Of 9 Figure 1 Tissue-Specific Transcription Factors Are

Home , CEBPB, CREB3, CSDA (gene), DBP (gene), DLX1, DPF2

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Figure 1 Tissue-specific transcription factors are upregulated in tissues they are specific to. Each row is a tissue; each column is a tissue-specific transcription factor set; the color of a square denotes the mean expression of the transcription factor set in the tissue, with green denoting upregulation and red denoting down regulation. Page 2 of 9

Figure 2 Tissue-specific transcription factors plotted by their increase in hubness and standardized gene expression in tissues they are specific to. Most tissue-specific transcription factors increase in expression in tissues they are specific to, and those that increase in expression also tend to increase in hubness. Transcription factors that are essential genes are marked in red; the “top” transcription factors that show the largest tissue-specific increases in expression are especially likely to be members of this essential gene set (16/20 top transcription factors as compared to 115/203 transcription factors overall). For clarity, only the top TFs are labeled. Page 3 of 9

Tissue Samples Adipose - Subcutaneous 95 Adipose - Visceral (Omentum) 19 Adrenal Gland 12 Artery - Aorta 24 Artery - Tibial 112 Brain - Amygdala 24 Brain - Anterior cingulate cortex (BA24) 18 Brain - Caudate (basal ganglia) 37 Brain - Cerebellar Hemisphere 25 Brain - Cerebellum 31 Brain - Cortex 24 Brain - Frontal Cortex (BA9) 25 Brain - Hippocampus 25 Brain - Hypothalamus 23 Brain - Nucleus accumbens (basal ganglia) 29 Brain - Putamen (basal ganglia) 21 Brain - Spinal cord (cervical c-1) 16 Brain - Substantia nigra 26 Breast - Mammary Tissue 27 Colon - Transverse 12 Esophagus - Mucosa 18 Esophagus - Muscularis 20 Heart - Atrial Appendage 25 Heart - Left Ventricle 84 Lung 119 Muscle - Skeletal 139 Nerve - Tibial 88 Pancreas 19 Pituitary 13 Skin - Not Sun Exposed (Suprapubic) 23 Skin - Sun Exposed (Lower leg) 97 Stomach 12 Testis 14 Thyroid 106 Whole Blood 157 Total 1,559 Table 1 The number of samples for each tissue in our dataset. Page 4 of 9

Tissue Transcription Factors Adrenal Gland CREBL2, CREM, EGR1, EGR3, ETV1, ETV5, FOSB, FOSL2, GATA6, HOXA5, HOXB2, HOXC6, LEF1, MAFF, MEIS1, NFIC, NFIL3, NR4A1, NR4A2, NR4A3, PBX3, PLAGL1, SREBF1, TBX3, VDR, ZNF331 All Brain Tissues ARNT2, ASCL1, ATF2, BCL11A, CAMTA1, CREB3, CUX2, DEAF1, EGR3, EMX2, ETS2, ETV1, ETV5, FOXG1, HEY1, HIC2, HIVEP2, HLF, LHX2, LHX6, MAFB, MEF2A, MEF2C, MEIS2, MLLT3, MYCN, MYT1L, NEUROD2, NFIB, NPAS2, NR2F1, NR3C2, OLIG2, PKNOX2, PRDM2, SALL2, SATB2, SOX10, SOX12, SOX4, SOX9, TCF4, TCFL5, THRA, ZBTB16, ZEB2, ZIC1, ZNF22, ZNF238, ZNF365, ZNF423 Spinal Cord ARNT2, ASCL1, ATF2, BCL11A, CAMTA1, CREB3, CUX2, DEAF1, EGR3, EMX2, ETS2, ETV1, ETV5, FOXG1, HEY1, HIC2, HIVEP2, HLF, HOXB2, HOXB7, HOXC6, LHX2, LHX6, MAFB, MEF2A, MEF2C, MEIS2, MLLT3, MYCN, MYT1L, NEUROD2, NFIB, NPAS2, NR2F1, NR3C2, OLIG2, PKNOX2, PRDM2, SALL1, SALL2, SATB2, SOX10, SOX12, SOX4, SOX9, TCF4, TCFL5, THRA, TSC22D4, ZBTB16, ZEB2, ZIC1, ZNF22, ZNF238, ZNF365, ZNF423 Heart (Left Ventricle GATA4, GATA6, HIC2, ID1, ID3, IRF7, MEF2D, MLX, NKX2-5, NR1H2, NR2F2, and Atrial Appendage) RARA, SPIB, TCF21, TFEB, ZNF358, ZNF688 Lung ATF3, ATF5, CUX1, ELF3, ELF4, EPAS1, ERG, ETS2, ETV5, FOS, FOSL2, FOXF1, FOXF2, FOXO3, GATA6, HES1, HEY1, HIF3A, HLX, HOXA5, ID1, ID3, IFI16, IRF1, IRF7, IRF8, JUN, JUND, KLF11, KLF13, KLF4, KLF6, KLF9, MAFB, MAFF, MEIS1, MEOX2, MXD4, NFIB, NFIC, NFIL3, NKX2-1, NR1H2, NR2F2, PLAGL1, RUNX3, SNAI2, SOX17, SOX4, SPI1, TBX2, TCF21, TCF7L2, TSC22D3, ZBTB16, ZFP36L2, ZNF22, ZNF395 Muscle - Skeletal BCL6, CSDA, NEUROD2, NFIC, NR4A3, ZBTB16, ZNF7 Pancreas ATF3, EGR1, ELF1, ELF3, ETS2, GRHL2, HOXB7, ID1, JUN, KLF5, KLF6, NR1I2, NR5A2, SOX9, ZKSCAN1, ZNF22 Pituitary CREB3L2, CREBL2, EGR1, ETV5, MEIS2, MSX1, NR1D2, PITX1, PLAGL1, POU1F1, SALL2, STAT4, TBX19, ZBTB20, ZNF331, ZNF91 Skin (Suprapubic and BCL11A, GATA3, HES1, KLF4, KLF5, KLF6, TFAP2A, TFAP2C, TP63, Lower Leg) TWIST1 Testis CREM, CSDA, DPF2, EZH2, FOXG1, FOXM1, GATA4, GMEB2, HIC2, KLF11, LEF1, NR1H3, OSR2, PKNOX1, PLAGL2, SNAPC4, SOX5, SOX9, TCFL5, WHSC1, ZBTB32, ZNF473, ZNF688 Thyroid ATF2, CREB3L2, CREBL2, DBP, EGR2, ETV5, FOS, FOSB, FOXE1, FOXO1, HES1, HHEX, ID1, ID3, JUN, JUND, KLF9, MAFB, MZF1, NFIB, NKX2-1, NR1D2, NR2C1, NR3C2, PAX8, PKNOX1, SALL1, SOX4, SOX9, TBX3, TCFL5, TEAD4, VEZF1, ZFHX3, ZFP36L2, ZNF395 Whole Blood BACH1, BCL6, CBFB, CREB5, E2F3, ELF1, ELF4, FLI1, FOXN3, GATA3, HBP1, HHEX, HLX, IFI16, IRF1, IRF7, IRF8, JUND, KLF2, KLF6, LEF1, MAFB, MYBL1, NFATC3, NFE2, NFIL3, NFKB1, NR3C1, PBX2, RARA, RBPJ, RCOR1, RUNX3, RXRA, SP110, SP3, SPI1, STAT1, STAT4, STAT6, TAL1, TBX21, TFEB, TP53, VEZF1, ZEB2, ZFP36L2, ZNF200, ZNF217, ZNF238, ZNF267, ZNF274 General ARNTL, BMP2, CAMTA2, CASZ1, CEBPB, CIC, CLOCK, CREBZF, CXXC1, DDIT3, ELK1, ERF, ESRRA, ETV7, FOXJ1, FOXJ2, FOXO4, GLI2, GLI3, HOXB3, HOXC4, HSF2, HSF4, ID2, IKZF1, IRF9, JUNB, KLF12, MAZ, MGA, MLXIPL, MNT, MYBL2, MYC, MYT1, NFATC4, NFE2L1, NFE2L2, NFYB, NKRF, NR1D1, ONECUT2, PATZ1, PAX5, PHB2, PITX2, POU2F2, POU6F1, PPARA, PRRX2, SMAD1, SMAD5, SNAI1, SRF, TBX1, TCF20, TCF25, TCF3, TCF7L1, TFAP4, TRPS1, TSC22D1, TUB, USF2, ZBTB11, ZBTB33, ZBTB40, ZBTB7A, ZHX3, ZKSCAN3, ZNF117, ZNF146, ZNF189, ZNF195, ZNF212, ZNF219, ZNF236, ZNF24, ZNF282, ZNF415, ZNF419, ZNF44, ZNF629, ZNF646, ZNF675, ZNF76, ZNF85, ZNF93 Table 2 Specific and General Transcription Factors used in analysis. Specific transcription factors have been found to be specific to one particular tissue or set of tissues; general transcription factors have been found to be active across many tissues. Page 5 of 9

Tissue Number of Tissue- Tissue-Specificity Keywords/Prefixes Specific Genes Stomach 31 Stomach, Digest, Breakdown Thyroid 401 Thyroid, TSH, Thyroxine, Calcium, Cal- citonin Blood 730 T cell, interleukin, erythrocyte, oxygen, respiratory burst, B cell, antigen, im- mune, blood, chemokine, killer, MHC Skin 84 keratinocyte, skin, epidermis, hemidesmosome, melanin Testis 136 gamete, sperm, meiosis, meiot, fertiliza- tion, sexual, testis Pancreas 258 insulin, pancrea, digest, glucagon Artery 11 artery, arteri Pituitary 19 pituitary, adrenocortico, TSH, HGH, PRL, FSH, MSH, Luteinizing hormone, Prolactin, Growth hormone, Thyroid- stimulating hormone Lung 195 Lung, Oxygen, Hemoglobin, Respiratory Muscle 561 Muscle, Actin, Myosin, Muscul, Tro- ponin, Myofibril, Sarcomere, Contraction Adipose 459 Fat, Trigylcer, Adipo, Lipid Heart 679 Cardia, Heart, Muscle, Actin, Myosin, Troponin, Myofibril, Myocyte, Potas- sium, Ventricular Brain* 1618 Axon guidance, nervous system development, ion transport, transmembrane signaling receptor activity, glu- cose metabolic process, central nervous system development, brain development, dendrite, calcium ion transport, visual perception Table 3 Genes with tissue-specific functions, as identified by GO keyword. We defined 13 sets of tissue-specific genes; for all sets except for brain tissues, we used keyword search to identify genes with tissue-specific GO functions. Because of the importance of brain tissues to the analysis, we identified brain-specific genes by individually examining all 1618 GO functions and identifying 109 brain-related ones; the large number of brain genes is due to the fact that we selected genes which were highly expressed in our tissues. We provide the most common brain-related GO functions in the table above. Page 6 of 9

Tissue TF Genes of Interest Linked To/ p Total Genes Linked To Heart - Atrial Ap- NR2F2 8/35 4.915e-03 pendage Heart - Atrial Ap- ID1 6/22 5.778e-03 pendage Heart - Left Ventricle GATA6 7/30 7.411e-03 Heart - Left Ventricle ID1 4/15 2.558e-02 Lung HOXA5 5/33 4.934e-03 Lung NR2F2 7/36 1.873e-04 Lung NFIL3 5/28 2.352e-03 Lung FOSL2 8/29 4.128e-06 Lung JUND 5/35 6.380e-03 Lung KLF6 3/20 2.930e-02 Lung JUN 5/36 7.204e-03 Lung TBX2 6/34 9.294e-04 Lung ETS2 5/34 5.624e-03 Lung MAFF 4/35 3.054e-02 Muscle - Skeletal BCL6 6/34 2.188e-02 Muscle - Skeletal ZBTB16 7/39 1.254e-02 Pancreas ZKSCAN1 4/31 2.479e-02 Skin - Not Sun Exposed TFAP2A 3/26 1.147e-02 (Suprapubic) Skin - Not Sun Exposed KLF4 4/36 4.064e-03 (Suprapubic) Skin - Not Sun Exposed KLF6 3/31 1.854e-02 (Suprapubic) Skin - Sun Exposed TFAP2A 3/22 7.170e-03 (Lower leg) Skin - Sun Exposed HES1 3/34 2.372e-02 (Lower leg) Testis SNAPC4 3/27 2.834e-02 Testis KLF11 3/31 4.052e-02 Testis ZBTB32 4/37 1.285e-02 Testis ZNF473 3/28 3.118e-02 Thyroid SOX9 7/41 5.115e-03 Thyroid SALL1 10/46 1.133e-04 Thyroid FOSB 5/24 7.330e-03 Thyroid JUND 5/31 2.164e-02 Whole Blood IFI16 6/25 1.808e-02 Whole Blood GATA3 14/34 3.677e-07 Whole Blood STAT4 11/35 1.249e-04 Whole Blood LEF1 6/21 7.478e-03 Whole Blood BACH1 6/28 3.076e-02 Whole Blood IRF8 6/24 1.481e-02 Whole Blood NFKB1 6/28 3.076e-02 Whole Blood FLI1 7/29 1.061e-02 Whole Blood JUND 7/33 2.141e-02 Whole Blood VEZF1 7/30 1.282e-02 Whole Blood TBX21 8/21 2.366e-04 Whole Blood MAFB 13/36 5.517e-06 Whole Blood RUNX3 12/31 5.464e-06 Whole Blood SPI1 8/24 6.744e-04 Whole Blood ZNF217 9/30 7.507e-04 Whole Blood ZNF238 7/34 2.499e-02 Table 4 Tissue-specific transcription factors which were linked to an especially large number of genes of interest – tissue-specific genes, tissue-specific transcription factors, or general transcription factors. We filtered for transcription factors which were a) linked to at least three genes of interest and b) linked to at least twice as many genes of interest as random chance would predict. We include the binomial probability that each transcription factor would be linked to at least that many genes of interest by chance. Page 7 of 9

TF Brain Tissues Tissue Where Most Linked Genes of In- p to Tissue-Specific Genes terest/Total Genes Linked To NEUROD2 Amygdala, Anterior cingulate cortex (BA24), Cerebellar Hemi- Spinal cord (cervical c-1) 18/26 9.776e-09 sphere, Cortex, Frontal Cortex (BA9), Hippocampus, Spinal cord (cervical c-1) NR3C2 Cerebellum, Hippocampus Hippocampus 19/39 8.191e-06 MLLT3 Amygdala, Caudate (basal ganglia), Cerebellum, Hippocampus, Cerebellum 16/31 1.677e-05 Hypothalamus, Nucleus accumbens (basal ganglia) HLF Caudate (basal ganglia), Cerebellum, Cortex, Nucleus accumbens Caudate (basal ganglia) 20/44 1.763e-05 (basal ganglia), Putamen (basal ganglia), Spinal cord (cervical c- 1) MEF2C Amygdala, Anterior cingulate cortex (BA24), Caudate (basal gan- Amygdala 16/32 2.806e-05 glia), Cortex, Spinal cord (cervical c-1) ETV1 Caudate (basal ganglia), Cerebellar Hemisphere, Cortex, Nucleus Cerebellar Hemisphere 13/23 2.965e-05 accumbens (basal ganglia) SOX9 Anterior cingulate cortex (BA24), Caudate (basal ganglia), Cere- Caudate (basal ganglia) 19/43 4.630e-05 bellar Hemisphere, Cortex, Hippocampus, Nucleus accumbens (basal ganglia) ARNT2 Anterior cingulate cortex (BA24), Cortex, Frontal Cortex (BA9) Cortex 13/24 5.424e-05 OLIG2 Caudate (basal ganglia), Cerebellum, Hypothalamus, Nucleus ac- Putamen (basal ganglia) 14/30 2.268e-04 cumbens (basal ganglia), Putamen (basal ganglia), Spinal cord (cervical c-1) MEIS2 Anterior cingulate cortex (BA24), Frontal Cortex (BA9) Anterior cingulate cortex 15/34 2.942e-04 (BA24) MYCN Caudate (basal ganglia), Cerebellar Hemisphere, Cerebellum, Caudate (basal ganglia) 18/45 3.360e-04 Hippocampus, Putamen (basal ganglia), Spinal cord (cervical c- 1) BCL11A Cerebellar Hemisphere, Cerebellum, Nucleus accumbens (basal Spinal cord (cervical c-1) 21/59 7.502e-04 ganglia), Spinal cord (cervical c-1), Substantia nigra FOXG1 Cerebellum, Substantia nigra Cerebellum 7/11 8.788e-04 NFIB Frontal Cortex (BA9), Hippocampus Hippocampus 11/24 1.284e-03 ZNF365 Cerebellum, Cortex, Frontal Cortex (BA9), Hippocampus, Puta- Putamen (basal ganglia) 16/42 1.319e-03 men (basal ganglia) ZNF423 Amygdala, Anterior cingulate cortex (BA24), Cerebellar Hemi- Amygdala 16/42 1.319e-03 sphere, Cortex, Substantia nigra TCF4 Amygdala, Hippocampus, Spinal cord (cervical c-1) Amygdala 14/35 1.505e-03 CAMTA1 Amygdala, Anterior cingulate cortex (BA24), Cortex Anterior cingulate cortex 12/28 1.602e-03 (BA24) HOXC6 Spinal cord (cervical c-1) Spinal cord (cervical c-1) 15/39 1.702e-03 MYT1L Anterior cingulate cortex (BA24), Cerebellar Hemisphere, Cortex, Cerebellar Hemisphere 11/25 1.931e-03 Frontal Cortex (BA9), Hippocampus, Hypothalamus, Spinal cord (cervical c-1), Substantia nigra HEY1 Caudate (basal ganglia), Cerebellum, Cortex, Hypothalamus, Nu- Cortex 14/37 2.795e-03 cleus accumbens (basal ganglia) MEF2A Putamen (basal ganglia) Putamen (basal ganglia) 13/35 4.710e-03 LHX6 Amygdala, Caudate (basal ganglia), Putamen (basal ganglia) Caudate (basal ganglia) 10/24 4.966e-03 CUX2 Amygdala, Anterior cingulate cortex (BA24), Cerebellum, Nu- Nucleus accumbens (basal 13/36 6.203e-03 cleus accumbens (basal ganglia) ganglia) HIVEP2 Caudate (basal ganglia) Caudate (basal ganglia) 13/36 6.203e-03 NPAS2 Putamen (basal ganglia), Spinal cord (cervical c-1) Spinal cord (cervical c-1) 8/19 1.108e-02 LHX2 Nucleus accumbens (basal ganglia), Substantia nigra Substantia nigra 9/23 1.216e-02 SOX10 Hippocampus Hippocampus 11/31 1.319e-02 PKNOX2 Cortex Cortex 11/31 1.319e-02 ZNF238 Nucleus accumbens (basal ganglia) Nucleus accumbens (basal 8/21 2.111e-02 ganglia) ZEB2 Substantia nigra Substantia nigra 9/25 2.182e-02 Table 5 Brain-specific transcription factors which are linked to an unusual number of genes of interest. For each transcription factor, we give the brain tissues in which this occurs as well as the brain tissue in which it is most linked to brain-specific genes and the binomial probability in that tissue. Page 8 of 9

Tissue Group Genes with Most Increased Expression Genes with Most Increased Hubness Brain Tissues CACNG7, TNR, KCNJ9, GNG3, GPR19 ACTL6A, VRK2, HTT, LIAS, RNPC3 Non-Brain Tissues COL6A3, PDLIM1, CFD, OXA1L, DPT CDC42EP4, HIGD1A, MDN1, CYP27A1, ADAM28 Stomach and Colon ANO7, IHH, MUC13, PDZD3, CDHR5 IGF1R, PUS1, ADORA3, ABLIM1, SF3B4 Breast - Mammary Tissue, Adipose CCRN4L, CETP, GIPR, TNN, FFAR3 SPARC, KIFC3, C16orf7, MID1, LGR4 - Subcutaneous, Adipose - Visceral (Omentum) Heart - Atrial Appendage, Heart - TNNI3, NKX2-5, MYL7, NPPB, MYBPC3 XPA, GTF2E2, KPNA2, ANXA5, TJP2 Left Ventricle Artery - Tibial, Artery - Aorta ACAN, TNFRSF11B, NOV, WWP2, MRAP2 ARPC2, LYVE1, TRPV2, DCAF7, DGKD Adipose - Subcutaneous, Adipose - HAS1, RPS4Y1, KDM5D, GPAM, USP9Y DUS2L, MDN1, OXA1L, SPTBN1, FUNDC2 Visceral (Omentum) Spinal cord (cervical c-1), Hypotha- HN1L, SLC18A2, FNTB, SLC6A3, OXT CAPG, NAGA, ALKBH2, ACTL6A, ACAA2 lamus, Substantia nigra Hypothalamus, Substantia nigra SLC6A3, HCRTR1, SLC18A2, ABHD2, UBE2D1, LYAR, NDUFA4, ZNF174, SENP2 TPRG1L Amygdala, Cortex, Anterior cingu- EMX1, BAP1, PLEKHM2, ELK1, RTN4RL2 ZNF33A, TXN, ZFYVE28, MAT2B, CHMP1B late cortex (BA24), Hippocampus, Frontal Cortex (BA9) Skin - Not Sun Exposed (Suprapu- ASPRV1, DCT, LCE2B, KRT2, SERPINA12 APOE, CERS3, CCRL1, STC2, EIF4E2 bic), Skin - Sun Exposed (Lower leg) Cerebellar Hemisphere, Cerebellum CLK4, AGPAT6, EOMES, CRTAM, PAXIP1 SRSF5, VPS35, HERPUD1, BTD, NR2C1 Putamen (basal ganglia), Caudate LRPAP1, TMPRSS6, TRAC, TNFRSF8, CRYL1, SPRED2, PLAG1, BBIP1, RRAGD (basal ganglia), Nucleus accumbens PTPN7 (basal ganglia) Amygdala, Hippocampus NTS, SOS2, CCDC19, MCM7, CENPB CUX1, CKLF, HDAC1, UCK2, NCOR2 Cortex, Anterior cingulate cortex OPN3, NOMO2, LMTK2, ROS1, DCTN2 ZFYVE28, BBS12, GMFB, GLIS1, PDK1 (BA24), Frontal Cortex (BA9) Frontal Cortex (BA9) CNGB3, CLDN20, TPBG, CARTPT, NIF3L1 ZNF33A, GLIS1, UBE2G1, BTG3, GUCY2C Cerebellum PHIP, ITPR1, GPR63, SERPINC1, SCAI FAM84B, ERLIN1, QPCT, C4orf27, FNDC3A Colon - Transverse FABP1, GAL3ST2, MEP1B, NOX1, CA1 DDX3Y, FICD, MRPL22, EIF3B, ADORA3 Cerebellar Hemisphere MTPN, CHMP3, USP9Y, RPS4Y1, MAP2K1 HERPUD1, CTNNAL1, CDKL3, SGMS1, MTHFR Hippocampus TULP1, APOA2, IDH3G, PKD2L1, PNO1 CUX1, FGF17, ZBTB9, CHST2, UBE2D1 Heart - Left Ventricle SMYD2, MYL2, ADRA1A, MYL3, MZT2A DMPK, MID1IP1, C14orf1, LTBP4, PFDN6 Substantia nigra SLC6A3, EN1, PAX5, ALDH1A1, CXCL10 ST6GALNAC6, RHOH, CCDC113, CHML, PSMC3IP Artery - Aorta CSTF2T, GCNT2, KCNK17, IL13RA2, ADCY10, PVRL3, APBB1IP, SLC38A1, CYTL1 SEMA4D Adipose - Visceral (Omentum) ALOX15, MSLN, FOSB, ITLN1, HAS1 IKZF2, DCLK1, DUS2L, ABHD11, HAX1 Heart - Atrial Appendage MYBPHL, CHRNE, HAMP, NPPA, FAM21A FOSB, BEND7, GRB2, RILPL1, ODF2 Adipose - Subcutaneous MMP3, HOXC10, DKK1, POU4F3, ZIC4 MDN1, C16orf7, EML4, TMEM173, ABTB2 Nucleus accumbens (basal ganglia) WDR92, DTNBP1, ARHGAP6, TIAF1, PLAG1, RRAGD, CCL28, PION, DRG1 TIPRL Breast - Mammary Tissue TAT, SCGB2A2, OXTR, SCGB1D2, SPDEF ING3, SUPT5H, A4GNT, PON2, PLAG1 Muscle - Skeletal MYL1, MYLPF, MYBPC2, MYH2, TNNC2 FLOT2, RUFY3, PPIF, SCML2, TCF7L1 Nerve - Tibial MPZ, PRX, CLDN19, BIRC7, BMP8B PGM1, PLA2G16, UROS, TRDMT1, LDHB Skin - Sun Exposed (Lower leg) CYP1A1, PRR4, PRG4, ZIC1, MMP3 HIP1, MED12, DDAH2, AMMECR1, BRCA2 Lung SFTPA1, SFTPA2, SCGB1A1, NAPSA, FURIN, IGBP1, MBIP, SEPT9, H2AFZ SFTPB Esophagus - Mucosa GYS2, KRT13, CSTB, ERO1L, FAR1 NAA20, S100A8, ADD3, DCBLD2, S100A9 Pituitary POMC, GH1, POU1F1, LHB, GHRHR NDOR1, GEM, MAP4K4, WSB1, ACACB Artery - Tibial OR51E2, TMEM181, P2RX1, ITIH1, SOX6 SLC20A2, LRP2BP, CPSF7, RBM28, SOD1 Caudate (basal ganglia) ALDH1A1, IQGAP1, FLT4, BATF, CCDC19 BBIP1, OPRL1, CHAMP1, OR52N4, ZNF41 Hypothalamus OXT, HDC, ECEL1, DLX1, DIRAS3 DBI, NKIRAS2, GDE1, CELSR3, ZFAND2B Spinal cord (cervical c-1) FNTB, HOXB7, HOXB9, HOXA5, HN1L ADAMTS8, ZBP1, NF2, EIF4EBP1, ZFR Pancreas REG1B, AMY2A, CTRB1, CUZD1, CTRL ABCA7, PPRC1, PGAM4, MUTED, BET1L Anterior cingulate cortex (BA24) TTR, SLN, PSPHP1, SLC1A7, VKORC1 PPP1R11, BARD1, PGRMC1, B4GALNT4, BMP3 Testis IGF2BP1, TXNDC2, SMC1B, TCP11, PHF7 DDX3Y, KDM5D, CNN1, COL3A1, ACTG2 Skin - Not Sun Exposed (Suprapubic) HAO2, MAB21L1, ELOVL3, KRT81, CCDC53, FASTKD3, IGFBP3, NTNG2, KRTAP5-8 ANAPC16 Cortex TAOK1, INTS1, ZNF341, MGRN1, SGTA RB1, MTHFD1, PLK5, ZKSCAN5, PTCHD2 Putamen (basal ganglia) HS3ST3B1, MCM7, ALDH1A1, FBXW4, WBSCR22, SLC30A5, APLP2, ARHGAP21, CENPB COMMD3 Adrenal Gland CYP17A1, CYP21A2, HSD3B2, FDX1, ALKBH2, PCNP, SMARCA5, COX19, AKR1B1 TUBB4B Amygdala UTS2D, OCM, DTNBP1, WDR92, PRTN3 CDK2AP1, KCNK3, EFNB3, PABPC1, NFAM1 Whole Blood HBG1, HBG2, HBD, ALAS2, HBA2 NDFIP2, ERRFI1, PPM1A, APH1B, ST13 Thyroid TG, IYD, DIO1, TSHR, PAX8 DUSP28, CX3CR1, CLU, ATP6V1E1, KCNJ14 Esophagus - Muscularis FOXF2, GRPR, NKX6-1, CDC42EP2, NBN TRPM2, SHROOM3, VSIG4, PLA2G4B, TCF25 Table 6 The genes which diﬀer most dramatically at important split points in the hierarchy, as measured by changes in expression and hubness. Page 9 of 9

Tissue Functions of Most Upregulated Clusters Adipose - Subcutaneous extracellular matrix,extracellular matrix,extracellular matrix Adipose - Visceral (Omentum) multicellular organismal development,platelet-derived growth factor binding,extracellular matrix Adrenal Gland mitosis,M phase of mitotic cell cycle,mitotic sister chromatid segregation Artery - Aorta extracellular matrix structural constituent,extracellular matrix,skeletal system development Artery - Tibial extracellular matrix,extracellular matrix,muscle filament sliding Brain - Amygdala synaptic vesicle,transport,voltage-gated potassium channel complex Brain - Anterior cingulate cortex voltage-gated calcium channel activity,axon guidance,neuron cell-cell ad- (BA24) hesion Brain - Caudate (basal ganglia) voltage-gated calcium channel complex,glutamate receptor activity,chloride transport Brain - Cerebellar Hemisphere transport,nervous system development,chloride channel activity Brain - Cerebellum chloride channel activity,sister chromatid cohesion,central nervous system development Brain - Cortex regulation of axonogenesis,protein deubiquitination,nervous system development Brain - Frontal Cortex (BA9) transport,neuron migration,clathrin sculpted gamma-aminobutyric acid transport vesicle membrane Brain - Hippocampus synaptic vesicle,axon,ion transmembrane transport Brain - Hypothalamus potassium ion transmembrane transport,heart looping,regulation of insulin secretion Brain - Nucleus accumbens voltage-gated calcium channel activity,ion transmembrane trans- (basal ganglia) port,respiratory electron transport chain Brain - Putamen (basal ganglia) dendrite,regulation of insulin secretion,peripheral nervous system development Brain - Spinal cord (cervical c-1) regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate se- lective glutamate receptor activity,chloride channel activity,glutamate receptor signaling pathway Brain - Substantia nigra recycling endosome membrane,synapse assembly,post-translational protein modification Breast - Mammary Tissue structural constituent of cytoskeleton,antigen binding,extracellular matrix structural constituent Colon - Transverse M phase of mitotic cell cycle,phosphatidylinositol-mediated signaling,M phase of mitotic cell cycle Esophagus - Mucosa M phase of mitotic cell cycle,chromosome, centromeric region,keratinocyte differentiation Esophagus - Muscularis extracellular matrix,BMP signaling pathway,calcium-dependent cell-cell adhesion Heart - Atrial Appendage structural constituent of muscle,ventricular cardiac muscle tissue mor- phogenesis,mitochondrial electron transport, NADH to ubiquinone Heart - Left Ventricle structural constituent of muscle,NADH dehydrogenase (ubiquinone) activity,mitochondrial respiratory chain complex I Lung complement activation, classical pathway,cytokine-mediated signaling pathway,M phase of mitotic cell cycle Muscle - Skeletal muscle filament sliding,sarcomere,muscle filament sliding Nerve - Tibial extracellular matrix,extracellular matrix,dystrophin-associated glycopro- tein complex Pancreas calcium ion binding,SRP-dependent cotranslational protein targeting to membrane,translational initiation Pituitary centriole,respiratory electron transport chain,respiratory electron transport chain Skin - Not Sun Exposed (Supra- M phase of mitotic cell cycle,M phase of mitotic cell cycle,mitotic pubic) prometaphase Skin - Sun Exposed (Lower leg) intermediate filament,mitotic prometaphase,M phase of mitotic cell cycle Stomach mitosis,complement activation, classical pathway,M phase of mitotic cell cycle Testis chromosome segregation,mitotic cell cycle spindle assembly check- point,chromosome, centromeric region Thyroid detection of chemical stimulus involved in sensory perception of taste,cellular response to vascular endothelial growth factor stimulus,positive regulation of tyrosine phosphorylation of Stat3 protein Whole Blood T cell receptor complex,defense response to bacterium,prostanoid metabolic process Table 7 The GO functions of the three most upregulated enriched clusters in each tissue.