPER LYMPHATIC VESSELS DURING METASTASIS DN ONGUSAHA TP53 TARGETS 6 PICCALUGA ANGIOIMMUNOBLASTIC LYMPHOMA DN TAKEDA TARGETS OF NUP98 HOXA9 FUSION 3D DN MSigDB CHEN METABOLIC SYNDROM NETWORK RUTELLA RESPONSE TO CSF2RB AND IL4 DN 5 LI INDUCED T TO NATURAL KILLER UP VERHAAK GLIOBLASTOMA NEURAL HAN SATB1 TARGETS UP 4 CUI TCF21 TARGETS 2 DN NAGASHIMA NRG1 SIGNALING UP ZHENG BOUND BY FOXP3 3 ZHANG RESPONSE TO IKK INHIBITOR AND TNF UP ICHIBA GRAFT VERSUS HOST DISEASE D7 UP SCHUETZ BREAST CANCER DUCTAL INVASIVE UP PICCALUGA ANGIOIMMUNOBLASTIC LYMPHOMA UP 2 LIU PROSTATE CANCER DN MEISSNER BRAIN HCP WITH H3K4ME3 AND H3K27ME3 PASQUALUCCI LYMPHOMA BY GC STAGE UP 1 GALINDO IMMUNE RESPONSE TO ENTEROTOXIN NAGASHIMA EGF SIGNALING UP KIM WT1 TARGETS UP 0 CIC SP4 SP9 REL MAF IRF9 IRF7 IRF2 IRF1 IRF4 ERG E2F4 E2F1 ELF1 VAX2 KLF7 ZEB1 JDP2 ETV4 DPF1 ATF2 THRA PEG3 RXRA RORC RORA AHRR DDIT3 HIF3A HIF1A STAT3 FOSL2 KLF10 STAT2 STAT4 STAT1 TRP73 TRP53 PHF20 NR1D2 NR1D1 FOXO1 SCRT1 NFKB2 NFKB1 CREB1 PRRX1 MYT1L SMAD3 RUNX1 ZFP365 ZFP750 ZFP367 ZFP960 DMRT1 ZFP534 HOXB1 ZBTB32 KDM5B HMGA2 ZBTB7B PLSCR1 PLAGL1 BCL11B ANKZF1 PLAGL2 ZFP385A ZFP280B BHLHE41

aGOslimPos C030039L03RIK response to interferon gamma response to protozoan 11 or 7 response to virus 10 cytokine production single organismal cell cell adhesion t cell differentiation ) t cell activation involved in immune response 8

leukocyte migration raw myeloid leukocyte differentiation immune response regulating cell surface receptor signaling pathway P protein secretion 6 myoblast differentiation amino acid transport angiogenesis endothelial cell differentiation 4 intrinsic apoptotic signaling pathway Gene Set Gene muscle organ morphogenesis log10( ventricular cardiac muscle tissue development - cholesterol biosynthetic process 2 determination of adult lifespan Enrichment in brown fat cell differentiation mitochondrion organization 0 Rlf Irf9 Irf2 Irf1 Irf7 Vdr Lbr Cic Id1 Id2 Erg Sp9 Atf5 Atf3 Txk Pcx Pml Maf Tal2 Tox Utf1 Klf3 Batf Aff3 Dpf1 Ing2 Mxi1 Rest Sirt6 Etv4 Ikzf3 Rorc Rora Vax2 Edf1 Ift57 Bcl3 Mlf1 Ikzf2 Spib Rbpj Dffb Scrt1 Tcf25 Hes6 Hif1a Arrb1 Glis3 Hif3a Foxj1 Sos2 Jdp2 Msh5 Mafg Ddit3 Stat2 Stat1 Zbp1 Eno1 Stat3 Mxd1 Ssh2 Chd7 Phtf2 Nrip1 Akna Tnp2 Hhex Sap30 Rcor2 Plscr1 Nupr1 Tbx21 Oasl1 Dhx58 Nr1d2 Nr1d1 Foxs1 Thap3 Tead1 Ssbp4 Prkdc Mbd5 Foxp2 Bcl6b Bmyc Plagl2 Nfkb2 Nfkb1 Plagl1 Gata3 Gata1 Pparg Epas1 Zbtb5 Foxo3 Trp53 Trp73 Zfp654 Zfp263 Zfp395 Ankzf1 Rbbp8 Cebpg Zfp790 Cebpb Trim21 Nfkbil1 Srebf1 Zfp608 Zfp827 Nfkbib Nfkbie Ncoa3 Zfp266 Trim24 Aebp2 Zfp750 Zfp365 Snapc1 Fbxo21 Kdm5b Setdb2 Ppfibp2 Dnajc21 Trim30a Zfp280b Ppp1r10 Zfp385a Ppp1r13l Tsc22d3 Figure S16. Gene-set enrichment of ChIP+KO+ATAC TRN TF modules. We compiled gene sets C030039L03Rik from five databases: GO, Pathway Commons, KEGG, MAPP and Signatures from MSigDB. For each TF, we calculated the significance of overlap between the TF’s target genes and gene sets (hypergeometric CDF). For Kegg and Mapp databases, the color bar maximum is 7, and, for the other databases, the maximum is 11. TFs are clustered and color-coded according to the TF-TF modules in Supplemental Fig. S14, S15, S17. TF-TF module enrichments are consistent among gene sets and TRNs, providing robust predictions for modules in Th17 biology.