Understanding Microrna Dysregulation in Cancer and Its Effects on Protein Interaction and Transcriptional Regulatory Networks

Beyond Argonaute: understanding microRNA dysregulation in cancer and its effects on protein interaction and transcriptional regulatory networks

Sara JC Gosline, PhD ISMB – Late Breaking Research July 14, 2014 microRNAs (miRNAs) • Transcribed in nucleus • Processed by Dicer Drosha • Forms silencing complex with argonaute (Ago2) and Nucleus GW182 Cytoplasm • Binds 3’ untranslated region (UTR) of mRNA Dicer • Causes premature AAAA degradation of mRNA Ago2 GW182 1 Seed region sequence complementarity enables computational prediction of targets

AAAA

GAUGGAG CUACCUCA AAAA

miRNAs impose modest fold change

miR-7 Targets

Other mRNA

5000 6000 5000

3000 4000 3000

Number of of NumbermRNA Fraction less than value Fraction

miR-7 Targets 2000 1000

Other mRNA 0

0.0 0.2 0.4 0.6 0.8 1.0 -2 -1 0 1 2 -2 -1 0 1 2 mRNA expression change 12h mRNA expression change 12h after miR-7 over-expression after miR-7 over-expression

3 Grimson et al., Mol. Cell 2007 Yet miRNAs are implicated in many biological

processes

Let-7 Targets

Other mRNA

6000

4000

Number of of NumbermRNA

2000 Fraction less than value Fraction

Let-7 Targets

Other mRNA 0

0.0 0.2 0.4 0.6 0.8 1.0 -2 -1 0 1 2 -2 -1 0 1 2 mRNA expression change 32h mRNA expression change 32h after let-7 over-expression after let-7 over-expression

4 Selbach et al., Nature 2008 6/26/2014 The Cancer Genome Atlas - Data Portal

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TheAcute Myelo idCancer Leukemia [LAML] Genome200 Atlas200 (TCGA)02/04/14 More TCGA Information 6/26/2014 Cancer Details - Breast invasive carcinoma: Case Counts - Data Portal More information about The Cancer Genome Adrenocortical carcinoma [ACC] 80 80 06/13/14 Atlas program can be found by following the links below: Bladder Urothelial Carcinoma [BLCA] 412 366 06/25/14 TCTGCGAA w Heobmseite Contact Us For the Media

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Cervical squamous cell carcinoma and endocervical 308 257 06/25/14 Home > Cancer Details adenocarcinoma [CESC] AnnouTCnGcAe mpuebnlictastion guidelines Cholangiocarcinoma [CHOL] 36 0 Breast invasive carcinoma: Case Counts

CTaorlgoent andumenboecr a orf c Binreoamsta i n [CvaOsAivDe ] carcinoma samples: 462 450 06/23/14 500 (number subject to change) Esophageal carcinoma [ESCA] 185 176 06/15/14 Breast invasive carcinoma [BRCA] Total Exome1 SNP Methylation mRNA miRNA Clinical

GlioCbalassetsoma multiforme [GBM] 1064 1032 1059531 1044 1502418 1041 0160/0213/14 Organ-Specific Controlhttps://tcgas2 N/A -data.nci.nih.gov/tcga/N/A N/A N/A N/A N/ A N/A

H1eRaadw eaxnodm eN deactak asrqe u aavamilaobules a ct e ClGl Hcuabrc. Vinaoriamnat c [aHllinNgS dCat]a are available v5ia2 t8he links under Exo5m2e8 above. 06/25/14 5 2Organ-Specific ContrWeols ar efocus derived fonrom d sixonor cancersmaterial take nwith from in d>50ividual smRNA not match eandd to th emiRNA tumors in t hlevelsis study. S pecifically, Ktihdense ytis Csuherso wmouoldp hbeo bfroem [ K inIdCivHid]uals that did not have cancer but were able6 to6 donate tissue for o6th6er reasons (e.g. ra0pi6d / a2u5to/1p4sy programs, organ procurement programs, etc). N/A means that organ-specific tissue control data have not yet been collected for this tumor type by The Cancer Genome Atlas. KThiden TeCy G reAn Dala ctale Paor r cteal l d coaersc i nnootm hao s [Kt lIoRwCe]r levels of sequence da5t3a6. NCI's Cancer G5e3n6omics Hub (CG06H/u2b4)/14 is the new secure repository for storing, cataloging, and accessing BAM files and metadata for sequencing See all announcements data. Kidney renal papillary cell carcinoma [KIRP] 291 242 06/25/14 More TCGA Information Liver hepatocellular carcinoma [LIHC] 377 273 06/23/14 More information about The Cancer Genome Atlas program can be found by following the Lung adenocarcinoma [LUAD] 522 512 06/25/14 links below:

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https://tcga-data.nci.nih.gov/tcga/tcgaCancerDetails.jsp?diseaseType=BRCA&diseaseName=Breast%20invasive%20carcinoma 1/1 We can search for miRNAs with expression correlated with survival

High miRNA levels correlate with better outcome

Low miRNA levels correlate with better outcome

Cancer miRNAs associated with prognosis (p<0.01) Breast (BRCA) miR-27a, miR-99a, miR-15a, let-7c, miR-106b, miR-375 Pancreatic (PAAD) miR-338-3p, let-7d Liver (LIHC) miR-30d, miR-379, let-7f, miR-127, miR-532 Lung (LUAD) miR-199b, let-7d, let-7a, miR-15a, let-7f, miR-199a, let-7g Colon (COAD) miR-30c, miR-27b, miR-16, let-7g, miR-429, miR-191, let-7b, miR- 106b, miR-30b… Prostate (PRAD) miR-21, miR-10b, let-7f, miR-142-3p, miR-186, miR-338, miR-30e, miR6 - 127, let-7e miRNA effects are observed by measuring expression anti-correlation across patient samples

Target mRNA anti-correlated

Patients sorted by miRNA level

miR-122172 hsa −targetmiR−122−5p correlations targets in LIHC P = 1.67e in−12 liver cancer

miR-200744 hsa target−miR−200a− 5pcorrelations targets in BRCA P = 8.31e in −breast10 cancer

2.5

2.0

1.5

Target y

Target t i

y Target

t s

i Nontarget

Density s

Nontarget n n

2 Target e e d hsa−miR−122−5p

d hsa−miR−200a−5p Non-target

Non-target 1.0 Density

1 0.5

0.0 0 0 0.5 1.0 1.5 2.0 2.5

0 0 1 2 3 4

−0.6 −0.4 −0.2 0.0 0.2 0.4 0.6 −0.4 −0.2 0.0 0.2 Correlation -0.6 -0.4 -0.2Correlation 0 0.2 0.4 0.6 -0.4 -0.2 0.0 0.2 0.4 7 Pearson Correlation Pearson Correlation Hypothesis

miRNA miRNA function is determined by network of changes caused miRNA-mediated repression and measured by downstream changes in mRNA expression.

8 Goal

Characterize miRNA- miRNA mediated networks to : (1) Understand the role of miRNAs across cancers AND (2) Identify signaling proteins of interest that mediate these effects

9 Outline

• Pan-cancer analysis of miRNA-modulated networks

• Using networks to ascribe miRNA function

• Finding proteins of interest within cancer networks

10 Outline

• Pan-cancer analysis of miRNA-modulated networks

• Using networks to ascribe miRNA function

• Finding proteins of interest within cancer networks

11 mRNA-miRNA anti-correlation can be explained via a network miRNA • miRNAs degrade mRNA • Diminished protein expression disrupts protein interaction network • Transcription factors are unable to convey signal

Protein Transcription factor mRNA anti-correlated with miRNA upstream mRNA 12 Computational tools can quantify this network

miRNA • miRNA-mRNA target prediction can find targets • Protein-protein interactions from the literature can identify disrupted pathways • Transcription factor binding matrices can be used to predict DNA binding

Protein mRNA anti-correlated with miRNA upstream Transcription factor mRNA 13 SAMNet reduces a large network of putative interactions to the most meaningful S Protein Transcription factor mRNA

Each miRNA associated with prognosis is assigned color in graph

14 Gosline et al., Integrative Biology 2012 T Optimization reduces network to most essential nodes and edges S Protein Transcription factor mRNA

15 Gosline et al., Integrative Biology 2012 T SAMNet interprets data as a weighted graph

S Protein Transcription factor mRNA

Each edge between node i and node j has: •Wijc: weights on edges •Capij: capacity shared across all commodities

16 Gosline et al., Integrative Biology 2012 T Each cancer expresses a different ensemble of miRNAs

High median expression

Low median expression

Not expressed

Colon Pancreas Breast Lung Liver Prostate

17 Gosline, Pregernig, et al., In preparation Direct miRNA effects are encapsulated by predicted target weights across commodities S

miR-21 miR-122 miR-10b

6/30/2014 TargetScanHuman 6.2

Search for predicted microRNA targets in mammals [Go to TargetScanMouse] [Go to

TargetScanWorm] [Go to TargetScanFly] 18 [Go to TargetScanFish]

1. Select a species

AND

2. Enter a human Entrez Gene symbol (e.g. "LIN28A")

AND/OR

3. Do one of the following:

Select a broadly conserved* microRNA family

Select a conserved* microRNA family

Select a poorly conserved microRNA family Note that these families also include small RNAs that have been misclassified as miRNAs.

Enter a microRNA name (e.g. "mmu-miR-1")

* broadly conserved = conserved across most vertebrates, usually to zebrafish conserved = conserved across most mammals, but usually not beyond placental mammals

TargetScan predicts biological targets of miRNAs by searching for the presence of conserved 8mer and 7mer sites that match the seed region of each miRNA (ref. 1). As an option, nonconserved sites are also predicted. Also identified are sites with mismatches in the seed region that are compensated by conserved 3' pairing (ref. 2). In mammals, predictions are ranked based on the predicted efficacy of targeting as calculated using the context+ scores of the sites (ref. 3, 4). As an option, predictions are also ranked by their probability of conserved targeting (PCT, ref. 2). TargetScanHuman considers matches to annotated human UTRs and their orthologs, as defined by UCSC whole-genome alignments. Conserved targeting has also been detected within open reading frames (ORFs). A listing of these ORF sites can be found at the bottom of Supplemental Table 2 of reference 1.

This search page of TargetScan Release 6.2 retrieves predicted regulatory targets of mammalian microRNAs. Many targets are the same as those presented in previous versions of the TargetScan site (Releases 2.0, 2.1, 3.0, 3.1, 4.0 - 4.2, 5.0 - 5.2, and 6.0). Compared to previous releases, Release 6 extends context score contributions to include seed-pairing stability and target-site abundance (ref. 4), includes all 3' UTRs from RefSeq (rather than just the longest UTR from each gene), and includes more miRNA families.

http://targetscan.org/ 1/2 Protein-protein interactions are weighted by confidence in the literature S

19 Protein-DNA interactions are predicted from DNase I hypersensitive regions from ENCODE S

20 Predict protein-DNA interactions using motifs within tissue-specific DNase I hypersensitive regions

DNase I Hypersensitive region

Expressed mRNA

2 KB around transcription start sites

21 mRNA weights connect mRNA nodes to sink

22 T mRNA weights are assigned by anti-correlation to miRNA in question

miR-200 target correlations in breast cancer 744 hsa−miR−200a−5p targets in BRCA P = 8.31e−10

Target

t i

s NontargetTarget

n 2 e

d hsa−miR−200a−5p

Non-target

Density 1

0 1 2 3 4

−0.4 −0.2 0.0 0.2 -0.4 -0.2 Correlation 0.0 0.2 0.4 Pearson Correlation 23 ECE2 NFE2L3 NCF4 ABAT TARBP2

B3GAT3 TPCN1 M Y O 1 G SEPN1 CNDP 2 KCTD11 ALDH7A1 RAVER1 G LI1 MIIP SOX5 HMGA1 CNPY2 DLGAP1 HES4 ARHGEF18 KCTD1 TAF10 SSFA2 ZNF532 Z N F 1 3 8 SUFU CDK5RAP1 DLG4 EIF 6 BANF1

MID1 IP 1 Z N F 1 3 3 SFXN2 ARMC9 RUNX3 ACADSB ELK4 MITF

L MNB2 APOA5 ELF2 SOX9 MAF KCNA4 CTCF NRARP POU2F2 RHOJ C H M P 6 ZEB2 CALR MRPL9C20orf112 SEC11C CENPV ABHD15 TMEM200A CLN6 TSNAXIP1IL1 5 RA MED8 RNASE4 CYB561 LEO1 TUBB2A COPS6 ABL1 MS R B 3 NAB1 EPO CTBP2OTUD7 B EPHA2MGAT3 DYRK2 KIAA0391 KEAP1

T N S 1 CCDC15 ENAHPLEKHA4 RABL6 CCNE2 C 1 0 o rf8 8 GTF2IRD1 HOXB9 SAT1 TTC16 GADD45A MDFI C20orf24 GLRX3 M E D 3 1 MED10 C5orf54 EPOR SULF2 BGNSTEAP3 TREH ZWILCH FANCF Z N F 6 2 2 TPM4 RHOBTB3 PHLDA1 UBL3 ABCB8 ALG1 EPX ATP1B3 NUDT7 MY D8 8 F A M 4 6 A PRELID1 SEPHS1 SLC41A1 TBC1D10BW D R 4 5 NUCB2 DUSP4 CC2D1B MAT1A TNFAIP8L1 PMPCA CFLAR PFDN6 CCDC86 SPIRE2 MRPS15 NFIX S100PBP MTTP TAF9 GFRA1 SRRD EIF2B5 MAPK14 PPP1R3E RORA MYO9B POLD4 Z N F 5 7 2 SORBS2 TSEN3 4 M AP2K3 FSD1L RP S 1 4 SSR4 VASP ELMSAN1 TMEM183A PIK3R1 RARA ADRM1 LYPLA2 COX 4 I1 DUS1L ACSM3ZBTB4 LMO7 CIZ1 ATF2 P S M D 9 C1 0 orf1 2 ALDH2ADH6 MR P L 2 2 PFDN4 PHF21A ILF3 PRSS23 GRK4 C 1 o rf8 6 TM EM 51 M D H 2 HNF1A GPRC5B EDC4 ALDOAPCNA SPTLC1 MAP3K6RPL27A CDK1 0 MAP2K6 M A P 2 KFBXL19 2 ACAT1 SERPIND1 LRRC45 SEC61G MRPS3 1 PCGF1 KAT2B ASPDH ARPC3 CHPT1 BRMS 1 MICALL1 H E M K 1 NNMT RPUSD3 CKAP2 DEF8 Z N F 5 1 7 CYP27A1 C 1 5 o rf4 0 MAP4 S CML2 F IT M 2 MAP3K7 NES PELI1 EHMT2 KLC1SEPHS2 PPIARXRA RPS8 CAPRIN1 HAPLN3 GBA IRAK1 PJA1 HSBP1 BAK1 CTTNBP2NL FOXA2 SLC25A42 SYT11 ARL4C MARK2 PNKP RGS10 PSD4 SACM1L TM EM 65 CGREF1 BCKDHB RCC2 NPEPPS TRAF6 ATF4 CRADD PEX13 BCL7A BHMT2 M E D 1 CDC34 NSUN5P2 PLAG1 NARF ALDH8A1PYGO2 M T A 3 ZNF20 M ED15 SLC26A6 PRDM1 ELF4 IFT140 THPO ASPA FBXO45 RELB PNMA1 PDLIM7 TP53BP1 SDF2L1 GPX8 UBE2 D3 BTRC LDOC1 TCF3C 1 1 o rf9 3 LRRFIP1 TPM3 NCOA6 ARHGEF17 HAX1 F A M 1 8 4UGP2 A GLG1 ZFPL1 DCTN2 SMARCD1 TBCE Z B T B 3 4 GIT1 PML ACHE T HAP6 QARS GPR126 SLC6A12 DNAJB11 PAPOLA TM EM 165 REL RARG M E N 1 EPHB2 GNE MFAP3L DENND3 RBPJ ABI2 ATF7RASGRP1 TPD52L2 ANGPTL6ACYP2 FUS AGXT FXN FLII TADA2B CDKN1AKIAA0226 N R 4 A 3 RGS1 2 SOX6 BNIP2 HECTD1 CHST12 NFKB2 CSRNP1GAL3ST4 MYO1B MS H 2 DLGAP4 GPR124ACSM2B FXR2 PITPNM2 YEATS2 NUP210 PTK2 ASAP1 DMD S N W 1 RNF 1 2 6 MAOB PPM1A USP7 PTK2B FAM 129B BMPERFHOD1 OCLN WASF2 EXO1 ESR1 GLB1L2ABCC1 MAPKAP1 C 3 o rf1 8 VDR ADAMTS13 CREB3 C11orf54 KLHL36 CACNB1 PPARA RUSC1 KBTBD11 CDC37L1 HDAC2 T A T D N 3 ETS2 ANKRD13BNAGS PRMT2LARP1BABCC10 C8orf4 G T F 2 H 1 TBC1D22B NOMO1 SDHD NCOR1 LHX2EXOSC7 SRC LOXL2 SP8 ML H 1 GLTPD1 F M R1 PUF60 TANC1 CBX4 IKZF2 F BX W 7 SLC25A20 OSBPL3IFNGR2 CIDEB KLF11 SALL1 PAHHOMER3 HDAC3 UBE2D1 WWC3 CFL2 BRPF1 OLFML3 ACOX2 PPP1CB CHD1 ADRB2 F M O 4 CPEB3 NCOR2 DLAT GATAD2B HNRNPK CBFB CBR4 XIAP CASP3 BACE1 SCARB1 PPARG H S F 1 HCFC1 S UMO2 NCOA2 P D K 2 MANF SLC13A5 TBX5 CCNE1 PSENEN CBX1 KHDRBS2 SAP30 MED2 4 TRIM24 BLM DIABLO LY6E FM N L3 CDCA4 PPIB CTBP1 SIN3A IN G5 BRCA1 APOB ATAD3BTCEB1 TNKS ACTR3B FAM193A SNRPA KHDRBS1 BIRC2 SLC1A3 PNPO LONP2 CCNG1 UBE2I KITLG SP4 HTT IL 2 7 R B M 2 4 ARHGAP21MR P L 2 8 M B D 3 TOPORS FERMT2 ADK FMNL1 PTPN1 ZBTB16 SLC25A36 FGFR1 STK39 RNH1 TJAP1 TERF1 FBXO28 ITPKA NKX2-5 ERCC6HGFAC PBRM1 SCLY CCDC43ACTR5 FAAH RAI1 NR1H4 GALT ATM SM AD7 C1orf122 DBN1 JUN TNFRSF1B PRRG4 SP5 PRODH2 SUOX SLC22A3 CBL AXL PHB AFAP1SP1NDRG2 S100A 11 TRAF2 KLF9 CDK2 DNAJC10 C A D M1 PNRC1 PTS TP53 IVD SPRY2 GCDH ZDHHC13 IKBKB LUZP1 PGLS ANO9 CREBBPTMEM106C E2 F1 GIPC2RRM2 DIRAS3 HNRNPU M E D 7 ECHDC2 PIP5K1C ADAMTS7 SART1 FOS NFKBIA USP5 3 PDLIM5 MLKL SLC4A1AP STAT3 AR HBEGFTOMM40L RBM34RALGAPB STAU2W D R 8 3 RMI1 C6orf106 TDG SAE1 CREB5 MAP3 K5 GCGR DHRS4L1 ZCCHC24 RELA CITED2 ZNF618PCK1 EP300SPRY1 EPRS POU2F1 UQCRB VPS45 PLCB3 PIGU GYG1 HSPG2 FBXO11 S S 18 TFAP2C POLR2KPLA2G12B GNA1MR 4 P S 5 RALB CPSF3 CREB1 R N F4 PAAF1 ICA1L NECAB3EIF3B ZNF70 SLC9A1 M A P 7D 1 DAXX MPDZ FOXO1 TUSC2 AAK1Z N F 7 6 ITSN1 PRKAR1A KLF3 DLC1 TAB2 BPHL MAPK8MAPRE1 ST3GAL6 PNP MEIS1 TRPS1 T ME M1 4 C MFGE8GPD2COTL1 AVPI1 IGF1RGRB2 FRS2 GADD45GIP1 GTSE1 SLCO2B1MR P L 3 8 AT F 3 FGFR3 ETHE1 RPS6KA4MBNL2 PDF M ED 28 HADH GORASP2 VGLL4 TAZ ETS1 DHX34 KIF19 APC GLI3 S F X N1 STK10 CACNA1CCDR2LHDAC1 VPS37C P IN 1 HIF1AN SCMH1 PPFIA3 MRPL53 NFATC1 RBM17 DNAJC5 ENC1 RNPEPL1 RPN1 PEPD PRKRA RAB2A PRPF 3 1 EGFR HGS PTPN14 RPN2 EIF2S2 IGFBP3 RB1 CTNNB1 VHL FLNA AIMP1 TCOF1FOXK1 MAP2K7 SLC35C2 KLF10 Z N F 5 7 6 TMED9 C1orf115 ATP6V1H HIF1A SLC41A2 ZADH2 FASTK MLXIPL PRIM2 CYB5D2 ISOC1 COX7C MLEC ARHGAP24 AP3S1 Z N F 5 6 3 CACNB3 CTRL C1R GLIS2 ZBTB7B M D M 2 TIMM8A CDK16 HMGCL GLYCTK P I M 3 CRELD1 I D 3 MAP3K12 GPR89A ID 2 PAX6 ALAD CUX1 ACOT13 PSEN1 PLK1 SOS1 ANKRD3 9 MA P2 K 4 FYN CDH1 ARFGAP1 GRAP2 The result identifies edges and nodesAP1AR EREG TBP YWHAB SIGMAR1 KLHL15PSMG4 POP5 CTNNBIP1 GUK1 SCP2 STAMBP AIP BRF2 ARNT ERGIC3 D D X11 EZR P KP 4 GRHPR PHLDB1 MALT1LAMB1 SEC13 GET4 involved in miRNA signalingNUDC CDKN2A VCL CRYL1 COPZ1 IPO13 SP3 HRAS FASLG HLTF ECE2 NFE2L3 NCF4 DOK1 ABAT TARBP2 TPCN1 SPRYD3 SEPN1B3GAT3 M Y O 1 G TULP3 C 2 1 o rf6 2 RPS6KB2 CNDP 2 CABIN1 KCTD11 SLC35D1 ALDH7A1 RAVER1 SOX5 G LI1 MIIP VCP EIF 3 I HM GA1 CNPY2 DLGAP1 HES4 ARHGEF18 KCTD1 TAF10 SSFA2 SUFU FAM65A ZNF532 Z N F 1 3 8 DHPS CDK5RAP1 DLG4 EIF 6 BANF1 P DZ D2 NCDN FUT8 YIF1B W D R 1 3 PSMD7 MID1 IP1 MAP3K1Z N F 1 3 3 SFXN2 ARMC9 RUNX3 ACADSB ELK4 MITF CLIC5 S A M D 5 IQGAP1 LMNB2 APOA5 C2 SOX9 ELF2 SEPT8 MAF PIK3CA ALX1 KCNA4 CTCF NRARP POU2F2 RHOJ C H M P 6 ZEB2 CALR MRPL9C20orf112 SEC11C CENPV FRG1 ABHD15 CDK4 ADIPOR1 CLN6 TMEM200A TSNAXIP1IL1 5 RA MED8 RNASE4 CYB561 LEO1 TUBB2A COPS6 ABL1 MS R B 3 PDXP VIPR1 NAB1 EPO EPHA2MGAT3 CTBP2OTUD7 B DYRK2 KIAA0391 KEAP1 MCAM FBP1 T N S 1 CCDC15 ENAHPLEKHA4 RABL6 CCNE2 C 1 0 o rf8 8 GTF2IRD1 HOXB9 SAT1 TTC16 GADD45A POR SLC25A3 MDFI M E D 3 1 C20orf24 GLRX3C5orf54 S MAD3 LARP4B MED10 PKM EPOR SULF2 BGN STEAP3 ZWILCH TREH FANCF TPM4 ATP6V1F Z N F 6 2 2 RHOBTB3 PHLDA1 UBL3 ABCB8 ALG1 EPX ATP1B3 NUDT7 MY D8 8 C 1 o rf2 7 F A M 4 6 A PRELID1 M R P S 2 4 SEPHS1 SLC41A1 TBC1D10BW D R 4 5 NUCB2 DUSP4 CC2D1B MAT1A TNFAIP8L1 hsa-miR-21 IFT52 CFLAR PFDN6 CCDC86 PMPCA NFIX S100PBP SPIRE2 MRPS15 AHR MTTP RAF1 TAF9 GFRA1 SRRD EIF2B5 P S M D 1 4 MAPK14 PPP1R3E RORA MYO9B SORBS2POLD4 Z N F 5 7 2 METTL9 TSEN3 4 M AP2K3 FSD1L RP S 1 4 SSR4 VASP SYVN1 ELMSAN1 TMEM183A PIK3R1 RARA ADRM1 LYPLA2 COX 4 I1 DUS1L ACSM3ZBTB4 LMO7 CIZ1 ATF2 P S M D 9 C10orf12 ALDH2ADH6 MR P L 2 2 PFDN4 PHF21A ILF3PRSS23 C15orf39 TM EM 51 UBASH3B C 1 o rf8 6 M D H 2 GRK4 GPRC5B AT P6 V0 E1 EDC4 ALDOAPCNA SPTLC1 MAP3K6RPL27A HNF1A CDK1 0 M A P 2 K 2 SERPIND1 K IA A 0 1 9 5 MAP2K6 FBXL19MRPS3 1 ACAT1 RAC3 SEC61G TMEM173 LRRC45 PCGF1 KAT2B CNKSR2ASPDH ARPC3 CHPT1 hsa-miR-10a KLHL2 1 BRMS 1 MICALL1 H E M K 1 NNMT RPUSD3 CKAP2 DEF8 Z N F 5 1 7 CYP27A1 MRPL39 C 1 5 o rf4 0 MAP4 SCML2 F IT M 2 PLEKHG5 PELI1 MAP3K7 EHMT2 NES KLC1 PPIARXRASEPHS2 RPS8 AXIN1 CAPRIN1 HAPLN3 GBA PJA1 YWHAG IRAK1 HSBP1GOT2 DLX4 CCND3 TALDO1 PGM1 RUVBL2 BAK1 CTTNBP2NL FOXA2 SLC25A42 SYT11 ARL4C MARK2 PNKP RGS10 CYP8B1 PSD4 TM EM 65 SACM1L BCKDHB STOML2 CGREF1 RCC2 NPEPPS TRAF6 ATF4 CRADD PEX13 TIAM 1 METTL7A MTCH1 BCL7A BHMT2 M E D 1 CDC34 NSUN5P2 PLAG1 NARF hsa-miR-10b ADCY6 ALDH8A1PYGO2 M T A 3 ZNF20 M ED15 S M Y D 2 SLC26A6 PHGDH PRDM1 ELF4 CYB5R1 IFT140 THPO ASPA FBXO45 RELB GPX8PNMA1 PDLIM7 TP53BP1 HDAC4 SDF2L1 TCF3 TFR2 MTORUBE2D3 LDOC1 C 1 1 o rf9 3 BTRC LRRFIP1 TPM3 SERPINA5 NCOA6 ARHGEF17 HAX1 RIPK4 F A M 1 8 4UGP2 A YW HAZ TBCE GLG1 ZFPL1 DCTN2 SMARCD1 Z B T B 3 4 GIT1 PML ACHE T HAP6 QARS GPR126 SLC6A12 DNAJB11 NFIA TM EM 165 PRR12 PAPOLA REL RARG M E N 1 EPHB2 GNE MFAP3L DENND3 RBPJ ABI2 ATF7RASGRP1 TPD52L2 ANGPTL6ACYP2 ECM1 AGXT FXN FLII FUS BAG2 MAP2K1TADA2B hsa-miR-192 CDKN1AKIAA0226 N R 4 A 3 RGS1 2 SOX6 BNIP2 CHST12 NFKB2 HECTD1 CSRNP1GAL3ST4 MSH2 DLGAP4 GPR124ACSM2B MYO1B WBSCR22 FXR2 PITPNM2 YEATS2 NUP210 PTK2 ASAP1 DMD S N W 1 LUC7L3 RNF 1 2 6 CTAGE5 MAOB SMARCA4 USP7 CRK PPM1A PTK2B FAM 129B BMPERFHOD1 OCLN WASF2 METTL5 EXO1 ESR1 GLB1L2ABCC1 MAPKAP1 C 3 o rf1 8 VDRKAT7 ADAMTS13 RASAL3 CREB3 C11or f 54 KLHL36 CACNB1 PPARA RUSC1 KBTBD11 CDC37L1 HDAC2 T A T D N 3 ETS2 ANKRD13BNAGS PRMT2LARP1BABCC10 C8orf4 S T K 4 0 G T F 2 H 1 RHEB NOMO1 TBC1D22B CDK5RAP3 SDHD NCOR1 M A F1 LHX2EXOSC7 SRC LOXL2 SP8 ML H1 GLTPD1 STRN4 FM R1 KIF5B PUF60 TANC1 hsa-miR-194 CBX4 FBXW 7 SLC25A20 CIDEB OSBP IKZF2 OSBPL3IFNGR2 KLF11 SALL1 PAHHOMER3 HDAC3 UBE2D1 WWC3 CFL2 PPP1CB SLC2A2 OLFML3 ACOX2 CHD1 BRPF1 ADRB2 CPEB3 COBLL1 F M O 4 NCOR2 DLAT GATAD2B HNRNPK CBFB CBR4 XIAP CASP3 BACE1 SCARB1 PPARG H S F 1 HCFC1 SUMO2 NCOA2 MANF ZNF384 PDK2 SLC13A5 T BX5 CCNE1 KHDRBS2 SAP30 PSENEN CBX1 RPTOR MED2 4 FBLIM1 TRIM24 BLM DIABLO FM N L3 CDCA4 AZGP1 LY6E PPIB CTBP1 SIN3A ING5 BRCA1 PIPOX APOB ATAD3BTCEB1 TNKS TM6SF1 ACTR3B FAM193A DUS2 L SNRPA KHDRBS1 BIRC2 PNPO UBE2I SLC1A3 KITLG LONP2 MR P L 2 8 M B D 3 CCNG1 hsa-miR-99b SP4 HTT I L 2 7 R B M 2 4 ARHGAP21 TOPORS FERMT2 ADK FMNL1 PTPN1 ZBTB16 SLC25A36 FGFR1 STK39 RNH1 TJAP1 TERF1 FBXO28 CCDC43 ITPKA NKX2-5 ERCC6HGFAC PBRM1 SCLY ACTR5 GALT ALDH5A1FAAH RAI1 N R 1 H 4 JUN ATM SM AD7 PRRG4 CCNT1 C1orf122 DBN1 TNFRSF1B SP5 PRODH2 SUOX SLC22A3 CBL AXL PHB AFAP1SP1NDRG2 S100A 11 TRAF2 BAD KLF9 PTS CDK2 DNAJC10 IVD SPRY2 LIMK1 SMAD4 C A D M1 PNRC1 TP53 C 1 7 o rf5 9 GCDH ZDHHC13 IKBKB LUZP1 PGLS DIRAS3 ANO9 CREBBPTMEM106C HNRNPU E2F1 PIP5K1C ADAMTS7GIPC2RRM2 NFKBIA M E D 7 BDH1 ECHDC2 SART1 FOS USP53 PDLI M5 MLKL SLC4A1AP STAT3 AR HBEGFTOMM40L C 1 1 o rf8 3 RBM34RALGAPB STAU2W D R 8 3 RMI 1 C6orf106 TDG MAP3K5 SAE1 CREB5 GCGR DHRS4L1 ZCCHC24 RELA CITED2 ZNF618PCK1 EP300SPRY1 EPRS POU2F1 UQCRB VPS45 PLCB3 PIGU GYG1 HSPG2 FBXO11 SS18 TFAP2C hsa-let-7a SLC39A7MR P S 5 CPSF3 POLR2KPLA2G12B GNA1 4 RALB CREB1 R N F4 PAAF1 ICA1L T IM M 1 7 A HDAC7 NECAB3EIF3B ZNF70 SLC9A1 M A P 7D 1 DAXX FOXO1 TUSC2 AAK1Z N F 7 6 ITSN1 SKI MPDZ PRKAR1A DLC1 ST3GAL6 KLF3 MAPK1TAB2 BPHL MAPK8MAPRE1 DBT PNP T ME M1 4 C MFGE8GPD2COTL1 MEIS1 TRPS1 AVPI1 IGF1RGRB2 FRS2 GADD45GIP1 GTSE1 SLCO2B1MR P L 3 8 ATF3 FGFR3 ETHE1 RPS6KA4MBNL2 PDF M ED 28 HADH GORASP2 VGLL4 TAZ ETS1 D H X 3 4 KI F19 APC GLI3 S F X N1 STK10 CACNA1CCDR2LHDAC1 VPS37C PIN1 HIF1AN S C M H 1 PPFIA3 MRPL53 NFATC1 RBM17 DNAJC5 ENC1 RNPEPL1 RPN1 PEPD PRKRA RAB2A PRPF 3 1 EGFR HGS PTPN14 VHL RPN2 EIF2S2 IGFBP3USP38 RB1 CTNNB1 FLNA AI MP1 TCOF1FOXK1 MAP2K7 SLC35C2 KLF10 Z N F 5 7 6 TMED9 C1or f 115 ATP6V1H HIF1A GRK6 SLC41A2 ZADH2 FASTK ISOC1MLXIPL PRI M2 MLEC ARHGAP24 AP3S1 hsa-miR-122 ACSL1 COX7C CYB5D2 Z N F 5 6 3 CACNB3 CTRL C1R GLIS2 ZBTB7B M D M 2 TI MM8A NKAP CDK16 HMGCL GLYCTK LCAT P I M 3 I D 3 GPR89A ALAD CRELD1 MAP3K12 I D 2 UPB1 CUX1 ACOT13 P AX 6 PSEN1 PLK1 SOS1 ANKRD3 9 MA P2K 4 FYN LATS1CDH1 ARFGAP1 BCL2L1 DACH1 GRAP2 COMMD5 AP1AR EREG TBP HECTD3 YWHAB SIGMAR1 KLHL15PSMG4 CTNNBIP1 POP5 SCP2 GUK1 AIP RUNX2 STAMBP BRF2 ARNT ERGIC3 D D X11 EZR P KP 4 GRHPR PHLDB1 MALT1LAMB1 UBL5 NUDC CDKN2A VCL SEC13 CRYL1 GET4 COPZ1 hsa-miR-30a PPAP2B IPO13 SP3 HRAS FASLG DOK1 HLTF SPRYD3 Z N F 5 1 2 B TMEM120A TULP3SLC35D1 CABIN1C 2 1 o rf6 2 RPS6KB2 EIF 3 I P B X 3 AK3 VCP FAM65A DHPS CCNT2 CDK9 PDZD2 NCDN FUT8 YIF1B W D R 1 3 PSMD7 GLS MAP3K1 CLIC5 S A M D 5 IQGAP1 PIK3CA PTH1RSEPT8 C2 ALX1 CDK4 FRG1 PDXPADIPOR1 VIPR1 TRIOBP N4BP2L1 MCAM FBP1 POR SLC25A3 PKM SMAD3 LARP4B ATP6V1F RAF1 C 1 oAHR rf2 7 IFT52 M R P S 2 4 P S M D 1 4 METTL9SYVN1 UBASH3B C15or f 39 CNKSR2 K IA A 0 1 9 5 RAC3TMEM173AT P6 V0 E1 MRPL39 KLHL2 1 PLEKHG5 YWHAG AXI N1 G O T2 DLX4 CCND3 TALDO1 PGM1 RUVBL2CYP8B1 TUBG1 TIAM 1 METTL7A MTCH1STOML2 BCL2L11 ANKZF1FHL3 SPRED1 ADCY6 HNF4A PHGDH S M Y D 2CYB5R1 MLYCD MTOR TFR2 HDAC4 RIPK4 SERPINA5 YW HAZ PRR12NFIA ELK1MAP2K1 ECM1 BAG2 CBX5 WBSCR22 LUC7L3 CRK CTAGE5 SMARCA4 KAT7 METTL5 RASAL3 RHEB CDK5RAP3 S T K 4 0 KIF5B M A F1 STRN4 OSBP COBLL1 SLC2A2 ZNF384 FBLIM1RPTOR PRCC AZGP1 DUS2 L PIPOX ENPP1 TM6SF1 ALDH5A1 BAD CCNT1 C 1 7 o rf5 9 LIMK1 BDH1 SMAD4 C 1 1 o rf8 3 BCL2 T IM M 1 7 A HDAC7MAPK1SLC39A7 SKI MPP3 DBT AATF T AF 4 LTBP4 C1orf74 USP38 ACSL1 GRK6 PLXNA1 LCAT NKAP UPB1 LATS1 BCL2L1 HECTD3 DACH1 COMMD5 S M U G 1 RUNX2 H3F3A DHRS12 CT U2 UBL5 SERTAD1 PPAP2B Z N F 5 1 2 B TMEM120A PBX3 AK3 GLS CCNT2 CDK9 CAP2 PTH1R N4BP2L1 TRIOBP CEBPB BCL2L11 ANKZF1FHL3 HNF4AELK1PHLDB2TUBG1 SPRED1 CBX5 MLYCD PDE4DIP PARD3 ENPP1 BCL2 PRCC C1orf74 MPP3 AATF TAF4 LTBP4 ZFP1 PLXNA1 SERTAD1 DHRS12 CT U2 S M U G 1 H3F3A CAP2 PHLDB2 CEBPB PDE4DIP PARD3 NOTCH2 RAD54B RAD54B NOTCH2 ZFP1 GMPPA LTBP2 VIM GMPPA HAO1 CHCHD7TSSC4 LTBP2 R B M 3 9 CAT SKIV2L CACYBP VIM CHCHD7 SAA4 DCAF8 NR4A1 R B M 3 9 PANK1 SNRNP70 MTMR2 JAG1 GSK3B HAO1 TSSC4 FKBP1A TUBA1B RABGGTBPLSCR3 CXCL12 ZNF5 8 1 C 1 7 o rf5 8 TCFL5 N R 1 I 2 Z NF 1 9TOLLIP 7 CATCDKN2CCOL18A1 SLC10A1 SKIV2L AGMAT T M E M 1 7 6 A H S D 1 7 B 4 XRCC6 CACYBP PCK2 OGFOD2 SEPP1 DNMT1 CPB2 M T H F D 1 KLF15 KAT2A UBE2F SERPINC1 ITIH1 RNF24 DCAF8 AADAT TEAD4ABCC9 NR4A1 SAA4 TBXA2R SARDH ORMDL3 GMIP NDUFAF2 MR P S 7 TBRG4 GPX1 XRCC5 NT5DC1 DNAJC18 TRIM28APOH ANKRD13D T M E M 1 0 4 MTMR2 ETFDH JAG1 PANK1 ACACA SNRNP70 CYP4A11 ABCG8 GLYATL1 NAT2 GSK3B FKBP1A TMEM14A EPHX2 H S D 1 7 B 6 ACSM5 SLC6A1 CDO1 RABGGTB TUBA1B T ME M7 9 C 1 2 o rf7 3 PLSCR3 PEBP1 ARL6IP4 PACS1 ASGR1 H M 1 3 COIL PHACTR3 TGFB1I1 TTC38 DEAF1 PLEKHO2 EHHADH C 6 o rf8 9 CXCL12 ANTXR1STX6 MS TSPATS2 O1 PCYOX1 PROC PUS1 DCAF11 FTL ATP5E V A C 1 4 TCFL5 N R 1 I2 PYCR2 SRM TOLLIP APRT ZNF5 8 1 C 1 7 o rf5 8 KCTD10 CPN2 SYDE1 NME6 TFG ALB Z NF 1 9 7 CASP2 CRHBP ATN1 ACADM INTS1 TMEM2 0 8 ASCC2 RAB31 CDKN2CCOL18A1 ENTPD1 SETDB1 AGMAT T M E M 1SLC10A1 7 6 A XRCC6 RPAP2 HSD17B4 PCK2 FUNDC2

S100A10 OGFOD2 SEPP1 DNMT1 CPB2 NSF M T H F D 1 KLF15 24 KAT2A UBE2F SERPINC1 ITIH1 RNF24 AADAT TEAD4ABCC9 TBXA2R SARDH ORMDL3 GMIP NDUFAF2 MR P S 7 TBRG4 GPX1 XRCC5 NT5DC1 DNAJC18 TRIM28APOH ANKRD13D T M E M 1 0 4 ETFDH CYP4A11 ABCG8 ACACA GLYATL1 NAT2 TMEM14A EPHX2 HSD17B6 ACSM5 CDO1 T ME M7 9 SLC6A1 C 1 2 o rf7 3 PEBP1 ARL6IP4 PACS1 ASGR1 HM13 COIL PHACTR3 TGFB1I1 TTC38 DEAF1 PLEKHO2 EHHADH ANTXR1STX6 MS TSPATS2 O1 PCYOX1C 6 o rf8 9 PROC PUS1 DCAF11 FTL ATP5E V A C 1 4 APRTPYCR2 SRM KCTD10 CPN2 SYDE1 NME6 CASP2 CRHBP TFG ATN1 ALB ACADM INTS1 TMEM2 0 8 ASCC2 RAB31 ENTPD1 SETDB1

RPAP2

FUNDC2

S100A10

NSF Each cancer can now be represented by network

T ME M119 PTK7 L S M6 MAP 3 K3 GNG11 IPPK ANKAR PTH1R TNFAIP8 MYADM MLX SACS WIP I2 PAX2 PFKP SEPHS1 CCDC137 TBL3 MED13L ITGB8 ABTB1 RAB11FIP4 NFE2L1 PTPRE SO X6 KIRREL GRM8 MAPK8IP1 C1or f 159 ZBTB6 ISL2 SHOX2 PLAG1 SALL2 D2HGDH QSOX2 TSC22D4 PTP4A1 NEFL KIF26B STAT5A BNC2 MLXIPL CYTH1 CHFR T DRD10 MRPL9RAD51AP1 GNAI1 VPS13D INTS1 CNOT4 MRS 2 K IF17 ARHGAP17 COPS6 F Z D7 T RIM2 RAP2B BNC2 HO XA1 MYADMIFFO1 UBAP2 ELF2 GCH1 KIAA0368 ZYX CPA1 SALL2 MYCN C12orf52 HOXB9 DYRK2 ATF7 ESR2 NGF NTN4 TSC1 FLJ43663 SAV1 SAT1 CKAP2L ITGB2 PCNX CSTF2 GARNL3 TYMS AGAP2 SEC23ACHEK1 PAM Lung IQGAP3 FX R2 MDFI MAX SLC27A1ARF1 NGFR P OP 7 TGOLN2 PLA2R1 CLCN6 LATS1 CPOX TEF CACNA2D2 T HAP 2 FAM72B R IN 3 KIF22 MCM2 NTRK1 PLIN3 FAM103A1 PTBP1 ABI2 F AM 8 3 D CCNYL1 ABCA10 GRIK1 KCNA4 TACO1C14orf80 PARP1 ICA1 THAP7 SYNE1CLIC5 HMMR RTN4 ST5 LRRFIP1 RCE1 THOC1 PTMA S NX 4 NEK2 ACTR5 T P 5 3 I1 3 HCN1 C10orf12 ANXA6 TSC2 Breast EGR2 C2or f47 TNFAIP3 SN H G 12 P T P N1 2 SUV39H1 H2AFX LDOC1 RPS6KC1 ROBO2 DNAH14ATG4B ZFP36L2 DLGAP1 RHBDF2 RASAL3 PLSCR1 LIMK1 KCNAB2 SPC25GTF2IRD1 SERF2 ALOX5 RAP2A MYOCD SS18L1 ZC3H3MYC SHANK3 W D R 85 HCN2 TROAP PPP1R9B NGF HIP1R AXIN1 EIF2S2 ABL1 CDCA7 KIF1C NFATC3 MCM6 CEP250 STXBP2 LAPTM5 PLD1 KNTC1 RAN MTOR SHCBP1 ADAMTS8 DLG4 PRC1 ZNF653 I R F 1 CBX8 STK16 EHMT2 PDE1B SYT4 ARHGAP39 ARHGEF3 HNRNPC ZNF423 PAICS ELK1 GLI4 PDLIM7 BIN1 LARP1 CHRM1 HLA-E ZNF282 RIOK3 TNS1 HGS CFL1 RPS6KA1 TBK1 SCAPER P P M 1 F SLC8A1 ZYX REV1 FXYD1 STAU2 CPE MASTL CKAP4 ATHL1 SLC7A7 RBM10 TUBB KIF4A SPAG4 NCKAP1 NAALADL1 SLC24A6 LRCH1 CCDC150 RPS6KA2 WAS SOCS3 HSD17B10 DUSP1 PEA15 AFAP1L1 FOXP2 GLI1 HDX HBEGF NFE2L1 TJAP1 Z NF 598 KDELC2 UBR3 KBTBD7 RALGDS HNRNPAB RCC2 MAP2K3 VEGFA RUNX2 SUFU KIAA1 5 4 9 C2orf44 BTG1 BTG2 C17orf70HNRNPF ATF2 FOS BNIP2 SBK1 TBKBP1 CDK17 USP13 RHEB SGOL2 JAK2 ABAT GTSE1 Z C3 H6 ZFP36L1 CAMSAP2 SAR1A RCN3 SH2D1A IRF7 ZBTB16 C10orf10 ATF4 APCDD1 PDIA6 TUBA1B SGTA NCAPH KIF2C NLRX1 MAP 3K1 CORO1C ITM2B FASLG RALAYWHAZ SLMO1 PROS1 PR D M 1 PSMC4 HNRNPLMAPK1 GRASP KTN1 SHANK3 DCP1A KLF3 STARD13 STK19 PRUNE2 SAMD1 PRCC MBNL1 HPCAL1 DLC1 ECE2 FANCICPNE8 XR N 1 FICD TGIF1 PLK4 PTPN4 VLDLR CNKSR2 SOCS1 CRADD MAPK14 NTRK1 CD74 RFC2 PSRC1 PRCD PIK3CA YWHAB TOB1 FMR 1 UBE2B TNFSF9 S T MN1 TSEN34 ITGB1 C22orf39 TUBG1 NCKAP1 CCDC9 FBP1 RNF186 STARD8 MRPL17 DTNBP1 SDAD1 CREB3 SMAD3 CCT7 P KD1 DCTPP1 SIRT7 TM EM 189 MAP 2K4 NCKAP5 KIFC1 ARHGAP24 ZFYVE9 INSIG1 CRK GET4 SERPING1 CNOT8 TRIP 10 DSCC1 SEL1L PBRM1 TUBGCP6 VAMP3 GPR146 PRC1 POLA2 CRKL CHD4 SPN JUN MED31 HO X A9 ELK4 RASA3 ELK4 FUNDC2 RPS6KA3 RAB3IL1 E2F5 GORASP2 GARS GRK5 N4BP2L1 QKI ZIC3 M E D 15 Colon LMO 2 TCEB1 COMTD1MF S D2B ATP6V1F SOX13 DNMT3B CCND3 SP3 TRAF2 PHF17 PAG1 UBR3 PCYOX1 PDE2A MAP2K1 TBRG4 FYN EEF1D CHAF1A YWHAB CNOT6L HRAS ELK1 GATAD2B BEGAIN M O V 10 CFL1 STX4 CENPE LPL CNOT6 PCBP1 MAP2K1 Y KT6 SEC24C EPRSMKRN3 TSSC1 FLNA CCNG1 VAV2 FAS PTN RFX2 MAPK8 KIAA2026 KHDRBS2 DOCK9 JAG1 T PX2 KCTD5 RAF1 HIVEP2 T M E M 2 0 9 E4F1 LUZP1 PIK3CD CHD3 Z MY M2 ULK1 COPS7B MEIS1 GLI3 M T HF D2 UBE2D2 N TN 4 TNFRSF1A ECSCR OASL STEAP1 PSMC5 RAD18 LARP1 MT MR10 PECAM1 PBX3 RAB11A PCMT1 MAPK1 TANK CLDN11 UBE2W FXR2 KLF4 ZFYVE9 MAST4 CELF1 DLX4 MRAS CHMP2B KIAA0101 FAM58A TBX5 AXL STK10 STX3 CTSL1 GATAD2B CDK10 PLXDC2C12orf45 HCFC1RANBP2 CASP3 SH3BGRL TOB1 RMND5A PPAP2B PSMA5 STK19 CBX4 ABTB2 PTPLAD2 TCIRG1 SREBF2 MRPL3 FAM103A1 PR D M 2 EED KIAA1377 PLEKHA8 CNOT3 RHPN2 IL27 POLL DOK4 PTRF CYTH4 CDK4 PLEKHA8 MAP2K6 DMPK PLEKHG5 BRIX1 SLC22A17 D VL 3 C20o rf24 ARHGEF7 UHRF2 L M NB1 TME M63B RGS2 HIVEP2 PHB PSMD4 TUBG2TPX2 YWHAZ RBMS2 MXD3 SNAP23 NOTCH2 CXCL12 UBE2B IGF1R TFDP1 ACTR3 BMF RAF1 EZH1 ERGHBEGF PO U6F1 CDC14B CDH24 UBE2I UBE2N APBB3 MET PCNA CCDC102A NFATC4 ZFAND3 GPR4 CREB1 SHC1 RALGDS BAD PCSK5 S NX 3 3 CDKN1A BEGAIN PRKG1 KIF20A POU2F1 FUBP1 SIRPA FOXF2 CD2AP SOS1 PEA15 RYR1 KI F15SATB1 NCAPH D D X 1 1 LHFP MAP 4K3 GRIN2A VHL PLSCR1 MFSD7 THBS1 M BD3 MNTPMP22 PYGM MAPK10PURA YBX1 PSM D12 S MAD1 MEO X1 JAM2 ASCC2 TAF12 SLC25A19 RBMS1 W ASF3 TBX5 SEPHS1 PRKCDBP DNAJB11RBL1 SRPX PPP1R13L UNC13B GPRASP1 POLR2D PRNPERCC6L NR4A1 ARHGAP21 SMAD2 SMAD9 SP8 SRPX SUMO1 TRADD HDAC2 NOL11 ATF3 CDKN2A UBE2K AHNAK XIAP ATP6V1H N4BP 1 REPS2 MB D 3 CTBP1 CAV2 TBKBP1 AHNAK USP35 HJURP SLC12A4TAF15 RUNX 3 M AP2 P KD2 PUS1 TMPO MRP L9 FEN1NKX2-5 POLR2C C1o rf173 LE MD2TGFB1I1 SH3PXD2A STX3 FLT4 PLK1 DAZAP2 FKBPL ECE2 NFE2L3 NCF4 LYNX1 DICER1 PNO1 LMCD1 ARHGAP23C20orf112 FGFR1 Z NRF 1 SRCIN1 KAT7 LOR TNFAIP8PSMA7 TINAGL1 ABAT TCEAL4 CALU S IK3 RASSF5TERF1 STK25 SKIGNAQ BCL2L1 STX1A CELF2 TLE1 RET CDK2 SP3 TARBP2 PM P2 2 ARHGAP33 DIXDC1 HLTF HRASPAPLN T IMM17A PLS3 AP1AR PAWR SPPL2B PDGFBTOPBP1LDOC1 CREBBP ALX1 RNF11 FRS2 MTA1 RBL1 Z N F 2 1 7 TPCN1 YLPM1 LOXL1 TAF15 BCR HEXIM1 SATB1 B3GAT3 M Y O 1 G GEMIN7 TAF4 EHBP1L1MVP HSPB8M D MNOTCH4 4 RAPGEF4 SPRY2 POLA1 SEPN1 TBK1 MECOM LRFN4 PPP1R12B SLC9A3R2ELL ITPKC SUFBXW11 M O 1 EGFR GAN LIMCH1 SOX6 PO M T2 CRCT1 USP6NL HIF1AN N K X2-5 CNDP 2 BOK SP8 ZNF775 GSK3B PEAR1 TCF7L2 BCL11A RANBP2 FBXO28 BCL2 ABCE1CBFA2T3 SKIV2L BRF2 CKS2 GATA1 ZBTB16 SF3B3 PBRM1 KCTD11 UCHL3MYO15B CDKN2A SH2D3C MAPK8IP3GAS7 RNF20 CNOT2 Z F C3H1 TNFRSF14 H6P D CEP68 CBLSPRY1 ALDH7A1 M S H 2 DHFR OGFOD2M BD4 CHST7TOPORSHIF3A TBC1D17 TBC1D1 CHD7 CNOT8 BTG2 W D R 8 1 NR1 D2EEPD1 ZFPM2 MYC MBD4 RAVER1 SOX5 G LI1 LEPR RASGRP3 FBXO11 CLEC11A DEAF1 MIIP SAT1 C1QTNF6 M D M 2 PRELP RUNX1TNKS CHUK SOS1 MAP 3K5 TAF12 THOP 1 CCDC130 HYAL2 M X D 1 CBFA2T3 RCOR1 WHSC1 KLHDC8B TMEM200B ETHE1 ME D28SPRY1 USP6NLSUZ12 BTK SRRT TARBP2 TANK SPOCD1 KLHL20 ATM HO XA9 LMBR1L SAMD4ATIMP2 TFAP2C PTP4A1 FHL2 CDK9 HM GA1 CNPY2 EXO1 ANO 9 TMTC1IRF7 P INK1 TP53INP1RAI14 SMARCD3ACTB PKMYT1 P GAM1 TBP M E N 1 EGLN1 DLGAP1 HES4 TES RNF 4 0 IKBKAP VAMP3 RBM38 MSRA TXNIPFAM136AMYO15B APEX2 FLI1 RAD18 QARS SUB1 ENTPD1STAT3 UBE2D1 STX2 IPO13 HOXB9 C11orf84 ESPL1 TPO NR2F1 TRAF2 MECOM KCTD1 TMEM87A SCML2ZFYVE1 AFAP1L1NPM1 PTPN21 UBA1 MAP4K3 STX4SMAD4 MPRIP V I M GRB2 ARHGEF18 HO XB3 Z H X 2 PLEKHM3 APBA2 MAP2 FRS2 EHBP1L1 BCL2L11 B3GNT5ZN F821 SLC35A2 PYGO2 DPYD SSFA2 P IN 1 CNOT3 OAF FAM126A SH3GLB1 EXT1 RB1 TAF10 BCL2L11 NUMB M LH1 MBTPS1 SH3BP5SYDE2C20orf24 RET Z I C 3 TUT1 E2F6 SNRPA1 AGXT2L2 HIF1A DST UBE2I W T 1 TM U B 1 USP7 CIRBPCARD10 RBMS2 AVEN CCNA2 PLXNA4JOSD1 E2F5 SUFU KIF20B PPM1D BLM PIP4K2A CCDC85B C20orf194 RABIF CARM1ZBTB48 PREB GABARAPL1 MRP S 2 6 PIK3IP1 PHB PRPF40A ZNF532 Z N F 1 3 8 MAP3K7 NONO MCC FES ITPRIP KAT2B QARS LATS2 SO X2 GATA6 AIMP2 BACH1 EZH2 RORA CYB5D2 GINS 3 RTKN CITED2 PTPN1 U2AF2 HDAC1 CHD7 CD82 CALHM2EGLN2 BRIP1 UBE2V2 EDNRB W I P F 1 W IPI2 STX11 SIN3A CDK5RAP1 M X D 1 E2F1 CAT ROBO4 NKRF SNRPG MYLK EIF2S2 MA ML1 STAT5B P S MD1 CTCF TBP TBC1D3 DT X2 PRR19T Y W 3 ABCD4 SCN2B SNRPC SMARCA2 MOGS FO X N3 M X I 1LMNB2 C1 6 o rf9 1 CCNT1 DLG4 EIF 6 BANF1 CTCF NUDC SOCS3 FAS ASPA EHD1 FASTK FGF1 PLD1 CORO1C C11orf24 KCNA4 S M N 1 DNASE1L3 ERCC6 NCAM1 NFKBIA ME D 8 POU5F1 RNFT2 ACTA2 TCP11L1 TP53PCIF1 ARL4C P S M B 4 ARHGAP31 CDC34 W I P I 2 APH1B SP1SIPA1DIRC3 S100A10 JAM3 EGFL7 KLF11 SNAP23 HDGF EGFR SEC14L1 CIT HDAC1 ZGPAT PB X3 SLC25A38 ARID5A TAOK3 NR3C2 TUBB6 VSX2 MEIS2 TSPAN17 GIPC2 MID1 IP 1 GRIK1 ATF4 DBT MAP3K14GRB2 RASGRP3 RRAS DLGAP5PSMB2 PPP1R1A ARHGEF15 Z N F 1 3 3 SFXN2 ARMC9 RUNX3 ACADSB ELK4 MITF ELF2 GTF2I ENY2 SMAD7 ATF7 DNM T 3 A CBFB SO X9 NSF PPP1R9B ANKRD44SPTBN1 T P M 2 RASA1 CEBPA EDN1 PRDM8 ZNF1 9 7 ANXA1 TACC3 BRF2 S I M 2 TFDP1 MAP3K14 PDGFRA C 15orf39 HMG B1 CHL1 TUBB3 ARHGAP31DDX19A MAFB COPS6 AXL CHPF2 LRIG3PNKD FAM171A1 EIF2AK2 RSU1 LUC7L C D 68 SOX2 AXIN1 GSK3A FOXO1 PKN3 RAPGEF3 PRPF19 HTT T ME M65 CTNS GMEB2LAMA5POGZ BRCA1 SPRN REXO1 PTPN9 TTC7A TGFBR2 PLCG1 SLC9A9 DOK4 ARHGAP4 ARID4B Z CW P W 2 AURKB LMNB2 APOA5 MYADM M D M 2 ERCC6 MA P4K 4 ADCY4 SLC1A3 SETDB1 TFAP2C JDP2 SLC35C1 DEPDC1B GPR75 EFEMP1 CACHD1 MEIS2 BCL2L1 PSMD11 GRB10 NARF CCDC137 REPS2 GIGYF1 PPP1R14B HLF PAX6 CHMP1A UBE2NEP300BCL6 ACTR2 SEPT9 T OMM3 4 SLC35B2 ELF2 ORAI2 W W C2 ADRB1JMY ZNF449 JAK2 FOXF2 GRIPAP1 MDFIEIF3B SAT1 SHFM1 CBX3 ARNT CCDC82CLCN5 KIAA0907 W DR6 2 SOX9 MAF PLK1 ATIC RELA PILRB XPNPEP3 ME D 10 LSM12 CPSF1 P DIA4 M X D 4 C8orf76 PFN1 ELLP I N 1NPM 1 RAPGEF1DENND5A KIAA0907 DAXXCAV1 FAM50A ARFGEF1 CYB5R3 T ME M138 LAMC1 ZCCHC24 P 2RY 6 TNKS1BP1 SEPT4 EMP3SOX5 SEMA4C EWSR1 PAX6 CPSF1 DUS4L TGFBR3NAA10 CAP1 UBE2V2 YY1 KHDRBS1 L E MD2 SRSF11 PNP EBF2 CDH23KCNA4 PCNXL3FANCA NR5A1 M K I6 7 CTCF NRARP POU2F2 RHOJ C H M P 6 RASSF2CDK5RAP1 TNKS HJURP MEMO1 STXBP6 PMS2CL FZD1 CRK YAF2 BUB1B MAF CYBRD1 ATXN2L CDKN3 IKBKB ARID2 DAB2 FHL1 CEBPB T W F 1 TRIM28NOTCH4 NUTF2 ADA SH3BGRL CASP3 SCAPER FBXL3 DBN1 STARD13 PAAF1 M APCNKSR2 7D1 RRM2 ERG PTRF TAZ TCP11L2FAM13C NR4A3 ME D28 DSE LIMS 2 ZEB2 CALR RPLP1 KPNA4SIN3A PTGER4 C16orf59 LATS1 DGKZ NDN APBB3 ACP1C20orf112 PPP4R4 C7orf25 PLA2G4CTP53INP1BACH1RAMP2 ATXN7L3PJA2 KANK3 KLF13 ARHGAP6 AASS GLRX3 USP20 ADPRH E2 F1 B4GALT3MRPL9 CORO2B ARIH2 CCAR1 ZCCHC24 CCSTBL1X RUVBL1 ZBTB5 IGSF9 MRPL9 C20orf194 RAB8A CRIM1 CCNB2 PLEKHG1 BACH2 WHSC1MAP3K5 COL14A1 ACTL6A SEC11C CENPV ABHD15 SEC31A FST CUEDC1 I L16 SERF2 CDK1 M AM DC2 AHRZ NF 6 7 2 CCL7 FAM167B EGR1 TNFRSF1B RAD9AHDAC3TMEM132AJARID2 CCT5 RBPJ TARDBP ODF3B KCTD12 DDX 1 9 A PHACTR2 CTSAPLSCR4ACSL4 MAN2 A2 SNX1Z NF 7 6 7 PSMC5 DVL2PABPN1 FBXO28 LRCH1 PILRA FAM 193B S MAD7 DDX19B ORC2 KCNA4 SELO CDC20 FAM49A MSRB3 ABT1 F AM127C CLN6CAPN10 TMEM200A ING5 M D M 4 MEF2C OGFR TGFBR2 LRRC59 RNPS1 ASAP1 ABCF1 HABP4 P P M1 G RNASE4NACAD CYB561SH3TC1TSNAXIP1IL1 5 RA MED8 COPS6 RACGAP1 TERF1 SOCS1 INSR SVEP1 CHRDL1 H M GA 1 OSBPL1A GARS NCKAP5L LEO1 TUBB2A F BX O11 RNF20 ARHGEF39GTF2IRD1ANKZF1 TMEM120B MAP 4K4 SOD2 DOCK10 GSE1 EML4 HLTF EDNRB IDUA MARCKSL1 COPS6 SLC4A2 ABL1 MS R B 3H EXIM1 BCL11A ELMOD2 PPM1F FAM129AUBE2D3 NCOR2 TSNAXSCN4BTBRG4 PRKRIP1 CHD3 TUBA1C WRNIP 1RAB8B RASA1 MOB2 ETS1 EEF1E1 KANK1 KLF4 PCDH12PARVA U2AF2AKAP2 NCAPG SNAPC4STX1A CITED2 ANP32E CRBN GLTSCR2 ZNRF1 DIXDC1 ME D1 5 EPO MEF2D CNTNAP1 ANKRD6ARHGAP10 ZNF212 SETD5S NAI1 Z NF 8 2 7 PREX2 XRCC5 XRCC6 NUP 8 5 CDT 1 AP1S1 SLC39A13 ATXN2L MAX TTC28 ACVRL1 T P I1CCNE2 NAB1 DLG4 CSNK1D S100A8 PPARG UHRF 1 AMOTL1 FKBP2 PPARG W D R 9 0ZNF239 DAZAP1 ADRBK1 DLG 4 COIL DNMT 1 KANK2 ARHGAP27 ARHGAP21 OTUD7EME1 B PLEKHM1EPHA2MGAT3 SUN2 G TF2H1 TNFSF9 ITPKB KLC2RHOT2 MTMR10 KATNAL1 CAV2 FR M D 6 ARPC2 XIAP ETV5ARPC5L HOXA4 CTBP2 MEF2C ARID3B PPP4C RAD51AP1 TFAP2C ABL1 C11orf63MRPL42 GNB2L1 SIPA1 KIAA0391 KEAP1 PREX1 OSTM1 FBRSL1 TLK1 CTSZAVEN CBX5SH3BGRL2 DYNLL1 DYRK2 PSMD7 CKAP2LATM DLGAP4 CBX4 NFYC DDX 5 5 NEK2 C16orf59 CORO6 TM EM 100 UTRNLMBRD1 IPO13 E 2F3FLVCR2 TOPBP1 IKBKB T ME M9 1 TRAF6 R R M2EIF2S2 FBXO45 CTSO CCDC50 SNW 1MAML1 EXOSC2 SVEP1 FGF2 MAP7D3 S O X 5 C12orf73 PKMYT1 FAM193B PPP1R13LZ NF 5 1 0 RAD54B RBM23 SCAF1 PTPRB KHDRBS1FOXF1 DLGAP1 MBD1 HOXD9 Z M AT 3 S TX 6 TXNRD1 T N S 1 RGL1 L S M 4 CCDC15 ENAH PLEKHA4 CAMK1G FEZ1 D VL3 RBL2 TRAF2TIM P 2 ELMO2 QRICH1 ZYG11A PRPF38B HDAC4 ADCY4 LSM14B PAK3 ROBO3 RABL6 CCNE2 C 1 0 o rf8PURA 8 TAL1 TCF12 GTF2IRD1 EEF1G PSD DDX 19B TCEB1 PLEKHO2 TDG ALDH1B1W DR91 KLF5 LBR TIMM8A DCAF7 YWHAG SLC25A5 SPNS1 FANCD2 PIGU EGR1IRAK1 PIGK ITGB5 N R 1 H 2 GLTSCR1IFNAR2 RECQL ZBTB17 MSN ANKRD13DHIP1 R 3H D M 1 RAD51 POR GADD45A CENPO YTHDC1 RNF2 LSR MYCBP2 CENPO RRM2 DTNBP 1 TTC16 CCNT2 CRTC3 MORC3 TOPORS TRIM8 ME D 1 MS R1 MAML2SETDB1 PPAP2C SRCCAV1 HOXB9 PELI2 HTR4SAT1 T M E M 1 4 7 ZFHX3 NR2 F 1 PAPOLA WDF Y 1 COL18A1 HNF1BSNX8 RASGRP1 DBF4B ABI3BP HSPA1A CENPM CDH5 REEP4 UBE2CMDFI H M O X 2 C20orf24 GLRX3 SH2B3 TMEM140 NCOR1 LEPREL2 EP3 0 0 CCNY NR4A1 EPRS M E D 3 1 MED10 C5orf54 SM AD5 TP53NFE2L1 RTN4 CUL2 LZTR1 PTPN1 BMPR2T MOD1 STAT1ZNF692 EEF1G KLF9 ATP5G3 KLF13 KPNB1 HIST1H3A ZBTB17 SAP30L SULF2 SLC35C2 STEAP3 EPOR CDK9 LAMA4 Z F HX3 IRS1 PHLDA3 PAWR WT1 GADD45GTPI1 KIF18BMYO7A NFATC4ADPRHNOTCH3 EP400NL DCAF7 GYPC BANF1 SREBF2 BGN NRP1 MED8 PCNP SCN4BSTAM2 SMTN KIAA1462 DIXDC1M YH9 PCDH17 PHACTR2 ALX1 JMJD7-PLA2G4B EIF4EBP1 NDUFS 6 CCDC85B UBE2T EZH2 P OU2F1 TREH ZWILCH FANCF CKS2PTPN4 TSPAN4 SNTA1 ARFGEF1 ANGPT1 H3F3A CHS T11ATF3 SP1PSMC2T MC6 GGCT Z NDOCK1 F 6 2 2 TPM4 RHOBTB3 MLX REL IL1R1 NUP 98 TRIM28TMEM184A LEMD2 MPP3 CEBPB FLAD1 RAB11A STUB1 IL10RB EMILIN2 INSIG 1 ALG1 MLXIPL ATG4B PHKG1 PLXNB2ARHGEF17 LAMP2 PELI1 PPDPF KPNB1 RNF165 PDE8B FGFR2 ZNF598 CTU2 PGK1 PHLDA1 DAPK1 ANXA5 UBL3MY D8 8 ABCB8 EPX Z N F 611 GATA6 TRAIP SMAD7 CHMP2BATF1 ZNF25 FAM65AZ MNFATC1 I Z 2 SMARCD1 TCEB3B CCNY NCOR2 FERMT2 ATP1B3 F AM122A NUDT7KDR F A M 4 6 A PHLDB2 ABR BZ W 1 ARHGEF6 FAM 171A1 ZNF513 GMEB2CCDC130 ERGIC3EMP2 ALPK1 M E D 8 PHF20L1 SEC61A1 SPTBN1 PDF PRELID1 SIRPA PACS1SSBP3 LAMP3 MAP3K10 SCML2 CD302 NSUN5 NR3C1 SEPHS1PTTG1 NUP 2 1 0 SLC41A1 TBC1D10BW D R 4 5 DAND5 TPD52L2 CITED2 SS18 BRIP1 KAT2B MAF ETS1PSME3 NEURL4 MELK TIAM1 HDAC9 PPARG ADRB2MAN2 C1 TRPM7 FBLN2 DAXX NUCB2 TSHZ2DUSP4 CC2D1B MAT1A TNFAIP8L1 HSPH1 KPNA3 M AP3K5 VZNF1 I M 9 7 ADARB1 YWHAG THSD1 ZBTB47 RPL10A CSNK1G2 PMPCA CFLAR PFDN6 F IZ 1 LGI3 SMTN CALR PCMT1 STARD8 SNRPB KLF13 TOR3A UBE2D1 CBX7 ADAMTS10 CCDC86 MRPS15 GABARAPL2 NINL C15orf52 DDHD1 P2RY6 XR N 1 TLK1 RABIF JAG1 PLK1 KCNT2BAZ1B IRF1 HM GA1 AMIGO3 TENC1 TSPAN7EDEM2 CCNF NFIX KIF 2 3 S100PBP SPIRE2 DEGS1 TECPR2 GATA6 MEOX1 DOK2 NKX3-2 LMCD1 M E D 1 0 HIST1H4A AP 4 M1 MCOLN2 FGFR3 JARID2 FBXL19 GFRA1 MTTP TAF9 PRAF2DPEP2 SFTPCHEY2 HCN3 ARHGAP24 S1PR1ESR1 R N F207 AP3S1 MAP4K4 ANLN TLE4 H2AFY ARID5B SRRD EIF2B5 ZCCHC24 GPR124CCNT1 LMAN2ITGB3 PRKCZ G PR176ZNF414 DMD SERPING1 VHL PAMC7orf43 MCAM TUBA1C TIAM1 ELL SUB1 MAPK14SP4 PPP1R3E RORA MYO9B MRTO4 GTPBP2 BLM CBX3 PGAM5LMO2SELO S100A10 BCL2 IGSF8 SCAMP3 HNRNPL CALM1SLC36A1 KLF10 POLD4 Z N F 5 7 2 SLC35C2 ETV1 PLEKHH3 ILK RNF5CREB1 PPARA D LX4 RGS9 ZEB1 C21orf2 SORBS2 TSEN3 4 EMR2 TNIP1RAI2 G NB2L1LTBP4 AT X N7SKIV2L CNTFR TRIM37 C1orf172 NAB1 FXYD6 M AP2K3 FSD1L RP S 1 4 SSR4 VASP ATF3RANBP2 KIF4A PCBP1 RAD51 C1R GNAQ RPL26L1 V P S 72 CDCA4 FANCGSDC1 MATN2 GIMAP5 WT1CNNM2C 1 7 o rCHD4 f 5 8 STAT2 TCP11L2ADPRH RUNX 1 T 1 HDAC4W S B 1 ATP6V1F CEBPA CCND3 ELMSAN1 TMEM183A PIK3R1 RARA MLX TNS3 AP1AREEF1G KPNA2 CDK17 FLNA APPBP2 KDM5B SMARCD1 ARHGEF16 SNAI3 LRP3 M D M 4 T RP M2 LYPLA2 COX 4 I1 DUS1L ZBTB4ADRM1 AFAP1 GLI2 ENOPH1N O VAUBE2I 2 ANKRD13B FKBP2 UBQLN4 ATAD3B NR4A1 LLGL2 KLF2 ACSM3 SPRED2 SOBP SEPT9 EPAS1MED10 LENG8MEF2C BRCA1BANP SLC19A3 CRCT1NFIBVDR ITPR1 BCL6B PD ZD 2 TBC1D2B ESR1 Z NF 462 RNF165 CIDEB GTF2F1 UCKL1 CBX5 HSPB3 KCTD13 PER2KLF11 EEF2 ADAM 33 LMO7 CIZ1 ATF2 P S M D 9 LINGO1 ROBO4FGFR4 M AP4 CSNK2A2 VANGL1 STIP1 ME D 1 ORC2 RAD54L EPAS1 GRAMD1A KL C10orf12 ADH6 MR P L 2 2 SP4 AHDC1 SNRK C1 1 o rf8 4 GTPBP3 FAM20C RELT ESRP1 THOC3 ALDH2 PFDN4 E2F2 PDPK1 TOPBP1 XPO4BUB3 TRERF1SALL1EP300ZNF48USP7 FXR2 CREBBPCTBP1 CLIP4 MYLK C1orf216 LOR GNAI2DNMT3A NFYA DDX19B BNIP3L LTBP3 LTBP4 CENPA S AMD1 KATNAL1 PHF21A TM EM 51 ILF3PRSS23 TIMP2 KLC1 SPATA20EME2 CACYBPTANK PPARGC1B SMARCA5 PPP2CA ELAVL1 TP53 GRK4 C 1 o rf8 6 M D H 2 FBX W 7 CUX1 CALD1 FOXA1M AP4 CD3EAPNO TCH2 HIF1A PTCH1PPARA HAND1 SKA1 ZFC3H1 USP5 CHL1 TOPORS USP7 GPRC5B EDC4 BOC PTN CDC5L UBE2D1 ARL4C HIF1AN MAFB ANKRD35 RAP2B AIF M1 CCDC64 CCDC50 ALDOAPCNA SPTLC1 MAP3K6RPL27A HNF1A CMKLR1 PLAUR AMPD2 PPP1R13L ZSWIM4 PALLD NUSAP1TSC22D2 SRCSLMAP TAT ZHX1 HDAC5 IFNAR2 BTRC NSUN5 ARSB NTRK2 BUD3 1 MAP3K7 EIF2C2 CKAP2 CDK1 0 M A P 2 KFBXL19 2 SERPIND1 PBX1 ARNTNIPBL IL1R1 SUMO2 PSMD7 NOLC1 ACHE CTF1 STAB1BRD1 HS F 1 S M N 1 MAP2K6KLF3 MRPS3 1 ACAT1 MLXIPL NFATC2 DLG5 TRIB2 KAT7 M E N 1 TBC1D7 NFIB UACA ATP6V0B BRCA1 DPYSL2 S UZ 1 2 LRRC45 SEC61G PCGF1 CCNE1 AKAP2E2 F1 IFIT1 D VL 3 POU6F1 M IS 1 2 ADRB3 TRPS1 PTPN4 NRBP1 NPM 1GTF2H1 NFKBIA HBP1KAT2B CHPT1 ASPDH EGLN1 KTI12PIAS1PTPRM FCHSD2DUS1LB3GALNT1FANCI DKC1 ENY2SLC39A13TLL1 MEIS1 C20orf194 PLXNA3SLC2A4 HDAC9 CAMK2D BECN1 SMAD4 DT X1 SCML2 ARPC3 W D R 8 1 SYPL2AHRUTP14A CORO2B TRIP12 UBA1 PDE3BNFIA ZFYVE16ANKS1B EGLN1 MID1IP1 HEY2 PACS1 DENR CFLAR GOLGA3 LIG1 BRMS 1 MICALL1 NR2 F 2 PEX11G EGR1 ING4 SLC6A4 RSBN1 H E M K 1 PRDM1 PRDM2 HIF1AMRPL9 LAMB1BCLAF1 EPDR1ASB4 NR5A2 THSD7ARFX1 TCEB3B SELPLG PTPN21 SIRT1 NCOR2 STAT2 LIX1L FRMD4A SSBP1 TP53INP1 NNMT Z N F 5 1 7 RPUSD3 CKAP2 CDKN1A CDK2 RB1SLC35F6 HOOK2 SEPT9 GDF5 ASAP1 TOP3BCARD16 SAFB SLC39A1 SPAG9 CTCF DEF8 POLL PCNACYP27A1 NSF LAMB3 CRBNCDCA4EBF2POLR2A PO U2F1RAVER1 TARBP2 PRELP AJUBA ARMC9NCOA3 NCOA2ARHGAP11A UBE2T GNB2L1 LILRA6 EHD2 CTDSP1 C 1 5 o rf4 0 F IT M 2 KIF26B TMEM184C DDX23 MSL1 U FM1 PSMD3ATAD3A SH2B3 MDFIC PancreasMITF IFI30 E 2 F 4 GAS7 EBF1 Z NF 263 SMAD2 RRP1B TFG P IN1 MAP4 S CML2 TOX PAAF1 F2R PSMC5 GRIN2A POLR3H DAXX HAND1 SDC3 LBR HDAC3 BIRC5 BDNF GEMIN7 STUB1 PJA2 ARIH2 PELI1 MAP3K7 EHMT2 NES MYB KLC1 UHRF2 ATXN7L3B ARHGAP22E2F3 ASB2 EPRSTFDP1 IKZF2B4GALT6 NEDD4 PLAG1 PNRC1 M O V 10L1 B Z W 1 BCL2 NR2C2 KLF5 PPP1CB ERCC6 CDK4 CHD7 SEPHS2 C10orf10 GPX8MKLN1 KIF1B DCTN4 FO XF2 M AP7D1 MSRB3 S P 100 M X D 1TBX3XIAP ADD1 GLIS3 XRCC6 TRIM41 RNF4 CHTF18 EPB41L2 C10orf67 ZZEF1 BRIP1 PPIARXRA RPS8 HIF1AN MSN Z N F 4 2 3 N D U F A 1 2 LOC100134259ATP8B2CRKL NPAS4 ADRB2 GTF2I TRPV2 DOCK9 MAP2K6 ZFP36L1 PHF 15 CAPRIN1 HAPLN3 GBA NRXN2 SEC62PHF14GABBR1SP1KLF10 RTKN SUMO ZN 1 F37A FYN EPAS1F BX O1 7 GLG1 RGS5NR5A2 NCOR1 C20orf27 F BX O1 1 Z N F 710 CYP46A1Z N F 287 SSH1 M TA 2OSBPL5 SLC25A45 HEXDC UBA1 DNASE2 FBXW 11 IRAK1 PJA1 PRKCH ENC1 NAP1L1 CDH5 RPAP3 ATF7 GLI3 ARFIP2 F O X N 3 KXD1 RCN3 NRIP 1 WASF3 SLIT2 MAF L3MBTL3 RNFT2 IKBKAP HSBP1 FUNDC2 PUS1 NDN ACVR1 M AN1 A2 PAWR S NX 18 ISL2 POU2F2 E2F6 ZBTB4 WBSCR22 S100A11 SETD7 HMG B1 ATP13A1 BAK1NLK SFRP4 SH2D3C DENND3 POC1A M L H 1 CLOCK CHST2 ITGAM FOXA1 S MP D4 PRDM1 FAM13A CTTNBP2NL FOXA2 SOX5 SLC25A42 COX5ASYT11 RBMS1 ZNF24 TAF12 SREBF2 RHOG GANPCNXL3 NFKBIBS1PR5 BEST1ARNT PCNX KIAA0895L PKP4 NCOA6DBF4 EHD1 ATM RGS10 PDGFB CHMP2B MYLIP PRSS23 SFN HAND1 CDV3 RNF144AW T 1 TR IM 37 ANO6 TSEN54 CTNNB1 HDAC3 ARL4C MARK2 PNKP ZNF775SEC22C INSIG1 METRNL ELK3 CPEB4SH2D1A SUFU TAB1 SNRNP70 CENPT CDC73 M E DSM 1 A D 1 CENPI NONO TSFM PSD4 SACM1L PHB AKT1STAT1 SLC9A3R1LDOC1HTT FAS ATF2IPO8 CYP46A1DPEP2 ARAP3 HSPA1A ACTR3 TMEM41A STAT3 TM EM 65 BCKDHB RCC2 ORAI2 VHL MF S D 2 B NFIX EDN1 GET4 NR0B2 PRUNE2 STAT1 SH2D4B CHUK CGREF1 MED1SUV420H2 PURA EDEM1 HAT1 RFFL PEAR1DMPK VASH1 SO X9 PDSS1 NACC1 BCL2L1 RELA NPEPPS TRAF6 ATF4 CRADD PEX13 SYNRG E2F5BRF2 TBP CCNB1 ELF2 NXPH3ITGA8 M M P 1 4 MIE R2 IL4R BECN1 STK11IP DEAF1HDGF AZI 1 CDK5R1 KAT2B PDCL3 MDM2 SLC12A4 AKAP8L BNIP3FNBP1L UBQLN4RARA NR0B2NFAT5 NCOA4CD302 F E N1 PEX14 BCL7A RAB2APDE4B IL1A RBM19GSPT1 PCDHGB7 CHFRTCF7L1 CASP3 PSMC2SPATS2ELMO2 HMG20B SLIT3 NMUR1 AR NRIP1 IRS 2 BHMT2 CUL2 TCEB1 SIDT2 SIN3A UBR3 ZNRF1 TADA3 F Z D8 RBPJ EHMT2 TMEM185B MAST4 M E D 1 PLAG1 NARF AR ARHGAP10 SKIL METTL7AMLF1IP KLHL20 LYPLA2 NSUN5P2 ZNF624ADCK1 PTPN4 FLI1DCAF13POGZ CYS1 HIC1FBXO33 ETS1 COTL1 ANKRD12 TR IM 46 NFICNPLOC4 DNAJB4 ST3GAL3CTDSP2BRD8 NCOA2 CDKN2A T OMM4 0 PRKCZ CDC34 CAND1 RRAS ABHD8 MXRA7HDAC2EFR3A NUP 8 5 FASLGPAG1 SU V39HHDX 2 M IB 2 TYK2 IP6K1 LHFP NACC1 CCNF XRCC2 BLM PRKCI ALDH8A1PYGO2 REEP5 BAZ1B D VL 3 AMD1TMED7 SGTACCNY S1PR4N4BP1 HEYL RBMS1 GLIS2 NCOA2 S MC4 MAPK14 TM O D 1 CUL4B RBX1 TCEB3 RASGRP1XRCC6 ACVR2A IRF7APLP2 SUB1 FMNL1LCLAT1ITPR1 UBE2B FLNASIRT1 MAP 2 K3 EFEMP2 XRCC5 INCENP TEX11 POLD1 MAPRE1 LPL COL27A1 NCOA4DCC CREBBP DDX 4 1 M T A 3 SOCS2 TAF15 HEG 1 LARP1 BBX FA M 189A 2 PPP1R14B S N W 1 GIMAP8 ZNF668 APC PARD6A ZNF20 M ED15 PARD3B PLA2G12A HDAC1 APTX RP2 MRAS ITGB3BP U2AF 2 LARP4B PSEN1 UFC1GP RIN1 CSNK1G2 SAT1PBRM1 MED13LCTDSP2 SASH1 TNFRSF1AVEGFCARHGAP24 RANGAP1PDGFRB CACNB3 M BD3 AT N1 CDC45 GOT2 JAM2 HNRNPC CDH1 RAB1A ATF2 ARHGEF19MRPS21 MARK1SLC26A6 SBF2 FAT4ETS1 DAPK3RNF144BRASSF4MLLT1PTRF DENND1A ACOT9 PGAM1GMFB DNAJB5 THBD C10orf12 S MAD9 SKI PRDM1 ELF4 ADPRHL1 ATP13A1 PRPF40A ARMCX3 ANKRD17 TELO2 PDZRN3NCOA6LDB3 FZR1 VLDLR NEDD4 CREB1 GFER IFT140 THPO ASPA XRCC5 SULF2 ARHGEF3PTP4A1 ITGAV D D X 11 KLHL17 NUSAP1 NRG1 FBXO45 RELB PDLIM7 TP53BP1 RASD1 NUDT7 PAIP1 P IM1 GJC1 FNIP2 APP NTNG2 RELB RASIP1 PTPN14MUM1 TACC1 APOL3 ATAD2 CARHSP1 GPX8PNMA1 ZNF615 POLR2D CD81 W IPI2SCN8A TGFBR1USP8 MYOCD FAM171A1 NCOA6 LIMS2PABPC1LT NS 3 KCND2 CTNNBIP1 MEPTPN14 D10 NCOR1 RMND5A DDA1 HOX B3 ProstateACVR1 UBE2D3SDF2L1 TCF3C 1 1 o rf9 3 ZEB2 FA M 107A EZRKIAA0355 RAB18 CAV1 NCOA3 FANCG MEX3B APCGEN1 PRR11 PDZD2 SCN4B S TO X 2 NGFR BTRC LDOC1 TPM3 CBX4 SOX2 CXCL12 SYBU ERCC4RNF130 NCLTEAD4C17orf62RXRACSNK1G2 FASTK IGHMBP2 RELL2 NCAPG2 LRRFIP1 SLC30A5 ZBTB5 RELT RAB26 RAVER1 BDNF HDAC7MGRN1 LTA4H AURKB VDR TRABD SMAD3 PVRL4 PPP2CB NCOA6 ARHGEF17 HAX1 ACP5 KLHL20 KIAA1755DIABLO RGS10 EZH2 NUMA1 ITPRIP KIAA0907 FLNC MEF2BNB ADRBK2 Z NF 4 2 3 MEMO1 NFAT5 F A M 1 8 4UGP2 A TSC1 NCKAP1 STK19 ZNF219 CIC HDAC9 ZFP36L1 TYMS CTNNBIP1 BCL2L12 DGUOK HIVEP2 MOCS1 MEIS1 RRP12 TBCE COIL GLG1 RBL1 AP3B1 GTF2I W HSC1 TNKS2 AHR PRR24MGAT1 C10orf54 PAX6 KCNJ5 EME1 USP44 PRICKLE3 PPIL2 ITPR1 Z B T B 3 4 ZFPL1 DCTN2 GIT1 SMARCD1 NUAK1 HDAC2 ZBTB47 SH3GL3 HDGFRP2 GTF2I PPM1F PEX19 SLC4A5 PML QKI DIS3L MA P4K 4RYR3 EMP2MAPK14PRCC ZBTB47 CENPI ADCY4 CDK3ADAMTSL3 COIL PKP4 ASCC2 DP Y 3 0 ACHE T HAP6 QARS GPR126 M BD1 ZDHHC5 VASH1 MECOM PYCR1 MRPS2 ALDH1A1 POLR2DKIAA1755 DONSON VCL MAPRE1 EIF4B ZMYN D 11 MYB TERF1 SLC6A12 DNAJB11 TSC2 CPZ ZNF644 DOPEY1 TMCC2SATB1 BAG4W D R 1 9 USP33PPARGC1AC11orf24 IL15RA ZEB1ARRB1 FAM127A SHCBP1 T ME M1 3 2 A FDPS MYO 5B IRF5 MAPKBP1 EZR NDC80 APBA2 TM EM 165 ANKRD44GLRX CAPZA2THRAP3CDC34 EDNRBCOQ4 EXO1 ACAP3GATAD2B D H X 3 7 AHCTF1 PSEN1 FA M 107A GSK3B C19orf52 TEX11 ATF2 PAPOLA LRRC8E TM 9SF1RELAGEM U2AF2AQP1 NCOR2 C16orf91 CTBS NCOA1 KCNH1 SNX29 POLA2 MOGS JUN KIF20A REL GNE MFAP3L RARG M E N 1 ABI2 SMUG1 BEGAINSP3RUNX1T1 NOS3 Z N FBCL7A 26 ZDHHC8 SEC61A2 BAZ1B PLEKHM3 HOXA5 BCL2L11 EPHB2 TPD52L2 DENND3 RBPJ CCDC126RNF13 CBFA2T3 SPRYD3C12orf10 TBC1D5 TBC1D2B DSTYK GTSE1 FUNDC2 TBL1X UHRF1 RRP1 DENND5A RCBTB2 TRIB3 ZDHHC9 ATF7RASGRP1 FLII ANGPTL6ACYP2 SOX6 FUS IGF1R SPAG9 LYSMD3 HPS3ARL6IP5 C5orf24 W D R 1 3 DMXL1 M XRGPRC5C A 7 SEC61B CAPN10ARHGEF10L PIK3R1 T RIM 9 VAMP2PLCL1KIT RSPO1 CENPN GP N1 AGXT FXN TADA2B PABPC4 COPS6MYLK NUP 50 PICALMMOSPD1 RCOR1PHF3 MBD4 EEDBRD8 KLF5 KPNA6IKBKGKIFC3 C14orf132NFKB2 DSE FLT3LG THAP2 NECAB1 L3MBTL3 ACIN1 CLOCK GIPC1 NFKB2CDKN1AKIAA0226 T NS1 N R 4 A 3 UQCRB RGS1 2 SOX6 ELAVL4 KCNA4 ADPRH IPO 13 CCDC80C2CD2 MRPL23 FBXO32 DOCK8 CCNB2 LGI4 DSG2 NCSTN PAQR4 VDR MXD3 CRY2 BNIP2 CHST12 FUBP3 TAF4B C1S PCBP3 SRFHIP1 LY6G5B ARFGAP1 D 2H G D H CTNNB1 JUP ME D8 MAPK8 CHEK2 HECTD1 MTOR CFL1 BACE2 UBE2G2MITFMANEA TNFAIP8IFNGR1 ELMSAN1 CDH1 PW P2 PSMD2 TSLP NFKB2 RICTORCSRNP1GAL3ST4 PSMC2 I L6 YWHAB DAXX DPY19L1 HEY2 CHD4 NFASC T M E M 6 3 B MYO1FACADLTP 53I11 IRS2 ADCK5 USP13 PBK CYP2U1 PITRM1 ATF7 MSH2 DLGAP4 M E D 13 ACSM2B MYO1B PHF17 TRA2B ATP10D LAPTM4A XRN2 ELF2 TPM4 CCDC43NTRK2 TNIK ST8SIA6 KITLG BCL2L12 GFRA2 EEF1D JTB CLK1 RELB FXR2 GPR124 NUP210 GRIK1 ALX1 ABAT MSUN2 ED6 MARCH2 NCLN SLC25A39ARAP1 CENPM BCL6B PIK3CD M PP5 MAOA PTK2 ASAP1 PITPNM2 DMD YEATS2 RHEB HBEGF STAT3PACRGZN F787 TIE1 RAB33B PPARGADRB2 HK1 KPNA2 SIL1 GLI1 ADAMTS10 T R IM 5 9 ARHGAP4 LRRC49 CHST12 GTDC1 MAML 3 S N W 1 LRFN1 LRIG1 OSBPL9 ATP6V0D1 ETV1 LTBP3Z NFBTRC 7TGDS 0 PAK1 FANCA GAPDH CDC73 ARL8A LRRN4CL ODF 2 NFAT5 RNF 1 2 6 BCL7A MAOB LARP1 TACR2 CABIN1 MKI 67I P P T P N12 EIF2AK1 E P S 15 COX8A MGAT2 CORO6 TMEM5 PPP1R12CQKI APBA2 SLIT2GTPBP4 NR2F1 JAK1 TCF3 MAP2K7SARM1 CDC34 DCAF15 DLG5FBXL19 RHPN1 VCL CDCA8 CBX7 CNRIP1PRPF19 AHCYL1RNF 3 8 KLF3CALCOCO1ELF2 WSCD2 PLAG1 CDKL1 PPM1A USP7 PTK2B FAM 129B BMPERFHOD1SRSF6 OCLNYWHAQ M AMWASF2 LD1 CNKSR2SLC30A7 CLU SETD7 UBTF SRC ESR1KLHDC1 FBXL19TMEM39A S1PR2D H X 34 PIK3R3 MDH2 NAT6 M LH 1 MAPKAP1 C 3 o rf1 8 MTERFD3 AEBP2YWHAZ S 1 0 0 A1 0 SGK1 MAN1A1 RAD18 EPB41 PDP1UNKL RPLP1 FBP1 KTN1 BTK SCRN2 MEF2BNB EXO1 ESR1 GLB1L2ABCC1 MAP3K5 UBE2V2 TAPBP NRIP1 RXRAC1orf216 KLF4 CD34 WASL CDC42 PNPLA6 DNAJB12 NRN1 AQ P1 TMED3 ADAMTS13QARS TCEANC ZNF217 SNRPE UACA GLI3 KIF2A TNKS VDR SEMA4C MUM1 HSPA4 ATXN1LRRFIP1 MKL2 SLC27A4 SASH1A X IN 1 EPHA2LRP1 BTN3A3 AR CDC45 WIPF1 CA4 ZWINT GSN AMOTL2 MAPK14 NFE2L2 CREB3 KLHL36SETD8 ADAM22 HDAC4 MAST4 ADRB3 C4orf19MRVI 1 PITX2 SESN1CXCR5 ZFHX 4 AES CBL GLIS2STK40 DAZAP 1 RPN1 RXRA FOS C11or f 54 RUSC1 KBTBD11 TJP2 ATRX TUBA1A ANAPC7 ACE ELK4 TYK2 GSK3B GTPBP4 CBLEPHA2 SKP1 W NT 2 NCAPG CACNB1 ACTN4PRELID1 PPARA CDC37L1 HIST1H4A ARL5AH3F3AUHRF1BP1L DPYSL3 TPM3 CLIP1 SIRPB2MA P2K 6 IRS1 PARD6B NOTCH2 PSEN2 ARHGEF10 MAP 2K4 APBA1 HDAC2 ETS2 NAGS LARP1B C8orf4 PHF21ACHD9 D H X 9VDR SMARCD1 FASN TACC3 MRPL3 KIF 1 7 MCAM PPP1R12B T A T D N 3 ANKRD13B PRMT2 ABCC10 SEPT7 RAF1 S MAD1 YWHAGHDAC3 EHD2 RB1RAB7A ZYX RAG1ARL6IP5 PUS1KIFC2 RAVER1 MELK EIF5A HIF 3A CPSF4 G T F 2 H 1 RAP2A RALGDS MAGEA4 PFAS SLFN11 NFKBIA CCNT1 RXRABNIP2 SNRPB TMSB10 ARHGEF7 RANGAP1 NAGK RPS13 NOMO1 TBC1D22B HDAC9PMAIP1 CLSTN1 DLG4 PRDM1 DCAF7 TNKS DCBLD1 WAS VCL CLOCK GNAQ ECT2 MFAP 4 ZBTB6 C1QTNF1 SDHD NCOR1HRAS PLK1 VEPH1 AMOTL1 KLF9 ARHGAP32 LSM14B NFYA PTPN9 SLC25A13 PREX2 LHX2EXOSC7 SRC LOXL2 PDLIM7TMED3 PLAG1 M S H 2 ITSN1 NAA40C1orf35 PTGIR SHOX2 P RDM1 PRKD2 HIVEP2 SIRT1 PPP2R5C SP8 ML H1 GLTPD1 PIK3CA TERF2IP KIAA1549 FAM103A1 AKAP10CTNND1 BCL11APAG 1 PRKCDACTA2 ST X12MITF MRPL15 ACOX2 PPP1R3B SCRN1 ISL2 F M R1 PUF60 TANC1 TAF4 GRIK2 SETDB1 TRIP13 PPFIBP1 ASAP1 PTK2B PKNOX2 DFNB31 DTYMK CDK5RAP3 SCRIBZNF335 BIN1 SRRT VAMP2 FAM49B RPS6KB2C10orf54MKL N1 CAMSAP2 F BX W 7 SLC25A20 CIDEB M AN2A2 CBX5 GGA2 MEIS1 NUDT9RUFY2 PPP1R3D TBL1X RECQL FILIP1L PPP1R3D KIAA0247 LTB4R2 FBXO5 C15orf39 GATAD2A FAM107A ARHGAP10LEPR FAM171A1CBX4 IKZF2 OSBPL3IFNGR2 PAH D D X1 1 TGOLN2 RBPJ FLII FOXP2 CHST3 AMER1 CD2AP BAIAP2L1 T T Y H3 ZFP36L1DUSP10 PABPC1 KLF11 HOMER3 INCENPHDAC3FEM1B CHUK USP12 IRS2 TME M55A PODN CSRP1 MRP S 6 SWAP70RUSC1MATN2 SALL1 CFL2 LBR CLUAP1 AMFR KATNAL1 LAMB2 RUNX3 ADNP GLIPR1RASSF2 STAT1 PRDM5 N O D 1 UBE2D1 WWC3 PDE6D PCMT1 ATP7ASSFA2COL18A1 GSK3A RAB8B KDM1B NCK1 MYBL2 SIRPAMET NCOA4 PDCD4 LAD1 LRP1 OLFML3 ACOX2 PPP1CB ALX1 CHD1 CTDSPL2 ZBTB16 TBK1CHD3 BTRCMEOX1OSBPL3 TR IM 25 SH3PXD2B PIK3R4DPY19L3 BRD8 AGPAT4 ARPC1B FAT4 PIK3R1 ADPRHL2 P S MA3 MAP 3K1 BRPF1 MLX ADRB2 CPEB3 TCEB3B DLGAP1TNFRSF1B PIP5K1CKLHL15 MRAS NCOA1 SNCG STT3A PPFIA3 P IF 1 RARA SNW 1 BAX MAP K8IP 3 ETS1 F M O 4 AURKB GPSM2NCOR2 FOXO4 DBT RALBHSD17B4 GRIN2A STUB1 CLIC4SEPT9 LGR4 CD2AP PIK3R1 SYNM LEF1 NLRP 1 TAGLN2PLAC9TGFB1I1 X P O6 KIFSYT15 1 1 EIF4G1 TMSB4X DLAT GATAD2B MLXIPL HNRNPK NUP50 CBFB SPSB1 TFAP2CMCMBP STYX STARD8 AP1AR SPRY2 TRPM 7 ADCY9 MDGA1 EVI5 JAG1 M L F 2 C7orf41 PDCD4 CBR4 XIAP RAB13 C1QTNF1TGFB3 RTN4 F B X W 11 SRP54PRPF38B KIAA0101 CSGALNACT2NMUR1 CSNK1DITSN1 PLSCR4 W DR75SPRY2 GINS1 GTPBP4 PDXP PSMG1 PTDSS2 BACE1 PPARG CASP3ZNF449 HIST1H3AMAP3K14 KIF20BF AM2 1N 4 X B F1 IKBKAPICAM3 NDUFAB1 LUC7L3 ZNRF2 THBD ZNF791SNRPF Z HRPH3AL X 1 TRIM44 RUNX 3 ROM1LPIN3ZNF438 AAAS ANPEP LRFN5 RUNX2 CLK4 LARGE HCFC1 SCARB1 MYO5A KAT7 TESK1 PITPNM2 PRDM2FLII SUOX PAK1 SNX4 PITPNM3 NDUFA10 WASH2P PUSL1 H S F 1 S UMO2 NCOA2 ARHGAP31 VKORC1L1 FLYWCH2 GNAI2 SLC1A4 SLC39A8 ARSK GHR CDC42 MCM4 CHTF18 CSRNP1KLF4 MANF TRIM37 TNFSF9 LEPR ABL1 DSE W W C3 ZNF407 HFM1 RFTN1 MYOF LAGE3 BIRC5 DNAJB4 PDK2 SLC13A5 T BX5 CCNE1 KHDRBS2 TMED2 VLDLR LAPTM4B M AM L1 RUNX2TERF1 LAMA4 RXRB CCDC149ARHGEF7 CCRL2 FRMD3GSG2 AJUBA LATS2 CHD9 M AP 2 K3 PSENEN CBX1 C11orf95FBXO28Z NF 521 KCTD20 CDCA2 MA P3K 7 MET ECE1 CCDC102B FAM65AM N 1 PARD6B S M N 1 Z H X 1 EID3 ID2 SAP30 MED2 4 TRIM24 BLM PBX1 DIABLO EIF1AX KLF15 KPNA4 RBFOX2 FM R 1 NOC4L NTRK1 SCAND1 RARA CCDC57FLNAMAP2K6 NF IL 3 SEPP1 ADCY4 MAP3K3AKT3 SOCS3 CHMP6UBE2T SERF2 T IAM1LDHB DEAF1WSCD1 SCAMP1 ATP1A2 CAMTA2CDK9 TUSC1PLCG1 CREBZF PALM2-AKAP2 RCC1 DGKG STIP1 LY6E FM N L3 BRCA1 CDCA4 MAMDC2 T L N2 DCP1AS NW 1 RARA SNAPC4 GPATCH3 PTPRM PIP5K1B ADAMTS1 TCEB1 PPIB CTBP1PAIP2SIN3A ING5 PHF20L1 KANK2 NONO DLGAP4SHANK3MAGI1 TGFBR3 LRRN3 MITF RALY TOR2A DNAJB4 APOB ATAD3B TNKS Z NF 6 8 4 TRAF2 DDIT3COM M D10 IKBKB NCOA2 PRKAR1A MED26 PWADARB1 P1 POLG2 NR0B2 PUS1ACTR3B FAM193A BMS1 PSMD10NOS1 CERCAMPOMT1 ELAVL4 NCOR1 BTBD19 NR4A2ATCAYCDK2SNX30 PURA ZC3H7APNPLA6G D F11 NR4A2 ARID4A IMPDH1 GMIP W D R 1 SNRPA KHDRBS1 PKD2 C3orf58 TGFBR2HLTFDACH1 GPM6A RNF165 BPTF GLIPR2 SOX18 PCSK6 UCK1 FOS PAPD5 IRS2 HIST2H2ABPROX1 S TMN1EXO1 BIRC2 SLC1A3 KITLG I PO 13 TBC1D15 ATP2B4SYNPO2T M E M 4 3 PELI1 FYNPALM2-AKAP2 PCGF5PIK3R1 N R IP1 STAT2 RAI14 PNPO LONP2 CCNG1 SLC9A6UBE2I PJA2 HOXD9 JPH1 PRMT10W W C 1 CBX3 PLSCR1 FAHD2A MSN SO X6 IRS1 MAP2K4 CDH1 CTNNB1 RBPJ IRS1 CYHR1GPAA1 MAP K1 0 SP4 LRRC59HTT I L 2 7 SIK3R B M 2DENND5A 4 ARHGAP21MR P L 2 8 M B D 3 TOPORS COX6C TM9SF4 CTAGE5 HELZ RECK M AP 7 D3 GRSF1 C1QTNF2FLT1 RAC1 FMNL1 PTPN1 ZBTB16 SLC25A36 OSTCRIMKLBCSRP2TTC7BSLC43A2 HSPA1A ZBTB47 B3GALT2 EPHA2 PER1CCDC69 FERMT2 ADK RNH1 FBXO28 SOX2 EML1 NAA50SRSF7CCDC85B MAX TBKBP1 KLF5 SSPN ZNF91 ZNF627 ITGB3BP ALX4 PRELP CENPM TMEM169FGFR1 STK39 ERCC6HGFAC TJAP1 TERF1 ZER1 DNAJB9 PHGDH NF1 LRIG1 SMARCD1 WBSCR22C6orf211RLF CSGALNACT2 SCLY CCDC43 ITPKA NKX2-5 FAM73B SLC39A14 ADCY5TIFA CITED2 SRBD1LPPR2 SMAD4SPRED1 KCNAB2 AFF2 TAB2PACSIN2 SYNE1 RNASE4 UBQLN4 LIMK2 PBRM1 MLST8FAAH ACTR5 GALT UBR7 RNH1 ST M N2 S1PR1 ESRP1 CD28 PPARGC1A PARVA RAI1 N R 1 H 4 JUN ATM SMPPM1B AD7 PRRG4TP73 WWP1 MAP2K1 GPC1 NOVA2IGF2BP3 ZNF614FASLGCLIP4 SEC61G ARMC10 ANXA6CDC42 H O XA 3 NGF GEMIN7 YAP1 PPFIA3 NCAPD2CDK16 VAMP3 WAC C1orf122 DBN1SUOX TNFRSF1B USP30 PDE2A TRAF3 P I N 1 CASKIN1 SAMD4A SENP6 APBB1 PPAPDC3 HERPUD1 YTHDC2 GLIS2 SRMSP5 PRODH2 SLC22A3 CBL RRM2B AXL TMEM106B CALU EWSR1 MDGA1GATA6SORBS1GTF2IRD1 LRRFIP1TLE1 TMX1 SLC47A1 TTLL3 TM E M 201 PHB G PR135 AFAP1SP1NDRG2 S100A 11 TRAF2 KCTD12 TFRCW D R 8 5 GOLGA3 KIAA1432 EDN1UBE2N CCNE2 LATS2 KTN1 KIAA2018GHR AHCTF1 KLF9 CDK2 DNAJC10 IKBKE DNAJB14 EVC W NK1 H SFUPRT 1 KHDRBS1ESR1 C A D M1 PNRC1IPO4 PTS TP53 IVD SPRY2 DOCK7 PLK3 CDKN1A GAN SNX6 SPCS3NAA30 ANKRD26 IKBKB LUZP1 N T N 1 CEBPB TXLNG CCNK MYO5A MAP 3K1 PDGFCGCDH ZDHHC13 TGFBRAP1 SYNM HOXA3 CBX7 TNS1 ANK1 ME D 28 CHSY1 CHPF2 AJUBA FERMT2 NOL10PGLS DIRAS3 ANO9 CREBBPTMEM106C HNRNPU TRAFD1 DYNC2H1 CCDC88A DCC MAP3K14 UNC119B NFKB2 COX 17 CD2AP PLSCR3GJA5 PLBD2LRRC61 HEXIM1 GNA13 IFNAR2 PLCL2 Z HX 3 PPM1G E2F1CACHD1 PIP5K1C ADAMTS7GIPC2RRM2 NFKBIA M E D 7 KTN1 TTC33 IKBKB IRAK1 TBK1 DIP2CUHRF2SCD CAMSAP2 CDC42 TUBGCP4SOCS7 MRPS2 ECHDC2 SART1 FOS TAF9B USP53 ENPP4 C14orf132PBXIP1 Z N F 1 9 7 MYCN LPL INTS1 TMED10 FAM73AW BP2 W D F Y 2 PDLI M5C11or f 80 MAP9 ZIC3 TRADD RIOK3 COPS8 HCN2 HOXB9 ESYT1 CCNE1NEDD4MS RS 1 MAD3 JUN NR5A2 SSR4 MAP3K7 MLKL SLC4A1AP STAT3 AR HBEGFTOMM40L TRIM28TFIP11 DNAH5 ZNF410 PDCD4 CSRP2BP PLEKHA8 RABEP2MAPK8 CDC73PTPN14 TCF7L2 FOS NFYALIX1L RBM34 METTL12 C6orf106 NR4A3 MAPKBP1 UBE2D3 TET2 PALM TTC7A RUNX2 N R 4A 2 ERBB3 SVIL RALGAPB KDELC2 STAU2W D R 8 3 RMI 1 TDG MAP3K5 ALG10B POLD2KLHDC10 WRAP73 TRPC4APPDZD2 PLEKHO1MXRA8 CCL20 MYCNNCOA6TLE1 RAB3IL1 ATF3HR SAE1 CREB5 LNX1 HTR1E RPS6KA2 SKI COASY BCL2L12 THRB DHX37 TLR4HDHD2 PRRC1 CITED2 ALX4 TSC22D3 GCGR PCK1 DHRS4L1 ZCCHC24 RELA EP300SPRY1 DRAP1 TMEM120B PLEKHO1 SH3PXD2A HNF1BIRF7 ATP2A2PCNA KANK3 CRK MAX PCBD1 APH1A BOC M S H2 EPRS POU2F1 ZNF618 HSF1 VPS45 PLCB3 VAC14 T RIM2TANK 3 KIRREL SCYL2 CRCT1 DLX4MED 28 ZBTB38IGFBP6 NGFR KLHL21 JUN UQCRB AP3S1 ULK1 ADRM1ATM PUF 60 SPTLC1 SOX12 RAD54L RBM8A PRPF6 VEGFBCDK17 CPSF6 LDOC1LCHUKVGLL4 ITGB2 SMA DFASN 2 QSER1TRAF5 LRRC58 ITGB3 MAP3K3 PIGU GYG1 HSPG2 FBXO11 TFAP2C DTNA PAX6 HLF ATXN1LRIN3 EIF3G RANBP9 RASA1 ZEB2SMARCAD1 PAQR3TRAF6 NEK4 PARD6BARHGAP32 FGFR3 KCNB1GNA1MR 4 P S 5 RALB CPSF3 CREB1 S S 18 IRF6 MT MR3ZNF689 PRSS8 TTYH2SRSF7 ARL4D PEX14CHERP PAAF1 POLR2KPLA2G12B RNF4 CEP135 PRKAB1PAK2 PW P1 PELI3 QARS AR ACHE TBC1D10B CEBPA MED13L AP4S1 DBNDD2 YTHDF1 ICA1L P BX 3 NP M1 C1orf173CDKN2AGME B1BRD3 IGF2R PSEN1 GSC NECAB3EIF3B ZNF70 SLC9A1 M A P 7D 1 DAXX DNAJC24 SLC39A6 PML UBA1 MAP4K5M YH10 C12orf73 PTPN2 TEX11 M A PK 8 BMPR1B MPDZ FOXO1 IQSEC2TUSC2 AAK1Z N F 7 6 ITSN1 PRKAR1A TAF9 ZNF180 WNT9A SMYD3 DEKHIVEP2EP300 SLC1A1C1orf95 SMARCAD1 DAZAP2ZSCAN12 GPR63G2E3 PLEKHA5 ATXN7L2 EPDR1 GLI1 TAB3 DLC1 MAPRE1 XPO4 EIF4EBP2 SETBP1 FGF2TBX1SYT11FECH ZNF717 SMA DTBKBP1 9 N4BP2 MYCFBXO41ARL4D FLRT2 ST3GAL6 KLF3 ELK1 TAB2 BPHL MAPK8 ZBTB10 CSRP1 GRIK5 VIM F MNL 3 NR3C1 CREB1 PDCL ASCC2 EPHA4 TAGLN2 SOCS5 PNP N TN 1 MEIS1 TRPS1 EIF4A2 TMTC3 GNL3 FBXL5 BBS12 ARID4A SRCIN1SEC14L1 NCKAP1 T ME M1 4 C MFGE8GPD2COTL1 AVPI1 IGF1RGRB2 FRS2 CSNK2A1PDGFRB IKBKAP FLOT1ASXL2 PPARGC1BIFFO 1 ITGAV DICER1 MYCSN X4 PTAFR RPAP2 ZBTB1PAK1 TM EM 51 GADD45GIP1 KIAA1033 TRERF1 FBXW7 ENO X1 SP8 MS I2 GTSE1 SLCO2B1MR P L 3 8 FGFR3 ETHE1 OSBPL8 CLIP1 PKP4 POM121 M D MASB5 4 CRCT1 BRIP1 CREB5 FCHO2 IRAK1BP1 ARHGAP32 RPS6KA4 RBPMS2PDF ATF3 M ED 28 PIKFYVE T PM1 FARHGEF39 OX O1 POLLPDLIM3RRM2 RUNX3 B I N 1 MT1X MATR3 PHLDB1 GORASP2 MBNL2 TAZ HADH GYS1 MYL9 NEXNPSMC4 TDG FHL2GTF2H1 ELMOD3 BCL6 WDR4 4 BDP1 POU2F2 MDHRS3 A P2 K 4 LARP1 UBE2E1 PRCCM Y H 1 1 VGLL4 ETS1 D H X 3 4 GIT2 TUBA1APIP5K1C ADHFE1 ROR2 BAHD1 TRAF6 C17orFYNTOPORS f 70 PABPC1 ARRB2 DSTJMJD1C ZDHHC14SMPD2 ARHGAP31 SGPP1 KIAA1217 SALL2 KI F19 APC GLI3 BRF2 RNF111SLC25A15 GNG3 DOCK9 ERCC6 STAU1 SH3BGRLMAPK8IP3 S F X N1 STK10 CACNA1CCDR2L HDAC1 HOXB3 ELF4 AASDHPPT RHOQ THOC2 C1R ARRDC3 EPB41L2 PIN1 HIF1AN C6orf47CREMW D R 3 6 STRN4 NUPL1 TCF4 NRG1 MICAL3 VPS37C MRPL53 RBM17 Z N F 609 COPS5 P HFARFGEF2 11 HCN1PPARA FBXO11 SRELB 100A8STX17 PPP1R12C FAM13C MAN2A1 MIER3 S C M H 1 PPFIA3 NFATC1 DNAJC5 PEPD ENC1 PRKRA RAB2A GYG1 RNPEPL1 TBP HSPG 2 LEF1 CYTH1 ARIH2 STAG2 F Z D9 FRS2 GAB1 MAPK1BADTRAF6 PTTG1 C D 40 RPN1 HGS PTPN14 HM GB1 PRKAA1 HLX NX F 1 ZFYVE9 MDM2 PPP1CB SDF2L1 PRPF 3 1 EGFR RPN2 GABARAPL1 NFKBIA SKI RNF20 ZNF629 MAP3K1 EIF2S2 IGFBP3 CTNNB1 VHL FLNA ANO6 ZC3H7B ZFYVE16 GFPT2 NTRK1CLSTN1 EIF2C2 UNC45A ARRB1 LRP1 IBTK UBR1 PAK1 VDAC2 AI MP1 TCOF1 RB1 KDM5B ING5 ELK3 CDK6 CBX2 ANKRD6 C 10orf137 BCL2L11 HLF FOXK1 MAP2K7 CNTRL SLC35C2 MAP1B AFF4 NFYA ZFRP2RX7 SCD BRD3 G D F6 ACTA1 MAP2 SRFBP1 MEF2BNB KLF10 Z N F 5 7 6 TMED9 C1or f 115 ATP6V1H HIF1A PRPH2 DV L 2 UBE2D3 SQSTM1 HIVEP1 SLC41A2 ZADH2 RYR2 POU2F2 ITGA3 PSMB5 SHPRH TM EM 214 ZBTB7A FASTK MLXIPL PRI M2 PLCL2RUNX1 TSPAN4 KSR1 MDFI ST 5 GRB2 SEC23A PKP4 TPPP CYB5D2 ISOC1 COX7C MLEC ARHGAP24HOXA9 AP3S1 CCNYL1SETDB2 MAPK1LINGO1PAPOLA DAZAP2 HSBP1MDFISEC24D ZNF641 BAP1 HLTF PEX19 IL11RA MTOR YWHAB Z N F 5 6 3 CACNB3 CTRL C1R GLIS2 KCTD20 TNFRSF1A LARP1B LTBP1 H O XA 9 FASLGCREBBPFAM167B BRCA1TLE1ADAP2 NFIXCPNE8 CHD6RAC1HIPK1 HS2ST1 ZBTB7B M D M 2 TI MM8A TMEM161A SMURF2 PAG 1 ENY2 HRH1 ITSN1 SPRY1 ZNF148 ATP5C1 CDK16 HMGCL KLF3 IMPA1 SLC4A7 SPEG SETD7 LHFP ELK1ARL5APAIP2 CNOT2 BCR DOCK4 MAPK10 ID3 GLYCTK GPR89A SHOX2 RECK STX1ALOR PSEN1 R MN D 5A ISL2 SLC35F2 HOXA1 KIAA0100CDC34 RNF11 MBNL2 UBE2D2CCDC85B ARID2 YWHAZ P I M 3 CRELD1 MAP3K12 I D 2 SEC24A JAK1 ALAD MAF TARBP2 MTPN ARMC1MTMR6RASSF8 IRAK1 CLDN12 CCNY UBE2D3 CUX1 ACOT13 AGGF1 P AX 6 PTPN14 BCL7A HOXB9ITGA5U F M 1 RBBP5DDX 19A EPS15 GDI2 RHEB PSEN1 RHOGZMYND11 PUF60 NCLN Z HX1 RPS13 SHC1 ELF1 TENC1S N X 18 SOS1RASSF8 PAIP2B TACC1 NCKAP5 SERF2 MLX ANKRD3 9 DHX9 SH2D1A GRB2 ADRM1 BEND6 MAP4K3 HERC1 W W C 2 PLK1 SOS1 PBX3 ZNF436 KPNA6 APBA2 RNF 122 CNOT6 SN X4 PSMD11 CRY1 EGR1 BIRC6 MAP2K1RCN2 MAP2K4 FYN ARFGAP1 PSM D1 DPF 2 SOX7 AHCTF1 EIF2AK2 VAV1 BMPR2 USP47UBE2A CDH1 KCTD17 PKNOX1 CHD6TP53 DES PRPF4B RAB2A SUFU YWHAG BCL2L1GRAP2 TBC1D12 BRPF3 AHCYTBP SLC25A3 STX3 DSTYKDUSP1 OSMR LPPR2 ITGB1 KHDRBS1UBE2D4 ACADM SAV1 AP1AR EREG PPM1A RINT1 FOS PDLIM1 ME N1 SOAT1 B4GALT7 HADHB W DR3 7 ARL6IP4C7orf60 VAT1 F AM 124A DT X 2 RNF186MAP1LC3BDNM1 S TIM 2 HOXA9 YWHAB NSD1 LRRC8C TGFBR1 CBL EBAG9 AHDC1 FHL3 SIGMAR1 HMGA1 STAT3 TUBB6TM EM 209SEPT7BAG6 PD ZD 2 RAC1 CASP3 KLHL15PSMG4 POP5 STK16 CCDC130 MAGEL2DAP GOLGA2 TAF5 IRAK1 CTNNBIP1 SCP2SLC25A35 BCL7A RELBL3MBTL3PHLDA1EIF2S2 HCFC1 UBE2N SLFN5 CBX6 GFOD1SLC7A2 RASA1 SCOC IREB2 RBMS3 NGF GUK1 AIP GMPS PSMZNF652 D14 C2orf69 TAB2 WAS LAPTM5 IGFBP5EDEM2 PEX11BZC3H6 MLXIPL RANBP2 STAMBPM D M 4 M X D 4 ZNF771 CNOT3W DFY1 YAF2BRF2 GLI3 TMSB4X TRDMT1 SH3PXD2A PHACTR2 N P M 1 ARNT POU2F2 ERGIC3 OTUD4 GBA PSMC5 RILPL1 RET ZBTB6W DR4 4 TIM MG 17A NA12 VAC14 ARHGEF7 PER2 MDFI D D X11 EZR P KP 4 RFX6 GRHPR PHLDB1 BLMH RUSC2UBR5 LPP EREG SOX5 PPARA MALT1LAMB1 PDLIM5 IGF2BP3 NGF ACBD3 MAP3K7S M A D 7 RNF11NUP 9 8 STK32B SRCSLC24A6 RAB28 ZFC3H1 SPRY2 TP53INP1 SEC13 GET4 STXBP3 RRAGDIL18 CTNNBIP1 CHST12 CNOT3 CCDC9HDGFRP2 ZNF680 NUDC CDKN2A VCL CRYL1 ARL15 COPZ1TRPC1USP11 IPO13 SP3PCDH12 SNAP23DUSP1 TRIM39 KIF2A BCL2L1GTF3C3 BLM SCML2 COIL SLC2A13 PPIP5K2 ATP8B2PAAF1 TGFBR3 FRS2 REL FMNL1 DIRC2 MSRB3 PBX3 ERCC6 HRAS FASLG DOK1 PRLR HLTF GLIS2 RELAKLF3 GPS2 HSPB1 COL6A2 EGFRSP8 EURL PACSIN1 XIAP SPRYD3 TTLL11 PEX14 RNF14MKNK1 ME D1 5 PLD3 FUNDC2 EGLN2 SERF2 PELI1 ANKRD17 RAF1 TULP3 CABIN1C 2 1 o rf6 2 RPS6KB2 VAM P2 CAPN7 DDX 19A ZCCHC11 GTDC1PRKAR1A IL6STTNIK USP7 MRC2 ABT1 SORBS1 MAP1LC3B NTRK1 UBE2I SLC35D1 CAV1ZBTB40 ACSL4 ELK1 S M N1 CTNNB1 TP53BP1 CREBL2 UBE2D1ACTR2 DCN VCP EIF 3 I MTCH2 MSRB3 NUMBL QRSL1 MFG E8UBE3A GUSP6NL NA12 APBB3 AGK ABL2 SPOPL ADAM17 C12orf23 SPPL2B TBCA VAV2 HOXB9 FAM65A FAS ZDHHC1 HN1 ABCD2 DHPS CRIM1 POLR3B KIAA0247 SH3BP4TO B1 EEF2K NCDN YIF1B W D R 1 3 CNOT2 GPRASP1TOR1AIP1 ZNF292 FURIN WISP1 MOB4 ELL PDZD2 FUT8 PSMD7 SENP2 YAP1 TCF7L2 ACVR1B KCTD3TBC1D19 C17orf70 SPRY1 DNAJC5FAM120CC16orf45 SOCS1 Z F P 64 RCN3 PELI1 MAP3K1 CLIC5 S A M D 5 IQGAP1 DENND4A ZDHHC9 FO XN3 CHD1 FAM179BCRISPLD2 KLF14 GNAI2 BCR BTG2M AN1A2 RNF 5 ADRB2 RPRD1B IN S M 1 BM P7 PCMT1 BRIP1 PIK3CA SEPT8 C2 ALX1 ARID1B GEMIN7 NR3C1 DLX4MTX1SH3BGRL3 TCEB1 SMARCA4 TOR2A UAP1 UTRN RAB1A GLS TUBGCP4 COL14A1 NEK3 ADCY3 E2F5 CDK4 FRG1 CNO T6 C11orf24PRICKLE1 MAPK1 FA M 184A EPRSMAPAVEN 4K3 PLXND1 ZNF800 EEA1 S T5 TRAIP HRASUBE2D1 PDXPADIPOR1 VIPR1 HIGD1A FASN PEAEGFR 15 CHMP2B GPATCH8 S U MO 1 BCDIN3D RAD18 PTPN12POLKCCNKFAM8A1 MCAM FBP1 PEX7 HIP1RHACE1 PEA15 ARL2BP NFKB2 KIF13A PABPC4 ADRB3 PKN1RASGRP1 SHC1 POR SLC25A3 SECISBP2L PEX19 TAGLN MVK ZNF254 BCL2L11 MAMLD1 CRB3 PKM S MAD3 LARP4B ATP6V1F PUM1 FNDC3B TEAD3 POGZ SNX2 PCBP1 SETD1B RNASEH2A PAAF1 C 1 o rf2 7 ANKFY1 CDK1 C8orf76 HSP90AA1 DHRS7B ORAI1 EPRS RAF1 AHRIFT52 M R P S 2 4 TMED1 PRKD3 PRPF40A FAM 120B DCUN1D1 M L H1 CHMP2B M AM P2 ED 28 P S M D 1 4 M E D 25 SEC63ZNF260 FNIP1 CTNNBL1 POU2F1 PAIP2 PLEKHA1 SYNE1 T A F 15 METTL9SYVN1 PEX11B CLPXARHGEF15 TBCC PLAG1 CUL2 UBASH3B C15or f 39 RBM7 SNRPB JUN M O B4 CENPF USP13 CXXC1 RAB11A M A M L1 K IA A 0 1 9 5 AT P6 V0 E1 ATP8A1 STX4 CHRNB2 SON OSBPL3 MEF2C GBP2 BTRC SOX9 EIF4G2 TYMSATX N7L2 D D X 1 1 SOS1 CNKSR2 RAC3TMEM173 KLHL2 1 RIF1 MET ARHGAP5 TAF13 GTF2F1 SUB1PLEKHO2 GJD3 PLEKHG5 MRPL39 NUDT16 FYCO1 KPNB1 XIAP KIDINS220 KAT7 KATNBL1 IGSF11 TP53 YWHAG AXI N1 APOOL RCC1 TPST1LATS2 UBE2D2RHOQ BRD1 OSR1 RUVBL2 ATXN1 PRUNE2 S M AD1 SP4 G O T2 DLX4 CCND3 TALDO1 PGM1 CYP8B1 CCDC22 HTT TJP1FBXO10 MAP4K3 BRCA1 TIAM 1 METTL7A MTCH1STOML2 CLN3 ARHGAP18 HEATR6RNF216 SP1AP1B1ACVR2B KCNMA1 VIM TFAP2C CREB1 TFDP1 ADCY6 TRAP1 STRN4 VHL VHL TOPBP1 S M Y D 2 RTN3 CHL1 FXN SPG20 SNTB2DLG1 ZGPATADNP2KLF10 MARCKS BCL2 OSBPL11 PHF19 HDAC4 PHGDH C15orf39PRIMA1 CYB5R1 LIMCH1 ISL2 XBP1 GNPTABNGFR CDH1 ISCU ENO1 USP38 DOK4 LOR HEATR3 HABP4 Z NF 221 D O K 4 MTOR TFR2 RIPK4 RPLP1SERPINA5 C16orf86 DAG1 NDST1 CHD3 GRB2 LAYN PSMC5 YW HAZ PRR12NFIA ANKRD42GALC CLDN12 ATF3 TNRC6BAPPBP2 DNAJB11KLF6 MKL1 TPCN2 SH3BGRL NR2F6 MARVELD2 U SP13 MAP2K1 ECM1 BAG2 UBE2K NAA16 S100A10 FARSA HIST1H4A FLNA RASA1 SAFB PIK3R1 WBSCR22 ZFYVE27 SPAG9 CREB5 KIAA1324 BNIP2 RGS5 PHF21A FAM126A FHL3 PLD1KPNA3 TCEB3 RET KLF10 LUC7L3 CRK CTAGE5 SMARCA4VEZF1 SM A D 2 SACM1L NR5A1 CHD8 LMO D1 NFIC METTL5 RASAL3 M AP 2K6 PLCG1 NFKBIE FABP3 CITED2 KAT7 S T K 4 0 PIK3CD ASCC2 MAPK8 NRG2LATS1 DISC1BACH1 FEZ1 KCNQ4 RHEB M A F1 CDK5RAP3 STRN4 NECAP1UBE2J1 MFAP3 ZNF616 ARHGEF6 SDC2ACTN1RASGRP3TRPC1 CASP3 UEVLDSETDB1 ZZEF1 PDE4A PA2G4 KIF5B OSBP VAMP3 ENTPD6 GNPDA2 L1CAM APBB3 USP12 STX1A PGRMC1 HSPB3 VLDLR BRW D3 MAF CTDSP2 DYNC1LI2POU2F1KIAA1462 PLCD1 COBLL1 SLC2A2 MYH9 MDN1MRPL17 SOS2 IDH2 CRK KPNA2SVIL ULK2 DLGAP1 MEF2A ANKRD46 TFCP2HCFC2 NFATC1 ZFYVE9UBE2B YWHAHZNF181BVES ZNF217 MATN2 BECN1 CREBBP NCOA1 ZNF384ANXA4 AZGP1FBLIM1RPTORSO X5RPP14 SEC24B ARFGAP1 KIAA1244 HS D17B6 ZNF330CCDC89 SP4 EREG WIPI2 EP300 DUS2 L PIPOX TM6SF1 USP16 AXIN1CCNB1 EPB41BCL6 SKP1 CBX4 QTRT1 SAMD4A EAF1 PAWR POLA2 NRL STAT5B EIF2B3 DHPSUBA5PAPD4 USP39 NR4A1NCKAP1 ZNF221 ALDH5A1PNMA1 BAD KIAA0907 STK40 CCNT1 FBRSL1 ISOC1 DUSP19 FGFR3UBE2I FOXP2 FAM13A STX7 EGFR C 1 7 o rf5 9 SALL2 LIMK1 BDH1 SMAD4 EEF1D AMER1 PHC2 SFMBT1 RCOR1 SLC6A1 Z NF 197 E2F1 TNS 1 RBPMSC 1 1 o rf8 3 HOOK3 DEAF1 DAPK3 AKAP1 ANTXR2 VCL XRCC5 S NAP 2 3 SGSM1GOLT1BZNF268 HIF1AN PITPNM2 U2AF2 TBC1D9B ZBTB16 FICD KLHL5 S OX 9 GP R124 SLC39A7 DNAL1 ACAT1 ATF4 UCK2 POLR3DTTC9C AFF1 DLG4 EDNRB CMIP T IM M 1 7 A HDAC7CRKLMAPK1 SKI ATP5C1 HLX STX3 HDAC1 HIF1A NDFIP2 PGGT1B DBT W T 1 ZYG11B COX19 CASK CNTFR RNF186MDH2 SIN3AKIDINS220RAB5A SMARCA5 MDFIC CTSO FUNDC2 HNRNP UL1 MAP7D3 FAM53C PRNPTRIM33 SLC6A6 CCL7 FBXO32 E2F5 CTBP1 KLF11 H3 F 3 A KAT2B USP32 SH3BGRL FYCO1USP38 PQLC1 MORF4L2 CBX3 TADA2B LIN54 ARHGAP24 NCKAP5L ESR1 NR5A1 LYST ACSL1 GRK6 LRRTM3 PAOX N U P54 FAM193B MAP2K1 CHD4TFDP1 ANKRD28 MACF1 FAT4ARHGEF2 NKAP ITGB8 DPP3 MAPK6 FBXO45 GSK3A XRN1 SP3 W D R 4 7 KHDRBS1 CAV1 LCAT UPB1PDPR LRP5 T M E M 159 S M AD3 MXD1 FERMT2PPIL4 TFGCDC27 KIAA1462KIAA1430 BCL2L1 CUL5 MAP2K4 MARCH5 KDELR2 W NK3 PTGFRN CRKL NACADCOMMD5 LATS1 F RMD6 HECTD3 DACH1 PSMA1ISG20L2 RORA SALL2 E 2F1 HDAC2 M SH2RAB9B SOCS2 ZNF567 COPS6 SIKE1 RPRD2 RUNX2 W W C 3 FBXL3 MKRN3 W N K 1 RABEP1 RGMA SATB1 RFXRBL1 6 ASAH1 PPAP2B UBL5 ZNF33A HIAT1 MTM1 SKP2 UHRF1 POLR2D PRKCSH LPL SP1 Z N F 5 1 2 B TMEM120A PBX3 BICD2 GMEB1 SMAD4 BEGAIN STX2 SENP7 ZADH2RAD23A NR4A3 TMEM106A AK3 CCNT2 CDK9 GSK3B CCNF UBR3 LRP6 TRPM7 D T W D 2 COG6 EXO1 HIF1ASEPT9 CACNA1H GLS KLHL29 PTH1R UBXN4C 11orf95 SLC9A3R1 CHM SLC26A11 IKBKG KATNB1 EIF4EBP3 DGKZ TCF7L1SHF N4BP2L1 TRIOBP YWHAGHIPK2 PSM D7 PTPN3 MBD2 LIFR ATP6V0A1 GALNT2 C1orf74 KCNA4 LPHN3 RB1 SUB1 FAM188ATRIM 59 R N F146 ORC2SPC25 IKZF4IKZF2 HIF1AN RPS6KA3PHLDB1 C12orf52 RSPRY1 PPP1R13L CASP8AP2 ECM2 HDAC4 LBR ZNF136 NDUFB3PKIG MOGS RNF170 BSPRY ANKZF1FHL3 TUBG1 SPRED1 BCL2L11 MLYCD INTS1 ZBTB11 SLC25A28MICAL1 GIPC1 KLF4 BRD2 LIX1LCBX5 HBEGF CASC4ZEB1 SET DRD1 HNF4AELK1 CBX5 THAP1 MON2 CCNY USO1 DOT1L GABPA SH2B3 TCEB3B SERTAD1 FLRT3 SRF BMP4 HTT UBE2E2 PTGER4MAPK14 N ID 1 M BD3 CSF1 RGMA NFE2L1 MX RA7 NGFR ENPP1 PRCC PCDHB6 TTC7A ZNF720 FBXO38EIF4E3 ARL13B KXD1 KIF3C LTBP1 CHST15PDLIM1 NRG 2 BCL2 TMED9 TRIB1 DUS3L PTPRG PHB SLC30A6 UTRN RNF149 IKBKE RASAL1 C1orf74CALM1MPP3ZSCAN16 MBNL1 PRPF40A AATF T AF 4 LTBP4 ZNF253 MAPK8IP3 TIAM1 UBTD2 ACAP2 NTRK2 LPHN2 PLSCR1 T PM 4 Z S W IM 6 PLXNA1 H3F3A VTA1 FZD8 LRP12ABHD13ZNF653 TM EM 33 JUP ANKIB1 NO M O 2 UBE2U PTPN4 SMC4 EYA4 SERTAD1 DHRS12 CT U2 S M U G 1 CEBPB CAP2 LIX1L P2RY11 MAP3K1 CPEB2 APC VAMP2SPPL3 ERBB2IP REPIN1 EPB41L1 PHLDB2 PDE4DIP PARD3 CCT5 GPI CDK2 ZEB1 SOX15 ZFP1 AKT3 MPRIPMICALL1 UBLCP1 SF3A2 PPAP2B YTHDF3 FBXO17 HSDL2 TRIP13 C16orf62RAD54B NOTCH2 LMO4 DUSP4 SMAD9 COMMD8 TRIM28MLYCDANGEL1SRXN1 ATP13A3 ASCC2 CD59 GMPPA LTBP2 VIM EDC4 DCAF7 CPEB2 CEBPBSMAD1 AMDHD2 ZBTB6 CLCN7 SH3RF3 CAP1 AP1AR HAO1 C20orf112CHCHD7 EPB41L3TSSC4 NDE 1 R B M 3 9 RPAP2 HSPA13 ANK1 DNMT3A NUS1 EEF1G UHRF2 HMGA1 KLHL21 BNC2 CATSLC35B2 SKIV2L CACYBP EID1 SNAI1 LRFN1PRPF38B ATP6V1G1 GABARAPL1 DHX33 TPCN1PTAR1 IFT81 FTSJD1 RHOB KPNA6ARNTC20orf194 PSMA5CCDC94TBC1D8B NFKBIL1STAG1 SLC25A46 W DFY3STAU1SRP9 PPAP2B C3orf70 SAA4 HEBP2 DCAF8 NR4A1 NOTCH2 C7orf41 ZNF354A XRCC6MIS12 Z N F 92 MTSS1L AKT2 DDX 2 6 B MAPK3 RUNX2 PARP8 YWHAZ EI24 USP25PAK2 MAT2B GLI3 MEF2C PANK1GAS1 MTMR2 JAG1 ATP5B CTNNA1 ACAP3SLC39A3 SSBP4 DLDERAP1 PHF7 SAT1 CDC6FKBP1ASNRNP70TUBA1BTGFB1I1 GSK3BLONRF3 RABGGTBPLSCR3 RMDN3 KIF16B LMAN1 GATAD2B CRTC1 MIER2 MRPL38 CXCL12 ELK4 CNTROB TWSG1SNRPG CRADD RIN1 CRELD2 PAX3 SPNS1JKAMPW RAP73 DARS MET HDGF W FIKKN2 N R 1 I 2 IGF2BP1 MAP2K3 PBRM1 METTL14SEC11C THOP1 SLC44A1 RIMKLB SM A D 2 ZNF5 8 1 C 1 7 o rf5 8 TCFL5 TOLLIP RMND5A TAF2 SUV39H1 TM EM 65 MCAM ESYT1 SP3 Z NF 1 9 7 USP4 ZNF12 ATF1 TM EM 121 ETF1 ICT1 FGFR1 SPEG OSBPL11 CDKN2CCOL18A1 SLC10A1 SLC25A33 UBQLN2 FAM103A1 CAMK2N2 ITGA1IGF2BP2AP1S3 SULF2 HDAC1 AGMAT T M E M 1 7 6 A H S D 1 7 B 4 XRCC6 PITPNB EPB41L3 RANGAP1 AKAP8L C17orf59RBAKRABL5 BDNF STARD13 DLX2 CALR CDC37L1 AHR DOCK9 PCK2 MAPRE1 LEMD3 CEP135 MAPK10 ATPAF1 M KNK1 SAFBGNL2 M AP3K3 FAM46C ZNF776 SMPDL3AMTHFD2APOL6 CHRM 3 POLR2K SIN3A SEPP1 CPB2 OGFOD2 ATF2 CHMP4C FKBP8 UBP1 E2F6YWHAE SMARCC1 RASD1 EXD2 ZNF45 DUS P 19 ARFGEF1 SRPXGATAD2B STK19 DNMT1 GOLGA4 TASP1 PRKD3 H M 1 3 ITCHANKRD53 HLTF ZBTB4 HHIP MYLK M T H F D 1 KAT2A ZNF236DAZAP1 SAMD4AARNT BSG FAM151B CBL MBD3 KLF15 SERPINC1 PFKM UNC45AGOPC RANBP2 ZNF672 FBXO3 MARCKS UBE2F W DR41 N U P 153 FAM122A SMC5 T A F 12 DEAF1 NACC1 VTI1B ARHGEF7 EFEMP2 ITIH1 RNF24 CTDSPL GMNN IPO11 RAPGEF5 RAF1 DDIT3 ACD REXO1 MRPL34 PLEKHA1 Z NF 6 9 5 AADAT ABCC9 JAG1 NEK7 MBD1 PWWP2A ADCY5 K L F 11 TEAD4 ATF7 EGFL7 KLHL22 CSNK2A2 CHAF1B ZNF845 COMMD2 CTBP2NEDD1 TBXA2R SARDH UPF2 CYCS IGF1R INCENP ZNF709 CBFA2T3 KANK1 SRF ANGPT1IL17RC LANCL1 SIK1 DENND5A MEX3B ARMC5 FYN P M M 2 ATP9A RBL1W H SC 1 ORMDL3 GMIP PLIN3 ZFP2 TXNDC9 PPME1 MPDZ HSF1CDK9 SN X16 PIK3R2 CTTNBP2NL ZNF346 BRF2 CCNT1 NDUFAF2 MR P S 7 DCAF17PPP1R12A LRP2 C21orf91 HDAC2 TBRG4 GPX1 XRCC5 SPIN1 RETEWSR1 NUDT11 BCL11BFNDC3ASNTA1 KIF4A TSEN15TECR C19orf10 DCAF13 M X D 1 NT5DC1 DNAJC18 PPP2R5E SLC2A11 ARHGDIA SIM2 HIST1H3A PATL1 EFNA5 PSMD9RBM27 DPY19L4 M E D 30 REV3L PIK3C2A PPARG TRIM28APOH ANKRD13D T M E M 1 0 4 PDE10A PCBP2 EHD1 VPS29 MYO10 SMAD4 APPL2 MEIS2 DLX4 SRC ETFDH TSC2 PRR14 CDC25A SLC11A2 ACACA NAT2 FAM126A LNP1 UTP11L ZNF275AIMP2 S H2D1A BEGAIN RELA CYP4A11 ABCG8 GLYATL1 CADM 1 B3GNT2 YWHAB CHSY3 FAM133B GTF2IRD1 EPHX2 HMGXB4 RYBP RFXAPZNF649 CKAP4 TBP GNAL TMEM14A ACSM5 NEK2 ZC3H14 RARA H S D 1 7 B 6 SLC6A1 CDO1 SYNJ2 C 1 2 o rf7T ME 3 M7 9 C1GALT1C1 CCNT1 REEP6 Z NF 1 0 0 ME OX 1 ADRB2 PEBP1 ASGR1 ARL6IP4 E IF4G2 BCOR RAP1ACDK1 MCMBPARHGEF12 ITGA5 ATG4C SEPT8 EPAS1 CDK9 EED PACS1 H M 1 3 COIL ZFXSMARCA1 HRAS ARID3B CDCA8 RPP14 C6orf62 TTC38 SPATS2L ZNF772 AURKB CHFR DEAF1 PHACTR3 TGFB1I1 RDX EIF4H ZP3EP400NL PLEKHO2 EHHADH SYNCRIP PIAS1 ALDH16A1 UBAP2 PDK3 ANTXR1STX6 MS TSPATS2 O1 C 6 o rf8 9 LY96 NQO2 MP P 2 APBA2 PROC PCYOX1 PUS1 TRUB1STAT4 MAPK11 PHIP UBE2W YTHDC1 PAX6 FOXF2 RAN RHEB RB1 ANAPC5 ELL2 NR3C1 HEXIM 1 DR1 RNF152 DCAF11 PPAPDC1B ASF1A FTL ATP5E V A C 1 4 DZIP3 MY O1F HSPA1AHEXIM1 S NX 2 5 PYCR2 SRM CCNT2 SCFD1 LSM10OGFOD2 ABL1 APRT ZNF267 ILVBL SRPK2 RCN1 SNX8 D H X9 KCTD10 CPN2 ELAVL4 ARID1AMAP1LC3A NR4A2 SYDE1 NME6 HDX YWHAQ DMD IFT122 NCOA6 NFKBIA MYCBP2 FBXO9 UBE2R2 SHANK3 ABL1 TFG ALB RRP12 SLC16A2 SETD7 CASP2 CRHBP ATN1 TNPO1 PHF20L1 MAPK9 STC1 GTF2IRD1 ACADM C10orf12 AHR KDELC2 KLHL8FGFR1OP2 DLGAP4 TMEM2 0 8 GATA4 DAB2 STK38L MPZL1 INTS1 PIK3CA LZTS2 TMTC1 MCRS1 AOX1 AKAP6 CTF1 SYDE1 MAPK8IP1 TSC1 BRIX1 DTNBP1SGK3 TNIP2 ASCC2 SNX13FBXL17 NUCB2 SDSL P ARM1 RAB31 SETDB1 KRIT1 E 2F3 NRSN2 HFE C11orf30 HYOU1 ITGB2 PXK ENTPD1 AP1AR DCTDNKIRAS2 KIFC2 BBS9 ELL GULP1TIMM13 C16orf87 SKI OLFML2A E2F2 BBS10 C6orf136 OPA1 DHX40 CAT NXF 1 MSR1 SELT NAGLU MCC BAZ2A CHUK TBC1D24 MMADHCIGSF10 M T M R 11 RNFT2 CDKN3 RPAP2 LMBRD1 LIMS1 PRDM2 GSTA4 ERP29 ADCK2 PPP3CA GLI1 CASD1 KIAA1147 FM N L3 Z IC3 CEBPB CCNB1 MTOR BFSP1 GGPS1 C5orf15 FB X W 11 NEFM BTF3L4 MAD2L1 HMG20A NBEA TGOLN2 STT3B LATS1 SRSF3 RALGDS ENC1 SEC22B ST5 CYTH1 IR F2 FUNDC2 ZNF184 RREB1 SIK3 W DR82 PPP1R12B DPYSL3 HEG1 ARHGAP29 KLF9 SLC12A4 ARSB GPR155 C21orf2 ABI1 FEN1 TRIM2 ELAVL4 NKX 2-5 SRSF6 LARP6ZNF414 BCL6BGNB4 EPCAM S100A10 FLCN PCDH9 FTO ATPAF1 FAM64A RRAGC M R V I1 PAX2 POLA1 FAM161A DCAF5 HCN2 PDE2A SUFU FAM102B COBLL1MPV17L2 SNRPF S OX 6 UBE3C SLC35F5 LAMP2 JMYZNF429 TES SEMA7A BIRC5 RXRA DST SRP68 STK17A C12orf52 CFL1 MED1 THUMPD1 FHL2 MECP2 CDK2 FYTTD1 TTC17 LSG1 CDT1 GJD3 SDK1 NFIALSM12 ETNK2 NSF MRPL37 ZNF665KEAP1 MRPS33 EIF4G2 ARHGEF3 D D X 3X FRMD4B RANBP1 COIL CCNF KBTBD7 CLIC4 DHRS11 IRAK3 TMF1 RAP2A MCC S H3P X D2B LMO 4 TBX5 FAM174A MGA W D R 5 Z MY ND1 9 SLC25A22PYCRL PTPN11 RICTOR G N G 1 1HN1L RHOT1 C16orf59 CBX3 CLOCK GAS 7 TLCD1 RNASEL SEPT8 DPP8 FLAD1 MSN S N W 1 STAT5B ZNF197 SLC25A39 SMA D 3 SCN4B Z NF 4 6 7 CAV2 UCK2NUDT 19 R B M 43 EFNB1 KANK2 AKAP11 CTCF RBMS 1 HCN1 TXN HNRNPA1 XRCC5 NHS CDK13 NBN NEDD8 PHTF2 CDC42EP4 MEIS1 MED10 U SP11 PLXNC1 NDUFV3 SPATS2L SLC29A2CDKAL1 UHRF2CCNE2 FGFR2 CDC42EP3 NRIP1 Liver TRAF7 S HMT2 XRCC6 ZNF263 SU Z12 CNKSR2 LPPR2 ME N1 E 2F6 ATP2B4 CHD7 FARSA MRPS28 FAM136A HMGA1 C9orf3 C7orf31 CBX5 FURIN CLDN7 PKP3 TACC3 CDKN1A TRIM28KCNMA1 MEMO1 ZCCHC24 CCDC7 KAT7 VIM CCNB1 DYM DVL3 SEC61B MED8 PLEKHG3POLD2 VANGL1 GRINA EZH1 SLC8A1 T ME M97 LBR PNO1 CCNE1 SSBP1 WRNIP1TRAF4 MEIS3P1 C19orf25 LMLN ROR2 PR D M 1 1 CCDC85B CRCT1 HNRNPLSLC25A33 RNF10 C9orf69 NCOR1 PPARA ACADSB KIAA1161 CACNA1C RND2 VDR TRIM41 MIER1 DCUN1D5 PDCD2L SLAIN2 KDELR2 FBXL20 FCHSD2 RO R1 EZH2 CUL4A POC1A PDCD5 TKT PTMA ITGA3 TCF3 RNASEH2A RRP12 SLC25A10 CAST CLIP4 FOXJ2 ZFC3H1 GJA1T OMM4 0 SYNM PCNA Z NF 4 7 3 IKBKE SYNPO2 CAMK2G NFATC3 HDAC3 EED FBXW7 JARID2 BRWD1 TBCEL LMX1A NCOA2 POLL

KTN1 ADCK5 NCOR2 NFKB2ZBTB16 NFATC4 CDKN1C LINGO1

TUBA1BDOLPP1 RHOQHBEGF KDSR FGD1 AR PSMB4 HNRNPFAHNAK2 FBXL12 PIGQ TMEM200B BTRC M I S 12 PLSCR1 CTNNB1 NCOA4

CDC73 CDC34 FAM103A1 25 Outline

• Pan-cancer analysis of miRNA-modulated networks

• Using networks to ascribe miRNA function

• Finding proteins of interest within cancer networks

26 Goal

Characterize miRNA- miRNA mediated networks to : (1) Understand the role of miRNAs across cancers AND (2) Identify signaling proteins of interest that mediate these effects

27 For each network, identify GO terms enriched in nodes related to a single miRNA S

28 T What biological processes do miRNAs regulate?

Breast Colon Liver Lung Pancreas Prostate

miRNAs correlated with Patient prognosis

29 GO biological processes This creates a large graph of miRNAs and functional roles

Identify functional experiments based on network predictions to evaluate role of miRNAs

30 Apoptosis/cell death pathways affected by different miRNAs

Breast Colon Liver Lung Pancreas Prostate

31 Cell cycle-related miRNAs

Breast Colon Liver Lung Pancreas Prostate

32 Outline

• Pan-cancer analysis of miRNA-modulated networks

• Using networks to ascribe miRNA function

• Finding proteins of interest within cancer networks

33 Goal

Characterize miRNA- miRNA mediated networks to : (1) Understand the role of miRNAs across cancers AND (2) Identify signaling proteins of interest that mediate these effects

34 Distinct cancer network value different signaling proteins

KIDINS220 MXI1 ITGB1 DAAM1 RRAGC JAK1 LAPTM5 C16orf45 MYCN ELK3 REST ENOX1 TUBB6 TENC1 HIPK3 MAX STK32BIGFBP5 BEND6COL6A2 STAT5A WISP1 RASSF8 GLI1 MYC MKNK2 SOX9 CSGALNACT2 ELK1 ITGAV PBX3 CREM TCF7L2 MRC2 ITGA5 DUSP1 RSPRY1 ANTXR1 MKNK1 TBPL1 RIF1 GJC1 RUNX3 DYRK1B CASP3 ARID4B NFE2L1 MAP4 MAF ELF2 HMGA1 MOB4 MAPK1TOB1 RFTN1 MAP3K1 SON NUAK1 YAP1 C1S XIAP NRP2 GTF2A1 SLC2A4 IL16 COIL ETS1 KIRREL KIF23 DST MSRB3 SATB1 TGFBR2 CYS1 BTAF1 GTF2E1 XRCC5 YWHAG MAP2K1YWHAH MBD1 PTPN3 BRF2 SETDB1 DAXX MAP3K5 XRCC6 LBR PAX6 BFAR WEE1 PML DVL3 YWHAB UBE2D1 HLX TBP DNMT3B CHST3 ZBTB6 MAP3K3 LTBP1 RDX CBX5 MXRA8 FRMD6 BRIP1 RNF128 RANBP9 LOXL2 NFYA RAF1 RANBP2 KATNAL1 TPM4 KAT7 TUBA1A PRR16 SORBS1 EML1 GLI3 GTF2IRD1 CDCA4 IRAK2 MDM2 ILK BRCA1 PPFIA1 MYB ARHGAP31 COX17 ZNF148 SEMA7A ABL1 PKD2 CALU HIPK2 TJP1 VIM TCF7L1 UBE2I KAT2B YWHAZTRIM28 SYT11 ARL3 MAP3K7 ING4 LARP1 SEMA4C TRAF6 ATP8B2 RFWD2 CREBBP TMEM74B CBX3 TAOK3 HRAS PJA2 ZNF197 FCHSD2 TARBP2 CEBPB FUBP1 TP53 CBX2 BAD MAP2K6RPS6KA5 EIF2AK2 CITED2 WIPI2 DCAF8 TSPAN4 ERCC6 PPARG TMTC1 ATF7 RASA1 BCL2 ATXN7L2 ATF3 MAML1 DDX19A MED26 GPR176PALLD MDM4 ATXN2 COL18A1 EP300 SEPT2 BID MAPK14 IL1R1 EMR2 MDFI SKIL SMAD7 COPS6 AKAP2 ARHGAP10 LYNX1 SMAD4 EGLN3 RHOC COL12A1 C1QTNF6 VHL RGS2 PRKG1 SOS1 BCAS3 ATF2 MYBL2 EGLN1 HOXB9 SMAD1 SMAD2 CUL2 FERMT2 HIF1A KDM5B

SMURF1

Liver Lung Pancreas Prostate Breast MAP4K3 CNNM2 HIF1AN Colon HIVEP2 CLIP1 CLOCK SAT1 ZKSCAN5 ATXN1 EGFR PRKCDBP ZFYVE9 ZNF622 TES CYTH4 GAB1 GRB2 APBB3 ADPRH FASN POU2F2 MED28 STX3 ARNT EXTL3 C14orf1 VPS13B HSPA8 JUN ACVR1 PTN MAP2 ARHGEF17 FGF2 EID1 RBMS1 FAM129A CALD1 SHC1 RPS19 SMAD3 BOC HEXIM1 NFKB2 PRDM4 YTHDC1 FOS

POLR3F SLC25A36 KDR PAPPA GLI2 CCNT1 CDK9

NCOR2 KHDRBS1 CBL BTRC E2F5 DDX3X MSN CCNT2 SKI CDC34 ITGB3AHR NR2C1 CD2AP ZFHX4 RBM6 SEC31AAMOTL1 PIP4K2A LAMA4 BTG3 TRIP11 CHSY1 HDAC3 CRKL TFDP1 RUNX2 RAB3IL1ANXA6 SNW1 PIK3R1 AFAP1L1KLHDC8BRAI14 CHUK PRDM2 NCOA2 FGFR1 IRF9 GHRSRC LMCD1 NOTCH2 NCOR1 SIK3 LAMA5 IKBKAP CYBRD1 SSH1 CD28 KLF10 STAT2 TMEM200B CRK SAMD4A CHEK1 PTPN1 MYLK E2F1 RB1 STAT1 IRS2 SPTY2D1 RELA DCBLD1 SP1SUFU SH2D3C ST3GAL6 VDR THRAP3 NFKBIA E2F3 CDK2 CCNE1 MEF2D KANK3 FBXW7 NCOA6 MAPK7 MCC SUB1 WDR47 MAFB NOTCH4 GPR4 DIXDC1 ASB1 SETD7 UHRF2 CDKN1A PPARA ARMC9 CTSB POU2F1 SLC22A17 ASXL2 EGR1 NAB1 BMPR2 NKX3-2 High weight TGFB1I1 GAS7 IKBKB MED1 HDAC1 SPEN PCNA EPRS TPM2 ZHX2 DNAJB4 HCFC1 GABPA MEX3B PRKD2 PARVA CBFA2T3 GSK3B NIN CHFR POLL NR0B2 RXRA MBD2 LIMS1 FZD8 SIN3A SH3BP5 AKAP11 NR5A2 NCOA3 PANX1 EFEMP2 MED10 SP4 HDAC2 THAP1 MAP3K14 ZCCHC24 LAMC1 LTBP3 SNX18 CTBP1 RBL1 FAM20C MED31 DEAF1 MOV10L1 ZEB1 SP3 RARA HEYL ZMYM2 ASCC2 FILIP1L HBP1 MXD1 MED8 EED ZNF532 HSPA6 KLHL5 CBX4 CKAP4 NR4A2 BEGAIN PLAG1 LPL GEM EZH2 Medium weight EZH1 RAB3GAP1 PTPN4 SH3PXD2B ELK4 KLF3 CLIP4 KPNA2 DPYSL3 HSD17B6 CUX1

FLI1 KLF4 SGK1 TLE4 35 Not in network Core nodes are shared across all networks • These nodes include common cancer drivers: – Hif1a – Grb2 – Src – TP53 – Myc

High weight

Liver Lung Pancreas Prostate Breast Colon Medium weight

Not in network 36 We can identify signaling proteins UNIQUE to specific cancer networks • Androgen receptor is uniquely selected by the prostate cancer network

Lung Liver Pancreas Prostate Breast High weight Colon

Medium weight

37 Not in network Nodes specific to particular cancer networks warrant further study • Smarca5 is unique to breast cancer

• We also found Dazap2 unique to pancreatic cancer. Dazap2 has been found to be down- regulated in melanoma but relatively unstudied in other High weight cancers.

Prostate Liver Lung Pancreas Breast Medium weight Colon

Not in network

Summary

• Using miRNA expression, miRNA expression and DNase I hypersensitivity data we can create miRNA networks of influence across various cancer types • These networks can be used to identify testable hypotheses to better understand the function of miRNAs in cancer • Combining miRNA and mRNA measurements in a network setting enables identification of key intermediate proteins 39 Ongoing work Text 6/30/2014 Fraenkel Lab - SAMNet Web Server • Network Home

People

Software and Tools permutation to Welcome to the web interface of SAMNet, or Simultaneous Analysis Publications / Downloads of Multiple Networks. This tool should help you analyze multiple gene expression datasets with upstream data. You can select from the examples we've provided below or enter your own files. Please SAMNetWeb read the tutorial for information on how to format your files. select targets

Job Submission Source Weights File (e.g. protein/genetic weights) Tutorial Upload protein weights file here*: SAMNetWeb Examples Choose File No file chosen Job Status OR select a test dataset: for validation Note: Protein node names must be consistent with protein node naming in the interactome or protein-mRNA weights file. Some external pages can be used to convert names if needed, such as DAVID, or HUGO. • Sink Weights File (e.g. mRNA weights) Functional Upload mRNA weights file here*: Choose File No file chosen http://fraenkel.mit.eduOR select a test dataset: /samnetweb experiments

Protein-protein Interaction File Upload an interactome here: Choose File No file chosen OR select a database interactome: • Validating Connecting mRNA weights to interactome Upload protein-mRNA edge weights file here*: Choose File No file chosen

OR select a database for TF to DNA interactions: nodes of

OR Check here to connect sink weights directly to interactome: Use sink weights directly interest Gamma (Default - 14): Hierarchical Use hierarchical capacities Capacities: (optional: for notification of 40 Your Email Address: Gosline et al., under review job status) (optional: limited to 3 Your user ID: characters)

References: 1. Gosline S.J.C., Spencer S.J., Ursu O., Fraenkel E. (2012) SAMNet: a network-based approach to integrate multi-dimensional high throughput datasets, Integrative Biology, 4:1415-27.

This website is free and open to all users and no login required.

© Copyright The Fraenkel Lab 2014, Massachusetts Institute of Technology. For more information contact fraenkel-[email protected] http://fraenkel-nsf.csbi.mit.edu/samnetweb/ 1/2 Acknowledgements Fraenkel Present: Funding: • Ernest Fraenkel National Cancer Institute: Integrative cancer • Amanda Daigle Biology Program • Toby Ehrenberger Travel funding to ISMB 2014 was generously • Martina Koeva provided by NSF. • Pamela Milani • Chris Ng • Coyin Oh • Natasha Patel-Murray • Leila Pirhaji • Gabriela Pregernig • Anthony Soltis • Meena Subramanian • Nurcan Tuncbag • Jen Wilson • Xiaofeng Xin • Ferah Yildirim

41 Questions?

42 Protein-DNA interactions collected from ENCODE and TRANSFAC S

Colon

Liver

Lung

Breast

Prostate

Pancreas 7/7/2014 Genes Transcription Factor of DNA Binding Sites & Gene Regulation - BIOBASE Biological Databases

ABOUT US PRODUCTS SOLUTIONS SERVICES LIBRARY NEWS & EVENTS

TRANSFAC® Transcription Factor Binding Sites

TRANSFAC® is a unique knowledge-base containing published data on eukaryotic PRODUCTS transcription factors and miRNAs, their experimentally-proven binding sites, and regulated genes. The extensive compilation of binding sites provides the most comprehensive data set of transcription factor – gene interactions available. The same data also forms the basis of HGMD® derived positional weight matrices which can be used with the included Match™ tool to 43 PGMD™ search DNA sequences for putative transcription factor binding sites – a method that is crucial for filling in gaps in the published literature. Integrated transcription factor ChIP-Seq, DNase TRANSFAC® hypersensitivity and histone methylated intervals from the ENCODE project complement the curated and predicted binding site data. Genome Trax™ Watch a short video

ANNOVAR™ Comparative promoter analysis of high-throughput microarray data based on TRANSFAC® positional weight matrices is provided in the companion ExPlain™ Analysis System, while the companion Genome Trax™ provides a ExPlain™ platform for mapping next generation sequencing variations to transcription factor binding sites characterized in TRANSFAC®. PROTEOME™

BRENDA

POSSUMweb

http://www.biobase-international.com/product/transcription-factor-binding-sites 1/1 Ongoing work: network validation

• Network permutation to select targets for validation • Functional experiments • Validating nodes of interest

44 Proteins selected stay constant are not detectable via mRNA seq, but found otherwise? • Find an example via RPPA or mutations

45 SAMNet is able to find functional enrichment of distinct commodities and key interactions/nodes.

Beta-Catenin-TCF7L2 interaction

46 Gosline et al., Integrative Biology 2012 Or using correlation data across patient samples

47 SAMnet identify edges in network that best connect ‘flow’ from one dataset to another

48 Gosline et al. Integrative Biology 2012 miRNA signaling is drive by small number of interactions • What fraction of targets are selected? What else can we say about this? Ask this later.

49 Ability to predict miRNA targets raises more questions

Search for predicted microRNA targets in mammals [Go to TargetScanMouse] [Go to

TargetScanWorm] PicTar WEB INTERFACE[Go to TargetScanFly]

1. Select a spCecihoosese S p e cieHumans: vertebrate

Choose Dataset: target predictions for all human microRNAs based on conservation in mammals (human, chimp, mouse, rat, dog) AND microRNA ID: hsa- let- 7a Click above for all microRNAs linked to RFAM 2. Enter a human Entrez Gene symbol (e.g. "LIN28") Gene ID: Click above for all RefSeq Id's linked to NCBI (Warning: may take ~20 secs) vertebrates: use RefSeq identifiers, e.g. NM_003483 or Gene symbols (for example HK2). AND/OR Tissue: 3. Do one of the following:

Search for targets of a miRNA Search for all miRNAs predicted to target a Gene Se arch for Tissue reset Select a broadly conserved* microRNA family Broadly conserved microRNA families

Select a conserved* microRNA family Conserved microRNA families

Select a poorly conserved microRNA family Po orly conserved microRNA families 50 Enter a microRNA name (e.g. "mmu-miR-1")

Go to TargetScan Custom if your RNA is not included in the microRNA families listed above.

Submit Reset

* broadly conserved = conserved across most vertebrates, usually to zebrafish conserved = conserved across most mammals, but usually not beyond placental mammals

TargetScan predicts biological targets of miRNAs by searching for the presence of conserved 8mer and 7mer sites that match the seed region of each miRNA (ref. 1). As an option, nonconserved sites are also predicted. Also identified are sites with mismatches in the seed region that are compensated by conserved 3' pairing (ref. 3). In mammals, predictions are ranked based on the predicted efficacy of targeting as calculated using the context scores of the sites (ref. 2). TargetScanHuman considers matches to annotated human UTRs and their orthologs, as defined by UCSC whole-genome alignments. Conserved targeting has also been detected within open reading frames (ORFs). A listing of these ORF sites can be found at the bottom of Supplemental Table 2 of reference 1.

This search page of TargetScan Release 5.2 retrieves predicted regulatory targets of mammalian microRNAs. Many targets are the same as those presented in previous versions of the TargetScan site (Releases 2.0, 2.1, 3.0, 3.1, and 4.0 - 4.2). Compared to previous releases, Release 5.2 considers site conservation in many more genomes, uses more sensitive methods to detect conservation, and reports when appropriate the probability of preferentially conserved targeting (ref. 3). We can integrate using individual over-expression experiments

51 Or using correlation data across patient samples

52 Or using static model organism data Integrated Regulatory Network Analysis Construction and Analysis of an Integrated Regulatory Network Derived from High-Throughput Sequencing Data

Ch ao Ch eng1,2, Koon-Kiu Yan1,2, Woochang Hwang3, Jiang Qian3, Nit in Bhardwaj 1,2, Joel Rozowsky1,2, Zhi John Lu1,2, Wei Niu4, Pedro Alves2, Masaomi Kato5, Michael Snyder6, Mark Gerstein1,2,7* 1 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, United States of America, 2 Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, United States of America, 3 Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 4 Department of Genetics, Yale University, New Haven, Connecticut, United States of America, 5 Department of Molecular Cellular Developmental Biology, Yale University, New Haven, Connecticut, United States of America, 6 Department of Genetics, Stanford University, Stanford, California, United States of America, 7 Department of Computer Science, Yale University, New Haven, Connecticut, United States of America

Abstract We present a network framework for analyzing multi-level regulation in higher eukaryotes based on systematic integration of various high-throughput datasets. The network, namely the integrated regulatory network, consists of three major types of regulation: TFR gene, TFR miRNA and miRNAR gene. We identified the target genes and target miRNAs for a set of TFs based on the ChIP-Seq binding profiles, the predicted targets of miRNAs using annotated 39UTR sequences and conservation information. Making use of the system-wide RNA-Seq profiles, we classified transcription factors into positive and negative regulators and assigned a sign for each regulatory interaction. Other types of edges such as protein-protein interactions and potential intra-regulations between miRNAs based on the embedding of miRNAs in their host genes were further incorporated. We examined the topological structures of the network, including its hierarchical organization and motif enrichment. We found that transcription factors downstream of the hierarchy distinguish themselves by expressing more uniformly at various tissues, have more interacting partners, and are more likely to be essential. We found an over- representation of notable network motifs, including a FFL in which a miRNA cost-effectively shuts down a transcription factor and its target. We used data of C. elegans from the modENCODE project as a primary model to illustrate our framework, but further verified the results using other two data sets. As more and more genome-wide ChIP-Seq and RNA- Seq data becomes available in the near future, our methods of data integration have various potential applications.

Citation: Cheng C, Yan K-K, Hwang W, Qian J, Bhardwaj N, et al. (2011) Construction and Analysis of an Integrated Regulatory Network Derived from High- Throughput Sequencing Data. PLoS Comput Biol 7(11): e1002190. doi:10.1371/journal.pcbi.1002190 Editor: Nathan D. Price, Institute for Systems Biology, United States of America Received December 17, 2010; Accept ed July 27, 2011; Published November 17, 2011 Copyright: ß 2011 Cheng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work is supported by the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]

Introduction near their target genes, while miRNAshybridize to RNA elements mostly located in the 39 untranslated region (39UTR) of their Eukaryotic gene regulation isperformed at multiple levels, each target mRNAs. TFs and miRNAs tightly coordinate with each 53 distinguished by different spatial and temporal characteristics. The other to ensure accurate and precise gene expression. Further- Figure 1. Schematiccombinationdiagramand orchestrationof the constructionbetween regulatory mechanismsand analysisin more,of thetranslatedintegrativeproteinsform regulatorycomplexesvia physicalnetwork.interactions.ChIP-seq data were used to various levels are central to a precise gene expression pattern, These complexes can function only if their constituents are determine target geneswhichandis essentialmiRNAsto ofmanytranscripticritical biologicalon factors.processesmiRNA[1,2].targetproperlygenesregulated.were predictedTherefore, eachusingTFPicTaror miRNAor TargetScanregulates a algorithms together with conservation informatioTranscriptionaln. The threeregulationtypesandof post-transcriptionalregulations formregulation,the basic largenetwork.numberTheof interactingsign oftargeteachgenesregulatory[8–11] andinteractiondifferent TFs was determined based on the correlation betweenmediatedTFbybindingregulatorsandincludinggenetranscriptionexpressiofactorsn, Extra(TFs)edgesand ofandprotein-miRNAsproteincontroloroneTF-TFgene combinin a combinatorialatorial interactionmanner s were incorporated. We studied the topologicasmalll non-codingstructureRNAs,of thesuchintegratedas microRNAsnetwork,(miRNAs),includingare two hierarchi[3,12,13]. calThisorganizationessentially formsandan integratedmotif enrichmengene regulatoryt. of the most important regulatory mechanisms [3,4]. At the network by connecting TFs and miRNAs with their interacting doi:10.1371/journal.pcbi.1transcriptional002190.g001level, TFs bind to promoters and enhancers to targets. A deep investigation of this network would help to further either activate or repress gene transcription [4]. At the post- understand the ‘‘language’’ of gene expression regulation at transcriptional level, miRNAs repress the expression of genes by multiple levels. downstream of thedegradingpre-miRNA.or inhibitingApartthe translationfrom C.ofeleganstheir target, wemRNAsapplied Networkprotein-codinganalysis has provengenesto beanduseful160in unravelingmiRNAs.the There are 22,096 TF- the same scheme to[5,6].identifyIn spiteTF-Geneof the dramaticanddifferencesTF-miRNAin their molecularinteractionstypes, complexitygeneof(includingbiological regulationTF-TF)[14–16].interactions,Different approaches452 TF-miRNA interactions, TFsand miRNAs share a common ‘‘logic’’ for the control of gene can be employed to gain more insight into the design principles of for human and mouseexpressionbased[7]. Bothonof themChIP-Seqare trans-actingdatafactorsfor that13functionTFs in biologicalandnetworks.10,069Recently,miRNA-genestudies have showninteractionsthat transcrip-(Figure 2). The number of human K562 cell line,throughandrecognizing12 TFsandinbindingmousespecificembryoniccis-regulatorystemelementscells tional targetsregulation variesfollowsa hierarchicaldramaticallyorganizationamongand regulatorsthe 22 TFs, e.g. the number of [41] (see MaterialsinandDNA Methods).or RNA. TFs bind to DNA elements often located in or at differentmiRNAlevelshavetargetstheir ownrangecharacteristicsfrom 2[17].to In73particular,with a median of 17. Although m iRNA-Gene r egulator y networ k. Predicted targets of the difference in target numbers may arise due to experimental PLoS Computational Biology | www.ploscompbiol.org 1 November 2011 | Volume 7 | Issue 11 | e1002190 miRNAs are identified by PicTar or TargetScan algorithm. In parameters such as the sequencing depth and the data quality, it C. elegans, we further refined the predictions by taking into account also reflects the biological functions of transcription factors. For the conservation of miRNA seed sitesin three (C. elegans, C. briggsae, the 22 TFs, the number of target protein coding genes and the C. remanei) or five (C. brenneri, C. japonica additionally) species. A number of target miRNAs are positively correlated (r = 0.9, 2 8 more detailed description can be found in [42]. Briefly, we P, 10 ). We compared the number of regulatory miRNAs for identified a total of 20,427 predicted conserved target sites within TFswith that of non-TFsand found that non-TF mRNAswere on 4,866 39UTRs for 2,244 genes. This set of predicted miRNA- average regulated by 4.6 miRNAs, whereas TF mRNAs were mRNA binding sites constitutes a framework for potential regulated by 6.3 miRNAs. This suggests that miRNAs are more interactions underlying miRNA post-transcriptional regulatory likely to regulate TFs than non-TFs (P = 1.2E-6, Wilcoxon Rank networks in C. elegans. In human and mouse, miRNA targets are Sum test), which is consistent with previous reports [25]. downloaded from [43,44] and predicted by TargetScan algorithm, To have a systematic overview of the integrated network, we which also take into account the conservation of miRNA binding examine the degree distribution of the network. As a result of site across multiple mammalian species. different typesof nodesand edges, there are several kindsof degree distributions (Figure 3). We examined the number of regulatory TFs for miRNAs as well as for protein-coding genes, and found Basic topology of the C. elegans integrated regulatory that both are best fitted by an exponential distribution (R2= 0.86, network 0.84), implying that a single target gene or miRNA isless likely to The basic integrated regulatory network of C. elegans consists of be regulated by many TFs simultaneously (Figure 3, top left and three types of nodes: 393 TFs (among which 22 have target right). The number of target genes, and target miRNAs for the 22 protein-coding genesand target miRNAsavailable), 5,574 non-TF TFs, on the other hand, are shown in Table S4. While it ishard to

PLoS Computational Biology | www.ploscompbiol.org 3 November 2011 | Volume 7 | Issue 11 | e1002190 Regression based analysis of GBM in patient data identifies TFs and MiRs

54 miRNA-mRNA expression integration

• Tsang et al, Mol Cell 2007 Looked for expression patterns among miRNA within introns of known genes

• Schmeier et al., BMC Genomics 2009 Used time course data to identify transcription factors that activate miRNAs miRNA

56 KEGG Abundance hsa-miR-183-5p hsa-miR-375

hsa-miR-30a-5p hsa-let-7f-5p hsa-miR-194-5p hsa05200:Pathways hsa-miR-10b-5p in hsa04210:Apoptosis hsa04914:Progesterone-mediated hsa-miR-10a-5p cancer hsa05221:Acute oocyte hsa05014:Amyotrophic myeloid hsa05222:Small maturation hsa04320:Dorso-ventral lateral leukemia cell hsa04720:Long-term axis sclerosis lung hsa-miR-122-5p potentiation formation hsa04664:Fc (ALS) cancer epsilon hsa05215:Prostate hsa04662:B RI hsa04916:Melanogenesis hsa03050:Proteasome cell hsa04622:RIG-I-like signaling cancer hsa04110:Cell receptor receptor hsa04623:Cytosolic cycle hsa05212:Pancreatic pathway signaling signaling DNA-sensing pathway cancer hsa05220:Chronic hsa04062:Chemokine pathway pathway signaling hsa04621:NOD-like hsa04010:MAPK myeloid pathway receptor hsa-miR-182-5p signaling leukemia signaling hsa05223:Non-small pathway hsa04370:VEGF pathway hsa05218:Melanomahsa04630:Jak-STAT hsa-let-7b-5p signaling cell signaling pathway hsa05016:Huntington's hsa04912:GnRH pathway lung hsa00280:Valine, disease hsa04660:T hsa05120:Epithelial hsa-miR-30d-5p signaling leucine cancer cell and cell pathway signaling isoleucine hsa04115:p53 receptor hsa05213:Endometrial hsa05214:Glioma in degradation signaling signaling cancer pathway hsa05130:Pathogenic Helicobacter hsa05211:Renal hsa04620:Toll-like pathwayEscherichia pylori hsa05210:Colorectal receptor hsa04722:Neurotrophin coli infection cell cancer signaling signaling infection carcinoma pathway pathway hsa04310:Wnt hsa05216:Thyroid signaling hsa04510:Focal hsa04520:Adherens hsa04540:Gap cancer pathway adhesion junction junction hsa-miR-21-5p hsa05219:Bladder cancer hsa04012:ErbB signaling hsa-miR-99b-5p pathway hsa00071:Fatty acid hsa-let-7a-5p hsa-miR-192-5p metabolism hsa04330:Notch signaling hsa04910:Insulin hsa04810:Regulation pathway signaling of actin pathway cytoskeleton 57