Page 1 of 9 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 de- velopment, ion transport, transmem- brane 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