Supplementary Tables

Supplementary Table 1. Differentially methylated genes in correlation with their expression pattern in the A4 progression model

A. Hypomethylated–upregulated Genes (n= 76)

ALOX5 RRAD RTN4R DSCR6 FGFR3 HTR7 WNT3A POGK PLCD3 ALPPL2 RTEL1 SEMA3B DUSP5 FOSB ITGB4 MEST PPL PSMB8 ARHGEF4 BST2 SEMA7A SLC12A7 FOXQ1 KCTD12 LETM2 PRPH PXMP2 ARNTL2 CDH3 SHC2 SLC20A2 HSPA2 KIAA0182 LIMK2 NAB1 RASIP1 ASRGL1 CLDN3 DCBLD1 SNX10 SSH1 KREMEN2 LIPE NDRG2 ATF3 CLU DCHS1 SOD3 ST3GAL4 MAL LRRC1 NR3C2 ATP8B3 CYC1 DGCR8 EBAG9 SYNGR1 TYMS MCM2 NRG2 RHOF DAGLA DISP2 FAM19A5 TNNI3 UNC5B MYB PAK6 RIPK4 DAZAP1 DOCK3 FBXO6 HSPA4L WHSC1 PNMT PCDH1

B. Hypermethylated-downregulated Genes (n= 31)

ARHGAP22 TNFSF9 KLF6 LRP8 NRP1 PAPSS2 SLC43A2 TBC1D16 ASB2 DZIP1 TPM1 MDGA1 NRP2 PIK3CD SMARCA2 TLL2 C18orf1 FBN1 LHFPL2 TRIO NTNG2 PTGIS SOCS2 TNFAIP8 DIXDC1 KIFC3 LMO1 NR3C1 ODZ3 PTPRM SYNPO

Supplementary Table 2. Genes enriched for different histone methylation marks in A4 progression model identified through ChIP-on-chip

a. H3K4me3 (n= 978)

AATF C20orf149 CUL3 FOXP1 KATNA1 NEGR1 RAN SPIN2B ABCA7 C20orf52 CWF19L1 FRK KBTBD10 NEIL1 RANBP2 SPPL2A ABCC9 C21orf13-SH3BGR CXCL3 FSIP1 KBTBD6 NELF RAPGEF3 SPRY4 ABCG2 C21orf45 CYC1 FUK KCMF1 NFKB2 RARB SPRYD3 ABHD7 C22orf32 CYorf15A FXR2 KCNH7 NGDN RASAL2 SPTLC2 ACA15 C2orf18 DAXX FZD9 KCNMB4 NKAP RASD1 SRFBP1 ACA26 C2orf29 DAZ3 G6PD KCTD18 NKTR RASEF SRI ACA3 C2orf32 DBF4 GABPB2 KDELR2 NNT RASGRF1 SRM ACA48 C2orf55 DBF4B GABRA5 KIAA0100 NOL5A RASSF1 SSH2 ACAT1 C3orf44 DBI GADD45B KIAA0226 NOLC1 RASSF3 SSH3 ACSL5 C5orf15 DCBLD2 GALNT10 KIAA0265 NOVA1 RAVER2 SSSCA1 ACTR10 C5orf34 DCI GALNT4 KIAA0513 NPY1R RB1CC1 STAG1 ADAM10 C5orf39 DCTD GALNT6 KIAA0564 NR4A2 RBJ STARD3NL ADAMTS7 C6orf134 DCUN1D5 GAS1 KIAA0664 NRAS RBL2 STK25 ADH5 C6orf138 DDB1 GBX2 KIAA1012 NRD1 RBM26 STK40 ADHFE1 C6orf166 DDHD1 GCC1-ARF5 KIAA1279 NT5C3 RBPJ STON2 ADRA1D C6orf48 DDX31 GCN1L1 KIAA1344 NT5E RCOR1 STX18 AGPAT5 C6orf66 DEAF1 GDF5 KIAA1429 NTN4 REV3L STXBP1 AGPAT7 C7orf44 DECR2 GDF9-UQCRQ KIAA1715 NUDT13 RFX5 SUCLG1 AGR3 C8orf32 DEPDC1B GDI2 KIAA1804 NUDT2 RHOF SUGT1 AGTPBP1 C8orf37 DGUOK GFRA1 KIAA1826 NUP153 RHPN2 SUMO1 AGTR1 C8orf42 DHX30 GFRA4 KIF27 NUP54 RLF SUMO2 AKR1B1 C8orf55 DIO2 GLRX2 KLF5 NUP93 RNF152 SUPT3H AKR1C3 C8orf58 DIP2A GLS KLHL11 OCLN ROBO4 SWAP70 ALDH1A2 C9orf125 DIP2C GLT8D2 KLHL20 OLFML3 ROCK1 SYNCRIP ALKBH5 C9orf21 DKK3 GM2A KLHL8 OPLAH ROD1 SYT3

ALKBH7 C9orf7 DLX2 GMDS KPNA4 OR1D2 RPL11 TACSTD1 ALS2CR4 C9orf82 DMTF1 GMPR KPNA5 OR2L13 RPL13 TAF10 AMIGO2 CA13 DMXL1 GNS KRT24 OR5R1 RPL27A TAF1B AMMECR1L CABC1 DNAJC10 GOLPH4 Kua ORC4L RPP21 TAGLN2 AMPD2 CALCR DNAJC19 GPAA1 LAMC1 ORC5L RPS6KA2 TARBP2 ANAPC1 CALM1 DNASE2 GPATCH8 LANCL1 OSBP RRM1 TBN ANKRD10 CALN1 DOCK7 GPC3 LASS1 OSGIN2 RRM2B TCEB2 ANKRD11 CAMTA2 DOCK9 GPER LBH OSR2 RSHL3 TCF12 ANKRD45 CAPRIN2 DPPA3 GPKOW LBR PAICS RTCD1 TCFL5 ANXA1 CASC3 DSC2 GPR108 LBX2 PAIP1 RTF1 TDRD5 ANXA3 CASP2 DSG2 GPR113 LCA5 PAQR7 RTN4 TDRKH ANXA4 CBARA1 DTNB GPR125 LDHB PARC RUNX1 TFAP2B AP3B1 CBLB DUSP4 GPR158 LENG8 PATZ1 RUNX3 TFIP11 AP3B2 CBR4 DYNC1H1 GPR162 LEPR PAXIP1 RUSC2 TGS1 AP3M2 CBY1 DZIP1L GPR63 LGR5 PBLD RWDD1 THAP7 AP4E1 CC2D1B ECT2 GRID1 LHFPL1 PCDH9 SAMD4A THOC5 APBA1 CCDC4 EDC3 GRIK2 LHX3 PCDHB11 SAMD9L TIGD2 APOL1 CCDC55 EDN1 GRINL1A LIMD1 PCDHB3 SAP30L TIMELESS APPBP2 CCDC57 EGR2 GRM1 LIN54 PCF11 SAPS1 TMC4 ARF5 CCDC66 EHD1 GRWD1 LOC128977 PCNA SASH1 TMCO1 ARFGEF1 CCDC77 EIF3S3 GSPT1 LOC144097 PDHA1 SATB2 TMED2 ARHGAP29 CCDC88A EIF3S6 GSR LOC196463 PDIK1L SCFD2 TMED5 ARHGDIA CCDC96 EIF4B GSTA4 LOC342897 PDK4 SCN3B TMEFF1 ARHGEF10 CCNG2 EIF4ENIF1 GSTO2 LOC440742 PDSS1 SCPEP1 TMEM1 ARHGEF11 CCNJL ELAC2 GTF2B LOC497661 PECI SCYL1BP1 TMEM132A ARHGEF12 CCR7 ELF2 GUCA1B LRP10 PEX5L SDPR TMEM134 ARIH1 CD151 ELF3 GUK1 LRP12 PFKP SEC24C TMEM139 ARL8B CDAN1 ELOVL1 H2AFX LRRC6 PGM2 SECISBP2 TMEM144 ARMC7 CDC2L5 EML5 H2AFZ LRRC8D PHF1 SELENBP1 TMEM150 ARMC9 CDC42BPA ENO1 HBII-240 LRRTM4 PHF10 SELL TMEM154 ARNTL CDC42BPG ENOSF1 HBII-429 LTV1 PHIP SELT TMEM16D ARRDC2 CDC42EP3 EOMES HBII-55 LYPLA1 PHTF1 SEMA3A TMEM18 ARRDC3 CDCA4 EPHA4 HBS1L MADD PIAS1 SEMA6A TMEM25 ARS2 CDCA7 EPHA7 HEBP2 MAL2 PIGK SENP3 TMEM32 ARTS-1 CDH11 ERBB4 HELB MAN2B2 PIK3CG SENP7 TMEM55A ASB5 CDK10 ERCC2 HERC1 MAP3K7 PIK3R2 SERF2 TMEM60 ASMT CDK8 ERF HERC4 MAP3K8 PIM1 SERINC4-HYPK TMEM63A ATBF1 CDKN2AIP ERGIC2 HES4 MARK4 PKM2 SERTAD3 TMEM87B ATE1 CDKN2B ERGIC3 HIST1H3H MBOAT2 PLSCR1 SETD8 TMEM9 ATP5A1 CDKN2D ERLIN1 HIST1H3I MBTPS1 PMP22 SETDB1 TMEPAI ATP5G3 CEBPA ERO1L HIST1H4K MCFD2 PODN SFXN4 TMPO ATP5J CEBPD ETS1 HLA-F MCM2 POLD2 SH3BP4 TMPRSS3 ATPBD4 CEECAM1 ETV1 HLF MCM3 POLR2C SH3GLB2 TNFSF18 ATXN1 CENPF ETV6 HMGA1 MCRS1 POLS SH3RF2 TNIP1 AVPR2 CEP250 EVA1 HMGA2 MEIS1 POU4F1 SHC1 TNPO2 AXIN1 CFB EVI1 HMGCLL1 MEIS2 PPAP2A SHC4 TOMM70A AZIN1 CFL2 EXOSC2 HNRPC MEN1 PPAP2C SIX4 TOP2A B2M CFLAR FA2H HNRPH1 MESDC1 PPARGC1A SKAP2 TPCN2 B3GALT1 CHD3 FADS1 HOXA6 METRNL PPIC SKIL TPI1 BCDO2 CHID1 FAM120AOS HOXB3 MFAP1-WDR76 PPIG SLC12A2 TPM1 BCL6 CHKB FAM130A1 HOXB7 MFSD2 PPIL3 SLC12A9 TRAP1 BHLHB2 CITED2 FAM13A1 HR MGAT4B PPM1F SLC16A6 TRHDE BIRC2 CKAP2L FAM3A HSD17B4 MGC33894 PPP1CB SLC1A4 TRIM39 BLCAP CLASP1 FAM3C HSDL2 MGC39900 PPP1CC SLC25A22 TRIM68

BMP5 CLCA1 FAM40A HYPK MGC45491 PPP1R13B SLC25A40 TRNT1 BNIP2 CLEC1B FAM83H ICA1 MGC50559 PPP1R9B SLC2A8 TRPM1 BOLL CLPP FAM98B ID3 MLL4 PPP4C SLC30A6 TRPS1 BRUNOL5 CLSTN1 FANCA IDE MLL5 PPRC1 SLC35B1 TSHR BTBD10 CNKSR3 FANCC IER3IP1 MLSTD1 PPTC7 SLC35D3 TSPAN12 BVES CNP FAS IFIT3 MME PRDM5 SLC35E3 TSPYL5 C10orf10 CNTD2 FASTK IFIT5 MRP63 PRDX1 SLC36A1 TTL C10orf137 CNTN6 FAT IFITM1 MRPL39 PREP SLC36A2 TUBB2A C11orf24 COBL FBXL17 IFT74 MRPS26 PREX1 SLC38A2 TUBB4 C11orf52 COL21A1 FBXL4 IGF2BP2 MRPS36 PRIM1 SLC44A1 TUSC4 C12orf10 COL5A1 FBXO21 IGSF2 MSH3 PRKAA1 SLC44A3 U15A C12orf30 COMMD5 FBXO5 IKZF2 MSRB3 PRKAA2 SLC5A4 U21 C14orf2 COMTD1 FBXW7 IL13RA1 MTF2 PRKAB2 SLC5A6 U45B C14orf32 CORO1A FEM1C IL15RA MTMR11 PRKCQ SLC5A8 U54 C14orf37 COX6B1 FER1L3 IL2 MTMR15 PRPF38B SLC6A5 U59A C15orf15 CP FGF12 IL31RA MTMR2 PRPF4B SLC7A5 UAP1 C15orf27 CPNE1 FGF7 ILKAP MTP18 PRPS1L1 SLC8A3 UBE2D2 C15orf37 CPSF1 FH IMPAD1 MTPN PRR13 SLC9A6 UBE2G2 C17orf57 CREBL2 FIBCD1 ING1 MTX2 PSCD2 SLCO3A1 UBE2W C17orf81 CREBZF FKBP2 INHA MVD PSMA5 SLFN11 UBP1 C18orf10 CROP FLJ11286 INPPL1 MVP PSMC6 SMARCAD1 UFM1 C19orf20 CRSP8 FLJ16641 INTS3 MYBPC2 PTN SMARCC1 UFSP1 C1QTNF7 CRTAP FLJ20309 INTS5 MYH7B PTPN13 SNAPC2 UNC13B C1orf114 CSDA FLJ32312 IREB2 MYO9B PTPN9 SNAPC3 UNC45A C1orf121 CSF1R FLJ32447 IRX5 NARS PTPRA SNRPA1 UNC5C C1orf149 CSNK2A1 FLJ37953 ISGF3G NASP PTPRB SNTB1 UNG C1orf151 CTAG2 FLJ38482 ISOC1 NCOA5 PTPRJ SNUPN UNKL C1orf183 CTAGE5 FLNA-EMD ISY1 NDNL2 PWP1 SNX8 UNQ9217 C1orf51 CTGF FLT4 ITGAE NDRG4 RAB11A SPAG9 UPF1 C20orf108 CTSC FLYWCH1 ITGB8 NDST1 RAB30 SPATA4 USP3 C20orf112 CTTNBP2NL FOXC2 JUB NDST2 RAB7L1 SPATA5L1 USP46 C20orf12 CUL1 FOXJ3 K4 NDUFA5 RAI16 SPATA7 VAMP8 VDAC2 WDR53 ZBTB20 ZKSCAN3 ZNF35 ZNF639 hsa-mir-335 VDAC3 WDR77 ZBTB43 ZKSCAN5 ZNF354B ZNF643 hsa-mir-378 VEPH1 WDSUB1 ZBTB7A ZMYM3 ZNF385 ZNF672 hsa-mir-448 VPS37D WEE1 ZBTB8 ZNF217 ZNF391 ZNF691 hsa-mir-542 VPS4B WHSC1 ZCCHC12 ZNF248 ZNF41 ZNF692 hsa-mir-554 VPS53 WNT7A ZDHHC5 ZNF250 ZNF452 ZNF706 hsa-mir-559 VPS72-PIP5K1A WRB ZFAT1 ZNF259 ZNF480 ZNF781 hsa-mir-642 VRK2 XBP1 ZFP30 ZNF271 ZNF488 ZNF786 hsa-mir-9-1 WAPAL XPA ZFP64 ZNF281 ZNF528 ZNF787 hsa-mir-99a WBSCR16 XPO1 ZFYVE20 ZNF285A ZNF533 hsa-mir-137 WDR34 YPEL3 ZHX1 ZNF311 ZNF565 hsa-mir-219-1 WDR51A ZBTB2 ZHX2 ZNF32 ZNF608 hsa-mir-23a

b. H3K9me3 ( n= 497)

AADACL2 ENDOGL1 LRRC3B RFC3 DYX1C1 LOC399947 RAD54L2 hsa-mir-147 ABCB4 EPB41L4A LYNX1 RFPL4B C1orf128 HAGHL OR13C3 TEKT2 ACA28 EPN1 LYPLAL1 RFXAP C20orf43 HBG2 OR1A2 TFAP2A ACA30 EXOC3L2 M6PR RGS11-ARHGDIG C21orf34 HBII-85-24 OR2A2 TGIF2LY ACA67-C21orf119 FAM107B MAF RHOBTB3 C21orf51 HCN1 OR2T10 TGOLN2 ACCN1 FAM113B MAGEA11 RIT2 C3orf17 HDC OR2T11 TLR2 ACHE FAM117A MAGEA8 RMND5B C3orf19 HDGFRP3 OR4C15 TLR3

ACTRT1 FAM131B MAGEB4 RNF126 C3orf39 HES5 OR4C16 TM6SF2 ADAM12 FAM13C1 MAP2K4 RNF7 C4orf16 HES6 OR4C3 TMEM133 ADCY4 FAM14A MAP3K7IP2 RPL26L1 C5orf29 HIC1 OR4K14 TMEM174 ADH4 FAM47B MARS2 RPS4Y1 C6orf182 HIST1H1B OR4Q3 TMEM5 AEBP2 FAM53A MBNL3 RSAD1 CA2 HIST1H2BE OR51B5 TMEM81 AHR FAM73B MBTPS2 RSPO1 CALML5 HN1L OR51I1 TMLHE AIRE FAM83C MED28 RTBDN CAPN1 HOXA2 OR52N4 TMPIT AKAP12 FASN MFAP1 RUFY1 CASP5 HPS6 OR52N5 TP53I3 AKR1C4 FBN1 MGAM SCN1B CBLN4 HPSE2 OR56A1 TRERF1 AKR7A3 FBN2 MGC27121 SCN3A CBX3 HRK OR5AP2 TRIM33 ALDH1A1 FBXL21 MGC34774 SCN4B CCDC83 HS3ST1 OR5AS1 TRIM5-TRIM22 ALKBH6 FBXO34 MGMT SCUBE2 CCDC89 HSD3B2 OR5D18 TRIM7 ANK2 FBXO44 MINK1 SEMA6D CCR8 IBRDC3 OR5K4 TRPA1 ANKFN1 FCHO1 MLLT1 SERPINF1 CCRL1 IGFBP3 OR5M1 TRPC3 ANKRD17 FDX1 MMP14 SFRP2 CD58 IGJ OR5T2 TRY1 ANKRD54 FHL1 MMP24 SGK CD83 IL13 OR5W2 TSC22D3 ANXA13 FKBP9 MMP27 SGMS1 CDC42 IL5 OR8B3 TSHB AOF2 FLJ20674 MON2 SGOL2 CELSR1 INSL5 OR8J3 TSNARE1 APBB1IP FLJ25439 MS4A5 SLAMF9 CENTG2 INSR OSBPL11 TTC32 APC FLJ30058 MTAC2D1 SLC12A8 CHPF IQUB OSR1 TULP4 API5 FLNA MTMR10 SLC22A16 CHPF-MGC99813 ITGA9 PAQR4 U109 APRT FLT3 MUC15 SLC22A2 CHRNA3 ITM2A PAQR9 U45C ARD1A FMR1 MXRA5 SLC25A28 CHSY1 ITPR2 PCDHGA12 UBE2J1 ARHGDIG FOXG1 MYBPC1 SLC25A33 CILP2 JARID1D PCDHGB7 UBE2V2 ARID2 FOXN3 MYCN SLC34A1 CMBL K8 PCMTD2 UBTF ARPC1A FUT9 MYEOV2 SLITRK5 CMYA5 KCNA3 PDCD5 ULK3 ARRDC1 GAB3-DKC1 MYL9 SLMO2 CNIH2 KCNE4 PDIA4 UNC5D ASB1 GABRA6 MYO1G SMC2 CNKSR1 KCNH5 PDIA6 UNC84B ASCC3 GABRQ NAPE-PLD SNRPE COL11A2 KCTD12 PDLIM3 UPK3A ATF2 GADD45GIP1 NAPG SNURF COPB1 KCTD3 PDLIM4 UTF1 ATG10 GALNACT-2 NCAPG2 SOX11 COPG2 KIAA0280 PFN4 VAMP3 ATP12A GDAP1L1 NCKAP1L SOX13 CPA5 KIAA0776 PHF16 VASH1 ATP2A1 GDF8 NCOA1 SOX21 CRAT KIAA0895 PHYHD1 VCAN ATP6AP1 GLIPR1L1 NELL2 SOX8 CREG2 KIAA1333 PIK3C2A VCX ATP6V0A4 GLT25D1 NF2 SPATA19 CRH KIAA1958 PIK3CD WDR35 BACE1 GLUL NFIB SPINK1 CSNK1G3 KIDINS220 PKNOX1 WDR72 BET1 GNA13 NKX6-2 SRPK1 CTPS KIF7 PLD2 WFDC6 BRS3 GNB1 NLRP4 SSBP3 CTTN KIRREL3 PLN WNK4 BSG GNG4 NOL1 SSU72 CTXN1 KLF6 PLXDC2 YEATS2 BTC GNG5 NPC1 ST6GALNAC5 CXorf1 KRT26 PNMA1 ZAN C10orf129 GPD1L NPTXR SULT2A1 CYSLTR1 KRTAP19-1 POLQ ZBED2 C10orf25 GPR101 NR1D2 SUMO3 CYorf15B KRTAP19-2 PPP1R3B ZDHHC1 C10orf4 GPR171 NR2F1 SVIL DAP KRTAP4-5 PRDM12 ZFAND5 C12orf12 GPR21 NRG3 SYNGR3 DAZ2 LAD1 PRDM14 ZFY C12orf5 GPR37 NRIP1 SYT10 DAZ4 LAPTM4A PROKR1 ZNF226 C14orf48 GRHL1 NSMAF SYT17 DDHD2 LAPTM4B PROSC ZNF503 C15orf21 GRIA1 NT5M SYTL1 DDR2 LCE3D PTP4A3 ZNF555 C18orf34 GSCL NXPH1 TALDO1 DGKE LCN6 PYGO2 ZNF567 C18orf8 GSTCD OLFM3 TAS2R14 DKFZp564N2472 LENG4 PZP ZNF577 C1QL3 GUCA1C OR10K1 TEC DMXL2 LHFPL3 RAB31 ZNRF1 C1S GUCY1B3 OR10R2 TEF DNAJC3 LIN28B RAB32 ZP4 hsa-mir-550-1 LOC51149 RBM15 hsa-mir-183 DNASE1L2 LIN7B RABGGTB ZPLD1 EIF1AY LOC643079 RBM33 hsa-mir-361 DSC1 LLGL2 RAC1 ZZZ3 ELF4 LOC90826 REG3G hsa-mir-488 DYNLRB2 LOC130074 RAD17 hsa-let-7a-1

EMB LRFN5 REV1 EMID2 EFNA1 LOC440836 RAP1GAP hsa-mir-510 hsa-mir-148a

c. H3K27me3 ( n= 672)

A2M C21orf29 CTSG FAM71B HLA-DRA KLK5 MPP6 OR5V1 ABCC8 C21orf62 CUTL2 FBXO39 HLA-DRB1 KLK9 MSMB OR6A2 ABTB2 C22orf31 CX40.1 FCAR HNF4G KLRF1 MSRA OR6B3 ACA56 C22orf33 CX62 FCGR2A HOXC10 KRT1 MTHFD1L OR6C2 ACOXL C2orf3 CXCL14 FCN2 HOXC11 KRT2 MTMR9 OR6C6 ACSL4 C6orf122 CXorf22 FCRL2 HOXC12 KRT20 MTTP OR6V1 ACTA2 C6orf156 CXorf57 FCRL3 HOXC13 KRT28 MXD4 OR6X1 ADAM30 C6orf165 CYBB FEV HOXC4 KRT38 MYH11 OR9I1 ADAMDEC1 C6orf97 CYP4B1 FFAR1 HOXC8 KRT71 MYOCD OTC ADAMTS2 C7orf16 CYP4X1 FGF23 HOXC9 KRT72 MYOD1 OXR1 ADCY1 C8orf15 DAAM1 FGF4 HSD17B12 KRT77 MYOM2 PAGE1 ADCYAP1R1 C8orf70 DACT1 FGF6 HSD3B1 KRT79 NAP1L2 PAGE4 ADORA2A C9orf61 DACT3 FGF9 HSPH1 KRT84 NBEAL1 PANX3 ADRA2A C9orf71 DCHS1 FLJ10324 HTR2A KRTAP10-11 NDP PAP2D AFM CA8 DCHS2 FLJ10781 HTR2C KRTAP10-12 NEBL PATE AGK CACNA1A DCTN1 FLJ45803 HUNK KRTAP21-2 NEFL PAX3 AKAP6 CACNA2D2 DCX FLJ46481 IFNB1 KRTAP5-9 NELL1 PAX4 ALDH1A3 CACNG6 DEFA4 FLT1 IGF1R LACRT NFATC2IP PCBP3 ALDOB CADM3 DEFB118 FLVCR2 IGFBPL1 LAIR2 NFYC PCDHA3 AMELY CAMK1D DEFB126 FOXB1 IGFL3 LCE1D NHLH2 PCDHGA3 AMICA1 CARTPT DEFB129 FOXI2 IGSF21 LCN9 NID1 PCTP AMMECR1 CAST DGAT2L6 FOXN4 IHH LCP2 NKD1 PDE6B AMPH CCDC105 DHODH FOXR2 IL10RB LEAP2 NKX2-2 PDE8B ANKRD39 CCDC108 DIO3 FRMD4A IL16 LEF1 NKX2-3 PDPN ANKS1B CCDC129 DKFZP564O0823 FRS2 IL1F6 LHCGR NKX2-5 PGBD3 ANXA10 CCDC3 DKFZP586H2123 FZD6 IL1RL1 LHFPL4 NLRP13 PGLYRP3 APCDD1 CCDC63 DLK1 GABBR2 IL20 LHX2 NOD1 PGM1 ARHGAP20 CCL15 DLX6 GAD2 IL21R LHX4 NPBWR1 PHACTR1 ARMCX1 CD1A DNMT3A GADD45G IL22RA2 LHX6 NPBWR2 PHACTR3 ASAH2 CD1B DNMT3L GALR1 IL2RB LHX8 NPL PHC3 ASB11 CD5L DNTT GATA4 IL3 LILRA1 NR3C1 PHKA2 ASB13 CD86 DOCK8 GBGT1 INHBB LILRA3 NRAP PHYHIPL ASB17 CDH4 DPPA4 GCK INS-IGF2 LILRA5 NRARP PIN4 ATP1A3 CDH7 DRP2 GDAP1 INSL4 LILRB3 NSUN7 PIP5K2C ATP2C1 CDX2 ECEL1 GDF10 INSM2 LILRB4 NTRK3 PKD2L1 ATP6V1B2 CDY1 EDN3 GIMAP1 IQCA LILRB5 NXT2 PLA2G2A ATXN7L2 CEACAM1 EFCAB3 GLB1L3 IRF4 LOC340602 OLIG3 PLA2G2D AURKC CEACAM5 EFCAB4B GLRA3 IRX4 LOC400120 ONECUT1 PLAC1L BACH2 CEACAM6 EGFL6 GLT1D1 IRX6 LOC401498 ONECUT2 PLUNC BFSP2 CECR6 EGFLAM GPHB5 ITGA11 LOC402057 OPRK1 PLXNC1 BMP3 CEL EGR4 GPR133 ITGA2 LOC643905 OR10G2 PNLIP BMP7 CES7 EIF4E GPR143 ITGAM LOC643923 OR1E1 POU1F1 BPIL2-FBXO7 CETN1 ELMOD1 GPR153 ITIH5 LOC653275 OR1E2 POU4F2 BST1 CHGB ELSPBP1 GPR31 JAM2 LOC89944 OR1G1 POU4F3 C10orf35 CHRNG EMID1 GPRASP2 JAM3 LOXHD1 OR1I1 PPAPDC1A C10orf53 CHST9 EML4 GRIN2A JMJD2B LPL OR1J4 PPM1E C10orf58 CLEC4D EMR1 GRIN2C KCNA6 LPO OR1M1 PPP3R2 C10orf72 CLEC4F EN2 GRIPAP1 KCNC2 LPPR4 OR1Q1 PPT1 C11orf74 CLEC4M ENPP2 GRM6 KCNE1L LTK OR2A12 PRDM13

C11orf75 CLGN ENPP5 GRP KCNJ9 LUZP4 OR2A14 PRH2 C12orf54 CLRN3 EPB41L3 GSG1L KCNK9 MAGEA1 OR2AG2 PRR15 C15orf32 CMAS EPHA8 GSH1 KCNN2 MAN1C1 OR2AT4 PRUNE2 C16orf68 CNN3 ERG GSH2 KCNS3 MAPRE1 OR2G3 PRY2 C19orf59 CNR1 ETV3 GTPBP4 KCTD15 MCM7 OR2H1 PSCDBP C1orf127 CNTN4 EVI5L GYG2 KIAA1166 MDGA2 OR2M4 PTCH2 C1orf61 COL13A1 EYA3 GZMB KIAA1576 MGC33407 OR3A3 PTCHD1 C1orf76 COL4A6 F5 GZMH KIAA1706 MGC34821 OR4A15 PTPRR C20orf135 CPZ F9 H1FNT KIF19 MGC99813 OR4D6 PUS1 C20orf166 CRCT1 FAH HAO1 KL MKNK1 OR4E2 PVALB C20orf185 CRTAC1 FAM123A HDAC8 KLF12 MMP21 OR4S2 PXT1 C20orf197 CSMD2 FAM124A HLA-C KLF4 MOSC1 OR51B4 PYHIN1 C20orf42 CST9L FAM12A HLA-DQA1 KLHL1 MPHOSPH6 OR51I2 RAB37 C20orf85 CSTF2 FAM59A HLA-DQA2 KLHL32 MPP2 OR52L1 RAD21 RANBP3L STK32C WBSCR27 SCGB3A2 TMEM16A ZSWIM7 SLC25A13 UGT1A3 RAX STXBP5L WDR40B SCUBE1 TMEM188 hsa-mir-105-2 SLC26A4 UGT1A7 RBM35A SYT2 WFDC2 SDK2 TMTC1 hsa-mir-124a-1 SLC26A9 UGT1A9 RENBP TAL1 WFDC8 SEMA4G TNFSF8 hsa-mir-129-1 SLC35F1 UGT3A1 RET TAS2R1 WNT8B SERPINA12 TNR hsa-mir-129-2 SLCO5A1 UNC5B RFPL2 TBC1D8B WNT9B SERPING1 TNRC6B hsa-mir-222 SMTNL2 UNQ473 RFX4 TBCEL WSCD1 SESN3 TNT hsa-mir-296 SNTG2 UNQ846 RHBDL1 TBR1 WSCD2 SETBP1 TRAF4 hsa-mir-377 SNX2 UNQ9391 RHCG TBRG1 XK SEZ6 TREM2 hsa-mir-379 SOHLH2 UNQ9433 RIMS2 TBX20 ZAK SH3BGRL TRH hsa-mir-381 SOX1 USP51 RNF111 TCEAL4 ZBTB16 SIGLEC7 TRIB2 hsa-mir-433 SOX14 UTS2D RNF150 TCEAL8 ZDHHC13 SIGLEC8 TRIM67 hsa-mir-453 SOX9 UTY RNF212 TCF21 ZDHHC21 SIRPD TRIM72 hsa-mir-493 SPACA1 VAX2 ROBO3 TCF4 ZIM2 SIX6 TSLP hsa-mir-495 SPATA12 VCX3A RPP30 TCL1B ZMYND17 SLC16A1 TSPY2 hsa-mir-515-1 SPATA8 VCY RPP40 TCP10L ZNF30 SLC17A3 TTC8 hsa-mir-519c SPINLW1 VGLL2 RPRML TEKT3 ZNF431 SLC18A3 TUBA3C hsa-mir-520a SPRR2A VN1R4 RPS19 TIP39 ZNF462 SLC1A6 TUSC5 hsa-mir-539 SPRR2F VWA2 RSPO2 TLE3 ZNF521 SLC22A12 TWF1 hsa-mir-592 SPRR2G VWC2 RSPO3 TLX3 ZNF536 SLC22A17 UBL4B hsa-mir-655 SRD5A2 VWF SALL2 TMC2 ZNF543 SLC24A4 UGT1A1 hsa-mir-7-2 ST8SIA2 WBP5

d. H3K9me3+H3K27me3 (n= 93)

ACN9 CAB39 HBQ1 OR51V1 SMAD4 CLDN12 LEPROTL1 OR5BU1 UBQLNL ADCY3 NCR2 HOXA9 OR52A1 SPINK6 DACT2 LILRA2 OR6C74 USF2 ADCY5 EZH2 HTR1A OR52B4 TKTL1 DGKQ LOC129607 P4HA2 UTS2R ADD1 FAM50A PTX3 OR52E2 TMEM187 DGKZ LRRC4 PCSK1N VAPB BBOX1 FGF14 OR51A4 OR52H1 TOP2B DMRTA1 MLN PDS5A ZNF25 BID FGF8 OR51B5-OR51B6 RASGRP2 TRIM34 DPPA5 MPP1 PFN2 ZNF295 BTBD3 FLJ38377 OR51F2 RETNLB CBX8 DYNC1LI2 MUM1L1 POMC ZWINT BUD13 FSCN3 OR51G1 RNPEP CDC42EP5 IRS2 NAT8L PRG-3 hsa-mir-325 C10orf67 GMPPA OR51M1 SELE CDKN2A ITGA8 OR52J3 PTPRT hsa-mir-491 C1QA HBD OR51S1 SF1 CDY2A JPH1 OR56B1 UBQLN2 EIF5A

e. H3K4me3+H3K27me3 (n = 62)

ACCN4 CHMP2B DRG1 IGSF9 KRT6B MAPKAPK5 PRKCB1 STEAP1 ADCYAP1 CHRNA7 F7 IKZF1 LCAP MGEA5 PRKCG TMEM176B ARMC8 CITED1 FAM38B KCNA2 LILRA6 MTO1 PSIP1 TMEM179

ASCL4 CSF2 FAM83F KCNG2 LILRB1 NETO2 SEC63 TRAM1L1 C11orf38 CTAG1B GRLF1 KIAA0404 LOC441177 NME4 SERPINB13 WDR32 CAV2 CYP26B1 HBG1 KIAA1622 LOC728758 OR51Q1 SKP1A ZNF510 CD53 DDX6 HBZ KIAA1754L LRP1B PGC SLC22A11 CHIC2 DNER HLA-DOA KLF10 MAP4K2 PIGM SNX3

f. H3K4me3+H3K9me3 (n = 214) ABBA-1 C19orf12 DKFZP434B0335 GFPT1 KLF13 OR52A5 RBMY1A1 THRAP2 ABR C19orf2 DOLK GGH LAMP1 OSCAR RCL1 THRB ACA37 C21orf91 DOT1L GMFB LARP2 OSTM1 REXO1 TLE6 ACA67 C22orf30 DPP7 GNAQ LIG3 PABPC1 RKHD3 TMEM8 ACIN1 C6orf150 DSCR2 GPC4 LIMK1 PCBD2 RNF145 TMEM8-LOC441743 ACTG1 C6orf49 DTD1 GPX7 LOC339123 PDGFB RNF38 TNNI2 ACTR2 C7orf26 EDF1 GSTP1 LOC401431 PDIA3 RPL26 TRIM22 ADAMTS1 C9orf106 EEF1A1 GTF2IRD1 LRFN2 PER3 RPS9 TRIM8 ADAMTS9 C9orf127 EFCAB4A GZF1 LUC7L PHF11 SEMA3D TSTA3 ADI1 CACNA2D1 EFNA4 HBE1 MANEAL PI4K2B SHROOM1 TUFT1 AMDHD2 CAPN2 EFNB2 HCCA2 MAP1S PIGZ SLC10A3 UBE3C ANGPTL5 CCDC120 EIF4ENIF1-SFI1 HELZ MDFI PIK4CB SLC24A2 UIMC1 ANKRD43 CCDC28A EIF4G1 HHEX MLLT6 PIP5K1A SLC2A12 VHL APBB1 CCDC64 ELL3 HLCS MLYCD PISD SLK WDR17 ARHGAP4 CCNI EMP2 HMGN1 MMP26 PLXNA3 SMAD7 WDR22 ARID4A CCRN4L ERRFI1 HMGN2 MRPL28 POU2F1 SNAP91 WIPI2 ARL2BP CGN EXOSC6 HOXA10 MTHFD2 PRKCD SNX26 YPEL1 ARL6IP4 CLCN7 FAM105B HP1BP3 MYH10 PRSS12 SNX7 ZCCHC6 ATF1 CLECL1 FBXO33 HPRT1 MYO5C PSMB4 SPAG4 ZIC2 ATG4D CRSP7 FGFR1OP HTR6 NAB1 PSMD4 SPAST ZIC5 ATP2A3 CTDSP1 FNBP1 IER5L NEUROG1 PTGER3 ST8SIA6 ZNF131 ATXN2L CTSD FOXH1 IFNGR2 NTNG2 PYGM STK11 ZNF174 AVPI1 CYFIP1 FRAT1 IGFBP7 OBSL1 RAB11FIP2 STK17A ZNF367 BOK DDX18 FZD8 IRS1 OCIAD2 RAB11FIP5 STXBP6 ZXDB BRD3 DDX3Y GAS6 JMJD4 OR51A2 RAD23B SYT8 mark BRWD1 DFNB31 GATA6 KCND3 OR51B6 RASGRP1 TH C16orf35 DHFR GCC1 KIAA1618 OR51T1 RBBP7 TH1L

g. H3K4me3+H3K9me3+H3K27me3 (n= 215) ACSL6 CAPZA2 FLJ16793 hsa-mir-219-2 LILRA4 OR51G2 SFMBT1 TMEM50B AGL CASK FLJ21062 hsa-mir-483 LOC150297 OR51I1-OR51I2 SLC22A4 TNNT3 ANKFY1 CAV1 FLJ26443 hsa-mir-675 LOC441108 OR51L1 SLC22A5 TP53BP1 ARHGAP26 CBLN1 FLJ30277 HSP90AA1 LOC55565 OR52A4 SLC2A13 TRIM5 ASCL2 CCDC93 FLJ37078 IFNAR1 LRRC24 OR52B6 SLC2A4RG TRIM6 ASZ1 CDH2 FOXA2 IFNAR2 LRRC47 OR52D1 SLC4A3 TRPM8 ATP11A CDX1 FOXP2 IGF2 LRRK2 OR52R1 SLC5A1 TSEN34 ATP5O CFTR FOXP4 IGF2AS LSP1 PCDH15 SLC6A3 TSPAN32 BCAP29 CHD5 FRS3 IGF2-IGF2AS MCF2L PCGF6 SLC7A10 TTYH1 BCL11B CNOT3 FUNDC2 IL4 MDFIC PFTK1 SLC9A3 UBE2G1 BIRC4 COL25A1 FZD1 IRAK1 MECP2 POGZ SMARCD1 UBQLN3 BPIL2 CRYZL1 GAB3 IRF1 MET PPP2R4 SNX27 UGT1A6 BRCC3 CTTNBP2 GART ITFG3 MGAT4A PTCH1 SON VAV3 BTG3 DDX43 GRM8 ITSN1 MIER3 RAB11FIP3 SPP2 VSTM1 C13orf15 DEPDC5 GTPBP10 KATNAL1 MOXD1 RAD50 ST7 WDR60 C17orf76 DHCR24 HBB KCNMA1 MRPL23 RBM12 STAG2 WDR76 C20orf44 DKFZp762E1312 HBM KCNQ5 MTCP1 RBM39 STEAP2 WNT2 C21orf13 DNASE1L1 HCFC1 KCTD11 MYADM RBMY1F STK11IP ZFAND2A

C21orf55 DOLPP1 HEBP1 KEAP1 NAT11 RCOR2 SUV420H1 ZNF800 C21orf59 DONSON HERC5 KIAA0999 NR2E1 RERE SYN3 C21orf63 ECGF1 HNT KIAA1822 NRXN2 RFPL3 SYNJ1 C22orf24 ENPP1 HOXA1 KIF3A NUP188 SELO TCERG1L C22orf28 EVX1 HOXA11 KIR3DX1 NXPH2 SERPINB10 TD1 C5orf35 EXT1 HOXA13 L1CAM OLIG1 SERPINB11 TES C6orf148 F10 HOXA3 LACE1 OLIG2 SERPINB2 TFEB C7orf42 F8 HOXA4 LAIR1 OPN1LW SERPINB7 THOC2 CACNG7 FBXO7 HOXA7 LARGE OR51B2 SERPINB8 TIMP3 CACNG8 FGF1 HS3ST4 LENG9 OR51F1 SFI1 TMEM37

Supplementary Table 3. Expression analyses of genes enriched with mono-, bi- and trivalent K4, K9 and K27 marks in A4 progression model a. H3K4 <->UP (n=120) ADCY6 EDG6 ITPK1 PCDH9 SLC7A8 ANKRD1 F2RL2 KIAA0258 PTK2 ST3GAL4 ADCY7 EVA1 JAG2 PITPNC1 SMOC2 ANKRD15 FA2H KIAA0513 PTK6 ST3GAL5 ADH1C F11R JUB PPM1H SNTB1 ANKRD6 FAM19A5 KRT8 PTN STAT4 AGPAT5 F2RL1 KCTD14 PSMB8 SPTLC2 AVPR2 FBXO6 LBX2 PTPN6 TACSTD1 B3GNT3 FDXR MAL2 RASSF6 TCN2 CDH3 GLT8D2 MST1R RHOV TP53I11 BCAN FLJ22662 MBD1 RBP1 TM7SF2 CDSN GMDS MTP18 ROBO1 TSGA10 CAMK2D FYB MCFD2 RBP7 TMC4 COX7A1 GRB7 MYEOV ROPN1L UGT8 CCNE2 GALE MCM2 RCOR1 TNFSF13 COX7B2 GSTA4 NANOS1 RRM2 UNC13D CDCA4 GJB3 MGC39900 RDH5 TNNI3 CYP1A1 GSTO2 NEURL SCEL YBX2 CYP2J2 GUSB NR3C2 SDPR ZADH1 DGKA HDAC2 NRG2 SIN3A SLC7A5 DDAH1 HK2 NR4A3 SECTM1 ZNF395 DUSP2 ID4 NUDT14 SLC20A2 PAPLN DUSP5 INPP5A

b. H3K9<->DOWN (n=51) ADAMTS16 JARID1B TRIM4 FLJ36031 TLN2 ATP10A NAV2 DNAJB4 HBP1 SLC3A1 AMPD3 KLF6 TSPAN2 GFPT2 RBMS3 ATP6V0A4 NAV3 FLJ25801 ICAM1 SLC9A9 ARMC4 LDOC1 CLEC4E GK RECK C1R NFE2L3 PANX1 IL6 SLIT3 ASB2 MOSPD1 CPAMD8 HOXA1 SERPINA6 CASP1 NME3 PIK3CD ITGAV ST8SIA5 CASP5 NR2C2 PAX2 ITIH4 CDH13 OPTN POPDC3 PSAP

c. H3K27<->DOWN (n=52) ABTB2 C10orf90 DCBLD1 GLIS1 PDCD4 AMPH CLDN10 EMR1 MMP19 PTTG2 ADAMTS2 CAB39L DDX50 GPC6 PDE2A ANXA6 COL27A1 ERCC6 MSX2 RXRG AK5 CD99 DIXDC1 HOXC9 PRSS2 ARHGAP22 CPNE7 FAM20A NR3C1 RUFY2 ALDH1A3 CEACAM3 DOCK2 IL4 PRSS23 ASTN2 CYLD FHOD3 OGT SAA1 ATP10D DACT1 FZD7 PCDHB2 SLC4A4 SNX19 TBRG1 TBXAS1 TNFSF10 TNFSF9 WNT8B ZNF197

d. H3K4-H3K27 <->UP (n=25) ABCG2 CYP26B1 HSPH1 POGK TRAM1L1 AP1G2 DNAH11 NME4 SDC2 CLYBL ADCK2 DCC1 HTR7 PPARGC1A XK CCL20 GMPR NOV SGPP2 SLC35F3 CHRNA7 HOMER1 PGC

e. H3K4-H3K9 <->UP (n=59) ANXA3 FOXA1 LAMA3 PDE9A SNF1LK CPSF1 HR LLGL2 PKP3 TMEM25 ARHGAP18 GSR LCP1 PEX7 TDRKH CTH ICA1 LSAMP RASEF TMLHE CEBPA HDHD2 LEMD1 PFKM TGFA CTSL2 KAZALD1 MITF RHOF TPD52 CGN HELLS LHX1 PIGQ TLE6 CYC1 KCTD12 MYO5C SELENBP1 TUFT1 EMD KHK NAB1 SEPP1 WHSC1 FGF7 KIAA0746 OSR2 SLC40A1 ZFP36L2 FAM49A KIAA0182 NXN SGK2 ZDHHC23 FLJ39779 KLF5 PCSK5 SNCA

f. H3K9-H3K27<->DOWN (n=22) ACSL4 CD44 MXD4 RCN1 TCF4 C1S JAK2 NCR2 SLN SSPN AHR GLT25D1 NKX3-1 ROBO3 ZNF25 CAMK1D LOH3CR2A PAM SMARCA2 PIK3C3 CCDC3 LRRC17

g. H3K4-K9-K27 <->DOWN (n=36) ASCL2 FLJ11286 LTBP3 RGMB TRIM5 ASB13 HNMT PALM2-AKAP2 SLC22A4 ECGF1 APH1B FOXA2 MLLT10 RKHD3 TRIM6 BCAP29 IRS2 PCAF SNX7 LARGE APOL3 GAS6 NNT SGK UGT1A6 CSF2 KCNMA1 PDLIM4 STK17A PINK1 FBN1 FGF12 PTX3 TRIM34 TRIM22

Supplementary Table 4. Differentially regulated genes associated exclusively with histone marks K4 K9 K27 K4-K9 K4-K27 K9-K27 K4-K9-K27 HDAC2 HOXA1 WNT8B EMD CYP26B1 NCR2 ASCL2 SIN3A PAX2 RXRγ HOXB7 MBD1 WNT3A IL4 CUTL1 RRM2 TRAM1L1 UTX TCF2 NUP210 SMARCA2 STAG1 ACTR2