Supplementary material 1

350 300 265 250 200 158 139 150

100 50 4 0 Biased Forward- Reverse- any orientation reverse (FR) forward (RF) orientation (FR+RF) Supplemental Figure S1. Biased-orientation of DNA motif sequences of transcription factors in T cells. Total 265 of biased orientation of DNA binding motif sequences of transcription factors were found to affect the expression level of putative transcriptional target in T cells of four people in common, whereas only four any orientation (i.e. without considering orientation) of DNA binding motif sequences were found to affect the expression level.

１ Forward-reverse orientation in monocytes

ZNF93_2 ZNF93_1 ZNF92 ZNF90 ZNF836 ZNF716 ZNF709 ZNF695 ZNF676_2 ZNF676_1 ZNF675 ZNF670 ZNF660 ZNF648 ZNF646 ZNF623 ZNF573 ZNF521 ZNF460 ZNF366 ZNF33B ZNF317 ZNF316 ZNF28 ZNF274 ZNF263_2 ZNF263_1 ZNF219 ZNF214 ZNF148 ZNF143_2 ZNF143_1 ZIC3 ZIC1 ZFP30 ZBTB6 ZBTB33 ZBTB24 YY1 YBX1 XRCC4_2 XRCC4_1 XBP1 WT1 USF TP63 TP53 TFE3 TFAP2A TCF3_2 TCF3_1 TCF12 TBX5 TBP SULT1A2 STAT5B STAT5A_3 STAT5A_2 STAT5A_1 STAT4 STAT3_2 STAT3_1 STAT1_6 STAT1_5 STAT1_4 STAT1_3 STAT1_2 STAT1_1 SRF_2 SRF_1 SPI1_2 SPI1_1 SPEF1 SP1_2 SP1_1 SNTB1 SMC3_2 SMC3_1 SMARCC2_2 SMARCC2_1 SMAD2_SMAD3_SMAD4 SMAD2_2 SMAD2_1 SLC25A20 SIX5 SIRT6 SIN3A SETDB1 RXRA_VDR RUNX2 RREB1_3 RREB1_2 RREB1_1 RFTN1 REST_2 REST_1 RELA RAD21_3 RAD21_2 RAD21_1 PTF1A PROX1 PRDM9 PRDM15 2000 PPARGC1A POU6F1 POU3F2 PLAGL1_2 PLAGL1_1 PITX3

Reverse PITX1 PHOX2B 1000 PAX8 PAX5 PARG_2 PARG_1 NR3C1 NR2F6 NR2F2 NR2C2 0 NR1I2 NKX2−5 NFYB NFKB2 NFKB1 NFIB NFE2 MYB_2 MYB_1 MLXIPL MINI20 MEF2A MAZ_3 MAZ_2 MAZ_1 MAX MAFA LBX2 KLF6 KLF5 KLF3 KLF14_2 KLF14_1 IRF7 IKZF1 HSF2 HOXC9 HOXC11 HOXB1 HOXA7 HOMEZ HNF4A_2 HNF4A_1 HMBOX1_2 HMBOX1_1 HIC1_2 HIC1_1 HES1 HENMT1 GTF3C2 GLIS2 GLI2 GLI1 GCM1_3 GCM1_2 GCM1_1 GATA6 GATA2 FUBP1 FOXO4 FOXN2_2 FOXN2_1 FOXA1 FOSB_2 FOSB_1 FOS_2 FOS_1 ETV4 ETS ESX1 ESR2 EN1 EIF5A2 EHF EGR2_4 EGR2_3 EGR2_2 EGR2_1 EBF E2F8 E2F_2 E2F_1 DNAAF2 DEC DBP CTCF_8 CTCF_7 CTCF_6 CTCF_5 CTCF_4 CTCF_3 CTCF_2 CTCF_1 CEBPZ_2 CEBPZ_1 CEBPG_2 CEBPG_1 BRF1_2 BRF1_1 BBX 5 − YY1 EBF EN1 ETS TBP BBX EHF USF DBP DEC WT1 GLI1 GLI2 IRF7 MAX SIX5 ZIC1 ZIC3 NFIB E2F3 E2F5 E2F8 KLF3 KLF5 KLF6 TP53 TP63 PAX5 PAX8 LBX2 TFE3 ETV4 TBX5 ESX1 HSF2 NFE2 XBP1 YBX1 ESR2 HES1 RELA NFYB MAFA IKZF1 PITX1 PITX3 SIRT6 NR1I2 GLIS2 STAT4 SIN3A E2F_1 E2F_2 ZFP30 SP1_1 SP1_2 GATA2 GATA6 TCF12 ZNF28 ZNF90 ZNF92 PTF1A SRF_1 SRF_2 ZBTB6 FOS_1 FOS_2 NR2F2 NR2F6 SPEF1 FOXA1 FUBP1 MAZ_1 MAZ_2 MAZ_3 MINI20 NFKB1 NFKB2 RFTN1 SNTB1 NR2C2 NR3C1 MYB_1 MYB_2 SPI1_1 SPI1_2 PROX1 FOXO4 HOXA7 HOXB1 MEF2A EIF5A2 RUNX2 HOXC9 HIC1_1 HIC1_2 PRDM9 STAT5B MLXIPL HOMEZ TCF3_1 TCF3_2 ZNF148 ZNF214 ZNF219 ZNF274 ZNF316 ZNF317 ZNF366 ZNF460 ZNF521 ZNF573 ZNF623 ZNF646 ZNF648 ZNF660 ZNF670 ZNF675 ZNF695 ZNF709 ZNF716 ZNF836 BRF1_1 BRF1_2 ZBTB24 ZBTB33 TFAP2A ZNF33B NKX2 CTCF_1 CTCF_2 CTCF_3 CTCF_4 CTCF_5 CTCF_6 CTCF_7 CTCF_8 REST_1 REST_2 PARG_1 PARG_2 GTF3C2 EGR2_1 EGR2_2 EGR2_3 EGR2_4 FOSB_1 FOSB_2 POU3F2 POU6F1 SETDB1 SMC3_1 SMC3_2 HOXC11 DNAAF2 STAT1_1 STAT1_2 STAT1_3 STAT1_4 STAT1_5 STAT1_6 STAT3_1 STAT3_2 PHOX2B GCM1_1 GCM1_2 GCM1_3 KLF14_1 KLF14_2 PRDM15 HENMT1 ZNF93_1 ZNF93_2 SULT1A2 RAD21_1 RAD21_2 RAD21_3 FOXN2_1 FOXN2_2 HNF4A_1 HNF4A_2 CEBPZ_1 CEBPZ_2 RREB1_1 RREB1_2 RREB1_3 XRCC4_1 XRCC4_2 SMAD2_1 SMAD2_2 CEBPG_1 CEBPG_2 STAT5A_1 STAT5A_2 STAT5A_3 ZNF143_1 ZNF143_2 ZNF263_1 ZNF263_2 ZNF676_1 ZNF676_2 SLC25A20 PLAGL1_1 PLAGL1_2 HMBOX1_1 HMBOX1_2 PPARGC1A RXRA_VDR SMARCC2_1 SMARCC2_2 SMAD2_SMAD3_SMAD4 Forward

Supplemental Figure S2. Pairs of biased orientation of DNA binding motif sequences of transcription factors enriched in upstream and downstream of genes. The number of genes with a pair of forward-reverse orientation of DNA motif sequences was counted using all pairs of the DNA motif sequences found in open chromatin regions, and statistical tests (chi-square test) were conducted in monocytes and T cells.

２ Reverse-forward orientation in monocytes

ZSCAN5B ZSCAN2_2 ZSCAN2_1 ZNF770 ZNF721 ZNF711 ZNF687 ZNF682 ZNF672 ZNF671 ZNF670 ZNF652 ZNF641 ZNF584 ZNF579 ZNF547 ZNF449 ZNF350 ZNF343 ZNF337 ZNF331 ZNF316 ZNF30_2 ZNF30_1 ZNF286B ZNF28 ZNF233 ZNF225 ZNF202 ZNF195 ZNF181 ZNF148 ZNF121 ZNF112 ZIC2 ZIC1 ZBTB7B ZBTB7A ZBTB2 ZBTB18_2 ZBTB18_1 WT1 USF1 TRIM28 TP53 THRB TFAP2E TFAP2B TFAP2A TEAD1 TCF7 TBP_3 TBP_2 TBP_1 STAT5B STAT5A STAT1 SRF_5 SRF_4 SRF_3 SRF_2 SRF_1 SPIC SPI1 SP8 SP4_2 SP4_1 SP3 SP2 SP1 SOX9_3 SOX9_2 SOX9_1 SOX11 Gene SMAD9 SMAD4_2 SMAD4_1 SMAD3_2 2500 SMAD3_1 RXRB RXRA_2 RXRA_1 RFX5 2000 RFX3 REST RBAK RAD21 PSMD9 PPARG 1500 POU5F1 POU3F2 POU2F2 POLR3A PLAG1 Forward PBX3 1000 PBX1 PAX6 PAX5_2 PAX5_1 PAX3 500 PAX1 PARP1 OBOX2 NR5A2 NR2F1 NKX3−1 0 NFY NFKB2 NFE2L3 NFE2L2 NFATC1 NANOG MZF1 MYOG MYF6 MYEF2 MYC_MAX MSX2 MAFK LHX4 KLF16 ISL1 IRX2 IRF9 IRF8 IRF4_3 IRF4_2 IRF4_1 IRF3_2 IRF3_1 HSF2 HSF1_2 HSF1_1 HOXD1 HNF1B HAND1_TCF3 GTF2I GABPB1_GABPB2 GABPA FOXR1 FOXP2 FOX FLI1 ETV7 ETV6 ETV5 ETV3 ETV2 ETS2_2 ETS2_1 EP300 ELF5 ELF2 EBF1 E2F3 DOBOX5 DNAAF2 CTCF_3 CTCF_2 CTCF_1 CREM CEBPZ CEBPB CDX2 CD59 BDP1 BCL6 BCL3 BCL11A_2 BCL11A_1 ATF3_2 ATF3_1 ATF2_ATF4 ASCL2 ALX1 AHR 1 − SP1 SP2 SP3 SP8 FOX FLI1 NFY ISL1 AHR WT1 IRF8 IRF9 ZIC1 ZIC2 SPI1 IRX2 SPIC E2F2 E2F3 ELF2 ELF5 TP53 PAX1 PAX3 PAX6 ALX1 BCL3 BCL6 EBF1 ETV2 ETV3 ETV5 ETV6 ETV7 LHX4 TCF7 CD59 HSF2 PBX1 PBX3 RFX3 RFX5 USF1 MZF1 SOX2 BDP1 CDX2 MYF6 REST MSX2 RBAK THRB MAFK RXRB GTF2I STAT1 CREM KLF16 MYOG EP300 SP4_1 SP4_2 TBP_1 TBP_2 TBP_3 ZNF28 SRF_1 SRF_2 SRF_3 SRF_4 SRF_5 ZBTB2 PARP1 SOX11 NR2F1 ASCL2 PLAG1 FOXP2 NFKB2 NR5A2 RAD21 TEAD1 FOXR1 HNF1B IRF3_1 IRF3_2 IRF4_1 IRF4_2 IRF4_3 GABPA CEBPZ MYEF2 PPARG HOXD1 OBOX2 CEBPB ATF3_1 ATF3_2 PSMD9 SMAD9 STAT5A STAT5B PAX5_1 PAX5_2 TRIM28 ETS2_1 ETS2_2 ZNF112 ZNF121 ZNF148 ZNF181 ZNF195 ZNF202 ZNF225 ZNF233 ZNF316 ZNF331 ZNF337 ZNF343 ZNF350 ZNF449 ZNF547 ZNF579 ZNF584 ZNF641 ZNF652 ZNF670 ZNF671 ZNF672 ZNF682 ZNF687 ZNF711 ZNF721 ZNF770 NANOG HSF1_1 HSF1_2 NFE2L2 NFE2L3 NFATC1 TFAP2A TFAP2B TFAP2E SOX9_1 SOX9_2 SOX9_3 NKX3 CTCF_1 CTCF_2 CTCF_3 ZBTB7A ZBTB7B POU2F2 POU3F2 POU5F1 RXRA_1 RXRA_2 DNAAF2 POLR3A DOBOX5 ZNF30_1 ZNF30_2 ZNF286B SMAD3_1 SMAD3_2 SMAD4_1 SMAD4_2 ZSCAN5B ZBTB18_1 ZBTB18_2 BCL11A_1 BCL11A_2 MYC_MAX ZSCAN2_1 ZSCAN2_2 ATF2_ATF4 HAND1_TCF3 GABPB1_GABPB2 Reverse

３ Forward-reverse orientation in T cells

ZNF880 ZNF846 ZNF84 ZNF790 ZNF786 ZNF770_2 ZNF770_1 ZNF75A ZNF721 ZNF717 ZNF714 ZNF701 ZNF681 ZNF676 ZNF668 ZNF639 ZNF616 ZNF585A ZNF582 ZNF568 ZNF546 ZNF534 ZNF355P ZNF287 ZNF263 ZNF253 ZNF219 ZNF124 ZNF117 ZIC1 ZFX ZFP3 ZFP14 ZEB1 ZBTB7B ZBTB7A ZBTB33 YBX1 TP63 TP53_3 TP53_2 TP53_1 TLX1 THRA TFCP2 TFAP4 TCF7L2_2 TCF7L2_1 TCF4 TBXT TBP TAL1 SRP9 SREBF2 SPI1_2 SPI1_1 SPDEF SP1_2 SP1_1 SOX5 SOX18 SOX13 SOAT1 SMC3 RREB1_2 RREB1_1 RREB RFX3 REL_2 REL_1 RARB RAD21 PRDM9 PRDM15 POU4F1 PLAG1 PITX2 PITX1_2 PITX1_1 Gene PDX1 PCBP1 PAX2 P50_P50 OTX2_2 OTX2_1 NRF1 NR2F2 1500 NR2C2_2 NR2C2_1 NR0B1 NFYA NFY NFKB1 NFIX NFE2_3 1000 NFE2_2 NFE2_1 NFATC2 MZF1 Reverse MYC_2 MYC_1 MXI1 MNX1 MINI20 500 MAF LHX8 LHX6 KLF1_2 KLF1_1 JDP2 IRF5 IRF 0 INSM2 INSM1 HPV16GP4 HOXA7_2 HOXA7_1 HOXA2 HOXA13 HNF1B HNF1A HMGA2_2 HMGA2_1 HIC1 HEY1 HBP1 GLIS2 GLI1 GFI1B_2 GFI1B_1 GFI1 GATA5 GATA4 GATA GABPA FOXO6 FOXO3 FOXN4 FOXJ3 FOXF2 FOXA3 ETV4_2 ETV4_1 ETV3 EP300_2 EP300_1 EMBP1 ELK1 ELF5 ELF4 ELF3 ELF1 EHF_2 EHF_1 EGR4 EGR3_2 EGR3_1 EGR2_2 EGR2_1 EGR1_2 EGR1_1 EBF1 E2F6 DUX1 DLX3_2 DLX3_1 DDIT3_CEBPA DBX1 CUX1 CTCF_3 CTCF_2 CTCF_1 CEBPZ CEBPE CDC5L_2 CDC5L_1 BRCA1 BDP1 BCL6 BATF BARX2 BACH1 ARID3A AR APEX1 AR IRF ZFX TBP NFY MAF GLI1 IRF5 ZIC1 GFI1 TAL1 HIC1 NFIX MXI1 E2F4 E2F6 ELF1 ELF3 ELF4 ELF5 TLX1 TP63 BATF PAX2 ELK1 JDP2 ZFP3 GATA BCL6 EBF1 ETV3 LHX6 LHX8 TCF4 ZEB1 RFX3 TBXT NFYA YBX1 SOX5 BDP1 DBX1 HBP1 HEY1 MZF1 NRF1 PDX1 SRP9 CUX1 DUX1 THRA EGR4 MNX1 PITX2 RARB RREB SMC3 GLIS2 SP1_1 SP1_2 ZFP14 TFAP4 GATA4 GATA5 FOXJ3 INSM1 INSM2 ZNF84 REL_1 REL_2 EHF_1 EHF_2 SOAT1 FOXF2 SOX13 SOX18 NR2F2 TFCP2 PLAG1 FOXA3 APEX1 MINI20 NFKB1 NR0B1 RAD21 FOXN4 BARX2 HNF1A HNF1B PCBP1 SPI1_1 SPI1_2 BACH1 GABPA FOXO3 FOXO6 HOXA2 BRCA1 CEBPZ MYC_1 MYC_2 SPDEF CEBPE EMBP1 KLF1_1 KLF1_2 PRDM9 TP53_1 TP53_2 TP53_3 ARID3A ZNF117 ZNF124 ZNF219 ZNF253 ZNF263 ZNF287 ZNF534 ZNF546 ZNF568 ZNF582 ZNF616 ZNF639 ZNF668 ZNF676 ZNF681 ZNF701 ZNF714 ZNF717 ZNF721 ZNF786 ZNF790 ZNF846 ZNF880 DLX3_1 DLX3_2 ETV4_1 ETV4_2 NFE2_1 NFE2_2 NFE2_3 ZBTB33 OTX2_1 OTX2_2 NFATC2 ZNF75A CTCF_1 CTCF_2 CTCF_3 ZBTB7A ZBTB7B EGR1_1 EGR1_2 EGR2_1 EGR2_2 EGR3_1 EGR3_2 HOXA13 PITX1_1 PITX1_2 POU4F1 SREBF2 GFI1B_1 GFI1B_2 PRDM15 EP300_1 EP300_2 P50_P50 ZNF355P ZNF585A CDC5L_1 CDC5L_2 NR2C2_1 NR2C2_2 HOXA7_1 HOXA7_2 RREB1_1 RREB1_2 HMGA2_1 HMGA2_2 TCF7L2_1 TCF7L2_2 ZNF770_1 ZNF770_2 HPV16GP4 DDIT3_CEBPA Forward

４ Reverse-forward orientation in T cells

ZNF880 ZNF777 ZNF773 ZNF770 ZNF721 ZNF718 ZNF714 ZNF658 ZNF625 ZNF592 ZNF580 ZNF549 ZNF526 ZNF484 ZNF468 ZNF44 ZNF410 ZNF41 ZNF341 ZNF300 ZNF282 ZNF28 ZNF267 ZNF257 ZNF256 ZNF239 ZNF219 ZNF214 ZNF189 ZNF180 ZNF174 ZNF17 ZNF143 ZNF134 ZIC1 ZFP69B ZFP2 ZBTB7A ZBTB41 ZBTB4 ZBTB33 ZBTB18 YY2 YY1 THRB TEAD1 TCF12_2 TCF12_1 TAL1 SRF_2 SRF_1 SPIC SPI1 SP2_2 SP2_1 SOX2 SMARC SIX6 RUNX2_2 RUNX2_1 RREB1 RORA RFX1_2 RFX1_1 REST RELB RELA REL Gene RARA RAD21 PSMD9 PPARGC1A PPARD POU2F2 PITX3 1500 PBX3_2 PBX3_1 PARP1 NRG2 NR4A1 NR3C1 NKX2−5_2 NKX2−5_1 1000 NKX2−4 NKX2−1 NFYA Forward NFY NFKB1_3 NFKB1_2 NFKB1_1 500 NFE2L2 MYOG MYCN MXI1 MTF1_2 MTF1_1 MLX 0 MEIS1 LHX6 LHX4 LBX1 KLF8 KLF6 KLF16 KLF13 IRF8 IRF5 IRF HSF1 HOXB6 HOXA10 HLTF_2 HLTF_1 HAND1 GTF2I GFI1 GATA4 GATA1_2 GATA1_1 GABPA FOXP3 FOXO3 FOXN4 FOXJ3_2 FOXJ3_1 FOXG1 FOXA2 FOXA1 FOXA FOS_2 FOS_1 ETV6 ETV3 ETV1 ETS2 ETS1_2 ETS1_1 ESR1 EP300 ELF3_3 ELF3_2 ELF3_1 EHF_2 EHF_1 EGR1 DMRTA2 DBP_2 DBP_1 CTCF_4 CTCF_3 CTCF_2 CTCF_1 CREB3 CEBPA CAP1 BTD BCLAF1 BCL11B BCL ALX1 1 4 − − IRF 5_1 5_2 YY1 YY2 BCL REL BTD NFY MLX IRF5 IRF8 ZIC1 SIX6 SPI1 GFI1 − − TAL1 MXI1 SPIC E2F1 KLF6 KLF8 ALX1 LBX1 ZFP2 ETS2 ETV1 ETV3 ETV6 LHX4 LHX6 HSF1 NFYA SOX2 CAP1 ESR1 RELA RELB FOXA REST EGR1 THRB NRG2 PITX3 RARA GTF2I RORA KLF13 KLF16 MYCN MYOG EP300 MEIS1 SP2_1 SP2_2 GATA4 ZNF17 ZNF28 ZNF41 ZNF44 EHF_1 EHF_2 SRF_1 SRF_2 ZBTB4 PARP1 DBP_1 DBP_2 FOS_1 FOS_2 FOXA1 FOXA2 FOXP3 NR4A1 RAD21 TEAD1 CEBPA FOXN4 NR3C1 GABPA PPARD FOXG1 FOXO3 HOXB6 CREB3 RREB1 HAND1 PSMD9 ELF3_1 ELF3_2 ELF3_3 HLTF_1 HLTF_2 ETS1_1 ETS1_2 SMARC ZNF134 ZNF143 ZNF174 ZNF180 ZNF189 ZNF214 ZNF219 ZNF239 ZNF256 ZNF257 ZNF267 ZNF282 ZNF300 ZNF341 ZNF410 ZNF468 ZNF484 ZNF526 ZNF549 ZNF580 ZNF592 ZNF625 ZNF658 ZNF714 ZNF718 ZNF721 ZNF770 ZNF773 ZNF777 ZNF880 NFE2L2 PBX3_1 PBX3_2 RFX1_1 RFX1_2 ZBTB18 ZBTB33 ZBTB41 ZFP69B MTF1_1 MTF1_2 BCL11B NKX2 NKX2 BCLAF1 CTCF_1 CTCF_2 CTCF_3 CTCF_4 ZBTB7A HOXA10 POU2F2 DMRTA2 GATA1_1 GATA1_2 FOXJ3_1 FOXJ3_2 TCF12_1 TCF12_2 NFKB1_1 NFKB1_2 NFKB1_3 RUNX2_1 RUNX2_2 NKX2 NKX2 PPARGC1A Reverse

５ Forward-reverse orientation in monocytes using H3K27ac histone modification marks

ZNF99 ZNF91 ZNF836 ZNF808 ZNF775 ZNF76 ZNF716 ZNF709 ZNF676_2 ZNF676_1 ZNF675 ZNF671 ZNF660 ZNF658B ZNF658 ZNF648_2 ZNF648_1 ZNF623 ZNF579 ZNF560 ZNF555 ZNF521 ZNF460 ZNF426 ZNF391 ZNF316 ZNF304 ZNF274 ZNF236 ZNF224 ZNF219 ZNF177 ZNF148 ZNF143_2 ZNF143_1 ZNF131 ZIC1 ZFP92 ZBTB6 ZBTB33 YY1 YBX1 WT1 USF TP63 TP53 THRA_2 THRA_1 THAP1 TFCP2 TFAP2C TFAP2A TEF TCF3 TBXT TBX5 TBX20 TBP SULT1A2 STAT5A_3 STAT5A_2 STAT5A_1 STAT4 STAT3_2 STAT3_1 STAT1_3 STAT1_2 STAT1_1 SRF_2 SRF_1 SREBF2 SPI1 Gene SP2 SP1 SNAI3 SNAI1 SMC3_2 SMC3_1 SMAD2 2000 SMAD SIX5 SIN3A_2 SIN3A_1 SIGMAR1 RXRB 1500 RREB1 REST_2 REST_1 RAD21 PTF1A PPARGC1A 1000 Reverse POU1F1 PLAGL1 PKNOX1 PITX3 PITX1 PBX2 500 NR5A2_2 NR5A2_1 NR2F2 NR2C2 NFE2 MINI20 0 MECP2 MAZ LHX2 KLF7 KLF5 KLF14 KLF1 JUND ITGAL IRF IKZF1_3 IKZF1_2 IKZF1_1 HNF4A_2 HNF4A_1 HNF1B HINFP HIF1A HIC1_2 HIC1_1 HEY2 HES1 HAND1 GLI2 GLI1 GCM1_3 GCM1_2 GCM1_1 FUBP1 FOXA1 FOSB FOS_2 FOS_1 ETV4_2 ETV4_1 ETV3 ETS1 ETS ESR2 ESR1 EPAS1 ENO1 ELK4 ELF3 ELF1_2 ELF1_1 EIF5A2 EHF EGR4 EGR2_2 EGR2_1 EGR1 EBF E2F6 DEC CTCF_6 CTCF_5 CTCF_4 CTCF_3 CTCF_2 CTCF_1 CHD2 CEBPB_2 CEBPB_1 CDC42EP3 BBX APEX1 IRF E2F SP1 SP2 TEF YY1 EBF ETS TBP EHF USF BBX DEC MAZ WT1 ZIC1 GLI1 GLI2 SIX5 SPI1 E2F6 ELF3 KLF1 KLF5 KLF7 TP53 TP63 ELK4 TCF3 ETS1 ETV3 LHX2 TBX5 NFE2 PBX2 TBXT YBX1 ESR1 ESR2 HES1 HEY2 JUND CHD2 EGR1 EGR4 ENO1 FOSB PITX1 PITX3 RXRB HIF1A STAT4 ITGAL SMAD SNAI1 SNAI3 KLF14 HINFP ZFP92 TBX20 ZNF76 ZNF91 ZNF99 EPAS1 PTF1A SRF_1 SRF_2 ZBTB6 NR2F2 TFCP2 FOS_1 FOS_2 FOXA1 FUBP1 MINI20 RAD21 THAP1 APEX1 HNF1B NR2C2 EIF5A2 RREB1 HAND1 HIC1_1 HIC1_2 MECP2 SMAD2 ELF1_1 ELF1_2 ETV4_1 ETV4_2 ZNF131 ZNF148 ZNF177 ZNF219 ZNF224 ZNF236 ZNF274 ZNF304 ZNF316 ZNF391 ZNF426 ZNF460 ZNF521 ZNF555 ZNF560 ZNF579 ZNF623 ZNF658 ZNF660 ZNF671 ZNF675 ZNF709 ZNF716 ZNF775 ZNF808 ZNF836 ZBTB33 TFAP2A PLAGL1 TFAP2C CTCF_1 CTCF_2 CTCF_3 CTCF_4 CTCF_5 CTCF_6 REST_1 REST_2 EGR2_1 EGR2_2 IKZF1_1 IKZF1_2 IKZF1_3 THRA_1 THRA_2 POU1F1 SMC3_1 SMC3_2 SREBF2 STAT1_1 STAT1_2 STAT1_3 STAT3_1 STAT3_2 PKNOX1 GCM1_1 GCM1_2 GCM1_3 SIN3A_1 SIN3A_2 SULT1A2 ZNF658B NR5A2_1 NR5A2_2 HNF4A_1 HNF4A_2 CEBPB_1 CEBPB_2 SIGMAR1 STAT5A_1 STAT5A_2 STAT5A_3 ZNF143_1 ZNF143_2 ZNF648_1 ZNF648_2 ZNF676_1 ZNF676_2 CDC42EP3 PPARGC1A Forward

６ Reverse-forward orientation in monocytes using H3K27ac histone modification marks

ZSCAN4 ZSCAN2_2 ZSCAN2_1 ZNF879 ZNF799 ZNF770 ZNF721 ZNF701 ZNF684 ZNF672 ZNF668 ZNF547 ZNF449 ZNF37A ZNF33B ZNF304 ZNF239 ZEB1 ZBTB33 ZBTB2 ZBTB18_2 ZBTB18_1 ZBED6 YY2 TRIM28 THRB_2 THRB_1 TFE3 TFAP2C TCF7L2 TBP STAT5B SRF_5 SRF_4 SRF_3 SRF_2 SRF_1 SREBF1 SP8 SP5 SP4_2 SP4_1 SP3 SP1_2 SP1_1 SOX9 SOX5 SOX2 SOX13 SOX12 SOX11 SMARCC2 SMAD4 SMAD3 RXRA_2 RXRA_1 RFX5 RFX3 RELA REL PPARG POU5F1 POU3F2 POU1F1 Gene POLR3A PAX5 OBOX2 NR2F1 NR2C2 NKX3−1 NFY 1500 NFE2L3 NFE2L2 NANOG_2 NANOG_1 MYF6 MYEF2 1000 MYC_MAX MSX2 MSC

Forward MGA MECOM MAML1_NOTCH4 MAML1_NOTCH3 500 MAML1_NOTCH2_2 MAML1_NOTCH2_1 MAFB KLF8 KLF7 KLF16 JDP2_2 0 JDP2_1 IRF3 HSF2 HSF1 HNF4A HDAC1 GTF2IRD1 GLI3 GLI2 GABPA_4 GABPA_3 GABPA_2 GABPA_1 GABP FOXP2 FOXO1 FLI1_2 FLI1_1 ETV7 ETV6 ETV5_2 ETV5_1 ETV4 ETV3_2 ETV3_1 ETV2_2 ETV2_1 ETV1_4 ETV1_3 ETV1_2 ETV1_1 ETS2_2 ETS2_1 ETS1_2 ETS1_1 ETS ESRRA ERG_3 ERG_2 ERG_1 ELK4_2 ELK4_1 ELK3 ELF3 CTCFL CTCF_3 CTCF_2 CTCF_1 CREM CNOT3 CEBPB CCNT2 BPTF BCL11A ATF5_2 ATF5_1 ATF3 ASH1L ARNTL APEX1 1 − SP3 SP5 SP8 YY2 ETS REL TBP NFY GLI2 GLI3 IRF3 MSC MGA ATF3 ELF3 KLF7 KLF8 PAX5 TFE3 ELK3 ETV4 ETV6 ETV7 ZEB1 BPTF HSF1 HSF2 RFX3 RFX5 SOX2 SOX5 SOX9 RELA MYF6 MSX2 MAFB GABP CREM KLF16 SP1_1 SP1_2 SP4_1 SP4_2 FLI1_1 FLI1_2 SRF_1 SRF_2 SRF_3 SRF_4 SRF_5 ZBTB2 SOX11 SOX12 SOX13 ASH1L NR2F1 FOXP2 APEX1 CTCFL ZBED6 ARNTL HNF4A NR2C2 ERG_1 ERG_2 ERG_3 HDAC1 FOXO1 CCNT2 MYEF2 CNOT3 PPARG OBOX2 CEBPB ATF5_1 ATF5_2 ESRRA SMAD3 SMAD4 STAT5B ELK4_1 ELK4_2 JDP2_1 JDP2_2 TRIM28 ETS1_1 ETS1_2 ETS2_1 ETS2_2 ETV1_1 ETV1_2 ETV1_3 ETV1_4 ETV2_1 ETV2_2 ETV3_1 ETV3_2 ETV5_1 ETV5_2 TCF7L2 ZNF239 ZNF304 ZNF449 ZNF547 ZNF668 ZNF672 ZNF684 ZNF701 ZNF721 ZNF770 ZNF799 ZNF879 NFE2L2 NFE2L3 ZBTB33 BCL11A ZNF33B ZNF37A NKX3 TFAP2C CTCF_1 CTCF_2 CTCF_3 MECOM THRB_1 THRB_2 POU1F1 POU3F2 POU5F1 RXRA_1 RXRA_2 SREBF1 ZSCAN4 POLR3A GABPA_1 GABPA_2 GABPA_3 GABPA_4 NANOG_1 NANOG_2 ZBTB18_1 ZBTB18_2 GTF2IRD1 SMARCC2 MYC_MAX ZSCAN2_1 ZSCAN2_2 MAML1_NOTCH3 MAML1_NOTCH4 MAML1_NOTCH2_1 MAML1_NOTCH2_2 Reverse

７ Forward-reverse orientation in T cells using H3K27ac histone modification marks

ZSCAN2 ZSCAN18 ZNF880 ZNF84_2 ZNF84_1 ZNF790 ZNF75A ZNF73 ZNF717 ZNF714 ZNF701 ZNF676 ZNF658B ZNF639 ZNF595 ZNF586 ZNF582 ZNF575 ZNF548 ZNF486 ZNF436 ZNF394 ZNF366 ZNF287 ZNF263_2 ZNF263_1 ZNF250 ZNF219 ZIC3 ZIC1 ZACN VAMP3 UF1H3BETA TRIM28 TP53_2 TP53_1 THRA TFCP2 TBX5 SRP9 SREBF1 SPZ1 SPI1_2 SPI1_1 SPDEF_2 SPDEF_1 SP1_4 SP1_3 SP1_2 SP1_1 SOX18_2 SOX18_1 SOAT1 SMC3_2 SMC3_1 SMARCC2 SMAD3 RREB1_2 RREB1_1 REST Gene RARB RAD21_4 RAD21_3 RAD21_2 RAD21_1 POLR3A P50_P50 OTX2_3 OTX2_2 OTX2_1 2000 NR3C1 NFYA NFKB1_2 NFKB1_1 NFIA NEUROD1

Reverse MYOD1 MYF6 1000 MYCN MNX1 MAZ_2 MAZ_1 MAF LHX8 LHX6 KLF5 0 JUN JDP2_2 JDP2_1 IRF9 IRF HNF1B HMGA2_2 HMGA2_1 HEY1_2 HEY1_1 GLI1 GFI1B GCM1 GC GATA2_2 GATA2_1 FUBP1 FOXO3 FOXF2 FGF9 ETV3 EP300_3 EP300_2 EP300_1 ELF4 ELF3 ELF1 EHF EGR1 E2F6_4 E2F6_3 E2F6_2 E2F6_1 E2F4 E2F1_3 E2F1_2 E2F1_1 DUX1 DLX3 DEAF1 DDIT3_CEBPA CUX1 CTCF_6 CTCF_5 CTCF_4 CTCF_3 CTCF_2 CTCF_1 CEBPE BCL3_2 BCL3_1 BATF_2 BATF_1 BARX2 BACH1 ARID3A AHR_ARNT GC IRF JUN EHF MAF GLI1 IRF9 ZIC1 ZIC3 NFIA E2F4 ELF1 ELF3 ELF4 KLF5 DLX3 ETV3 LHX6 LHX8 SPZ1 TBX5 FGF9 NFYA SRP9 CUX1 DUX1 MYF6 REST ZACN THRA EGR1 MNX1 RARB GCM1 GFI1B MYCN SP1_1 SP1_2 SP1_3 SP1_4 ZNF73 SOAT1 FOXF2 TFCP2 DEAF1 FUBP1 MAZ_1 MAZ_2 BARX2 HNF1B NR3C1 SPI1_1 SPI1_2 BACH1 VAMP3 FOXO3 CEBPE SMAD3 MYOD1 E2F1_1 E2F1_2 E2F1_3 E2F6_1 E2F6_2 E2F6_3 E2F6_4 TP53_1 TP53_2 BATF_1 BATF_2 TRIM28 JDP2_1 JDP2_2 ARID3A ZNF219 ZNF250 ZNF287 ZNF366 ZNF394 ZNF436 ZNF486 ZNF548 ZNF575 ZNF582 ZNF586 ZNF595 ZNF639 ZNF676 ZNF701 ZNF714 ZNF717 ZNF790 ZNF880 BCL3_1 BCL3_2 OTX2_1 OTX2_2 OTX2_3 HEY1_1 HEY1_2 ZNF75A CTCF_1 CTCF_2 CTCF_3 CTCF_4 CTCF_5 CTCF_6 SMC3_1 SMC3_2 SREBF1 POLR3A ZSCAN2 EP300_1 EP300_2 EP300_3 P50_P50 GATA2_1 GATA2_2 ZNF84_1 ZNF84_2 SOX18_1 SOX18_2 ZNF658B NFKB1_1 NFKB1_2 RAD21_1 RAD21_2 RAD21_3 RAD21_4 RREB1_1 RREB1_2 SPDEF_1 SPDEF_2 ZSCAN18 HMGA2_1 HMGA2_2 ZNF263_1 ZNF263_2 NEUROD1 SMARCC2 AHR_ARNT UF1H3BETA DDIT3_CEBPA Forward

８ Reverse-forward orientation in T cells using H3K27ac histone modification marks

ZNF880 ZNF8 ZNF777 ZNF718 ZNF681 ZNF678 ZNF579 ZNF551 ZNF549 ZNF491 ZNF468 ZNF440 ZNF366 ZNF335 ZNF281 ZNF256 ZNF239 ZNF235 ZNF174 ZNF155 ZNF132 ZIC3 ZIC1 ZFP69B_2 ZFP69B_1 ZBTB7A ZBTB11 ZBTB1 YY1 YBX1 TP73 TGIF1 TFAP2C_2 TFAP2C_1 TEAD1 TBX5 TBX2 STAT1 SRY SRF_2 SRF_1 SPDEF SP4 SP2_4 SP2_3 SP2_2 SP2_1 SP1 SOX17 SOX1 RXRA_3 RXRA_2 RXRA_1 RUNX2 RREB1 Gene RFX4 RFX1 REST RELA RARA PSMD9 PROX1 PPARD PBX3 2000 PBX2 PAX4 PARP1 ONECUT2 NRL_2 NRL_1 Forward NR2C1 1000 NR0B1 NKX2−4 NKX2−1 NFKB2 NFKB1_2 NFKB1_1 NFE2L2_2 NFE2L2_1 0 MYOD1 MEIS1 MEF2A MAZ MAFA LHX6 LHX4 LEF1 LBX1 KLF6 KLF3 JDP2 IRF HAND1 GFI1B GFI1 GATA GABPA_2 GABPA_1 FOXN3 FOXK1 FOXJ3 FOXA3_2 FOXA3_1 FOS_3 FOS_2 FOS_1 ETV6 ETS1 ESR1_2 ESR1_1 EP300 ELF3_2 ELF3_1 ELF2 EHF EGR1 EDF1 E2F4 E2F DBP CTCFL_2 CTCFL_1 CTCF_4 CTCF_3 CTCF_2 CTCF_1 CEBPA BHLHE41 BHLHE40 BCLAF1 AR 1 4 − − AR IRF E2F SP1 SP4 YY1 EHF SRY DBP MAZ ZIC1 ZIC3 GFI1 E2F4 ELF2 KLF3 KLF6 LEF1 TP73 PAX4 JDP2 LBX1 GATA ZNF8 ETS1 ETV6 LHX4 LHX6 TBX2 TBX5 EDF1 PBX2 PBX3 RFX1 RFX4 YBX1 SOX1 RELA REST MAFA EGR1 RARA TGIF1 STAT1 GFI1B EP300 MEIS1 SP2_1 SP2_2 SP2_3 SP2_4 FOXJ3 NRL_1 NRL_2 SRF_1 SRF_2 ZBTB1 PARP1 SOX17 FOS_1 FOS_2 FOS_3 FOXK1 NFKB2 NR0B1 TEAD1 CEBPA FOXN3 NR2C1 PROX1 PPARD MEF2A RREB1 SPDEF RUNX2 HAND1 PSMD9 MYOD1 ELF3_1 ELF3_2 ZNF132 ZNF155 ZNF174 ZNF235 ZNF239 ZNF256 ZNF281 ZNF335 ZNF366 ZNF440 ZNF468 ZNF491 ZNF549 ZNF551 ZNF579 ZNF678 ZNF681 ZNF718 ZNF777 ZNF880 ZBTB11 ESR1_1 ESR1_2 NKX2 NKX2 BCLAF1 CTCF_1 CTCF_2 CTCF_3 CTCF_4 ZBTB7A RXRA_1 RXRA_2 RXRA_3 FOXA3_1 FOXA3_2 CTCFL_1 CTCFL_2 NFKB1_1 NFKB1_2 GABPA_1 GABPA_2 BHLHE40 BHLHE41 NFE2L2_1 NFE2L2_2 ONECUT2 ZFP69B_1 ZFP69B_2 TFAP2C_1 TFAP2C_2 Reverse

９

** ** * 0.7 CTCF * 0.7 RAD21 * 0.6 SMC3 * 0.6 0.6 0.5 0.5 0.5 0.4 0.4 0.4 0.3 0.3 0.3 0.2 0.2 0.2 0.1 0.1 0.1 0 0 0 others any FR FR others any FR FR others any FR FR Ratio of EPI overlapped with interactions (Hi-C) chromatin H3K27ac Ratio of EPI overlapped with interactions (Hi-C) chromatin H3K27ac Ratio of EPI overlapped with interactions (Hi-C) chromatin H3K27ac

** ** ** 1 CTCF ** 1 RAD21 ** 1 SMC3 **

0.8 0.8 0.8 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0 0 0 others any FR FR others any FR FR others any FR FR Ratio of EPI overlapped with interactions (Hi-C) chromatin Ratio of EPI overlapped with interactions (Hi-C) chromatin Ratio of EPI overlapped with interactions (Hi-C) chromatin H3K27ac H3K27ac H3K27ac

Supplemental Figure S3. Comparison of enhancer-promoter interactions (EPI) with chromatin interactions in monocytes. EPI were predicted based on enhancer-promoter association (EPA) shortened at the genomic locations of biased orientation of DNA binding motif sequence of a . Total 59 biased orientation (40 FR and 23 RF) of DNA motif sequences including CTCF and cohesin showed a higher ratio of EPI overlapped with Hi-C chromatin interactions than the other types of EPAs in monocytes. The upper part of the figure is a comparison of EPI with Hi-C chromatin interactions with a cutoff score of CHiCAGO tool > 5, and the lower part of the figure is a comparison of EPI with Hi-C chromatin interactions with a cutoff score of CHiCAGO tool > 1. FR: forward-reverse orientation of DNA motif. any: any orientation of DNA motif. others: enhancer-promoter association not shortened at the genomic locations of DNA motif. FR H3K27ac: forward-reverse orientation of DNA motif found from open chromatin regions overlapped with H3K27ac histone modification marks. * p-value < 0.05. ** p- value < 10-5.

１０ Supplemental Table S1. Forward-reverse and reverse-forward orientations of DNA binding motif sequences of transcription factors in monocytes of four people

Forward-reverse orientation

DNA motif of TF Score TF Score TF Score TF Score TF Score TF Score SRF 75.45 STAT5A 31.24 SMARCC2 21.86 PRDM9 16.63 NFKB2 12.46 SIX5 5.49 IRF7 71.05 E2F8 30.62 ZNF695 21.78 HOXA7 16.61 PAX8 12.22 ZNF90 5.27 MINI20 61.68 TP53 30.56 ZNF28 21.77 RFTN1 16.42 NR1I2 12.15 SETDB1 4.79 CTCF 61.62 STAT5B 29.94 ZNF316 21.66 KLF3 16.38 RXRA_VDR 12.07 GATA6 4.44 E2F 59.32 STAT3 29.85 TBP 21.60 MAX 16.12 ZNF675 12.00 NR2F6 4.32 STAT1 58.94 FOS 29.75 NFIB 21.45 GTF3C2 16.12 NR2C2 11.58 ZFP30 4.32 ZNF317 55.97 CEBPZ 29.42 PHOX2B 20.82 LBX2 16.02 PITX3 11.51 NR3C1 4.29 CEBPG 55.46 RAD21 28.67 DEC 20.62 ZBTB6 15.97 SPI1 11.32 ZNF263 4.05 ZNF623 54.71 SMAD2 28.60 ZNF709 20.58 RREB1 15.69 BRF1 11.27 E2F3 3.40 ZNF93 54.23 GATA2 28.52 YY1 20.57 RELA 15.67 ETS 11.20 HMBOX1 52.99 KLF6 28.02 EIF5A2 20.55 TBX5 15.42 ZNF366 10.27 SMAD2_SMAD3_SMAD4 50.66 HOXB1 27.62 ZNF148 20.45 ZNF660 15.15 ESX1 9.84 FOXN2 49.88 GLI1 27.09 PAX5 20.05 HOXC9 15.13 DBP 9.79 SPEF1 49.52 GCM1 26.73 POU6F1 19.93 SIRT6 14.93 FOSB 9.33 ZNF646 43.95 ZNF676 26.66 FOXO4 19.72 PPARGC1A 14.92 ZNF274 9.25 TFE3 42.46 TCF3 26.32 EBF 19.26 GLIS2 14.89 BBX 8.67 MYB 41.98 EHF 26.32 ZNF648 19.12 ZNF573 14.78 TFAP2A 8.63 STAT4 40.54 TCF12 26.29 HENMT1 19.02 GLI2 14.61 NFE2 8.62 ZNF716 40.39 MEF2A 26.22 PARG 18.78 ETV4 14.59 HOMEZ 8.56 KLF14 39.64 HIC1 25.34 ZNF460 18.64 NFYB 14.02 HSF2 8.26 FOXA1 38.13 EGR2 24.92 SLC25A20 17.83 MAZ 13.97 ZIC3 7.75 USF 37.74 NR2F2 24.86 KLF5 17.77 RUNX2 13.65 HES1 7.72 EN1 37.01 PLAGL1 24.65 XRCC4 17.53 MAFA 13.58 NKX2-5 7.36 ZNF219 35.37 REST 24.53 WT1 17.34 HOXC11 13.48 PROX1 7.21 IKZF1 33.79 ZNF143 23.67 SULT1A2 17.34 ZNF670 13.41 SNTB1 7.15 ZIC1 33.60 YBX1 22.99 FUBP1 17.33 HNF4A 13.06 ZBTB24 6.96 SMC3 33.37 PRDM15 22.63 DNAAF2 17.26 ZBTB33 12.97 E2F5 6.26 ESR2 32.07 ZNF92 22.22 ZNF521 17.25 PITX1 12.95 POU3F2 6.10 TP63 31.98 ZNF214 22.11 XBP1 16.85 ZNF33B 12.75 MLXIPL 6.05 ZNF836 31.66 PTF1A 22.09 SP1 16.84 SIN3A 12.51 NFKB1 5.51

Reverse-forward orientation

TF Score TF Score TF Score TF Score TF Score TF Score RFX5 102.30 TFAP2B 34.55 ZNF449 27.96 PAX3 17.74 ZNF641 11.60 ZNF181 4.27 TCF7 75.34 TBP 34.47 ZNF233 27.66 REST 17.64 THRB 11.42 BCL6 3.84 SRF 65.52 ZNF670 34.33 SOX2 26.46 POU3F2 17.53 E2F3 11.30 TP53 2.62 ZNF28 63.89 ZNF350 34.30 RXRA 26.07 ETV6 17.34 SPI1 11.27 FOXR1 16.61 HNF1B 62.46 ZNF687 33.82 MYF6 25.85 ZNF671 17.29 EP300 11.02 SMAD4 16.28 ZNF225 62.18 NFKB2 33.05 MAFK 25.81 PLAG1 17.22 ZNF770 10.78 HOXD1 16.14 CEBPB 59.69 RFX3 32.74 CEBPZ 25.73 ZNF721 17.20 IRX2 10.71 ZNF228 16.09 NFY 58.96 NFE2L3 32.69 POU2F2 25.59 ELF2 16.98 SP2 10.63 ATF3 15.92 ZNF286B 54.73 TRIM28 32.27 ETS2 25.05 ZBTB7B 16.94 PAX1 10.43 MADS7 15.75 CTCF 53.16 SP3 32.22 HSF1 24.76 EBF1 16.93 ZNF672 10.05 IRF9 15.71 PAX5 52.57 FLI1 32.15 AHR 23.56 PBX1 16.38 SMAD9 9.99 CBF1 15.66 STAT1 52.11 RBAK 31.92 PAX6 23.48 ZSCAN2 16.18 RAD21 9.76 ZIC1 15.62 ISL1 49.73 NR2F1 31.80 IRF4 22.47 ATF3 15.56 ZNF337 9.71 THRB 15.37 ETV7 47.08 NKX3-1 31.55 ETV3 21.90 ATF2_ATF4 15.48 POLR3A 9.57 EP300 15.11 KLF16 46.45 ZIC2 31.40 FOXP2 21.72 ASCL2 15.40 FOX 9.40 ETV2 14.61 SP1 46.03 PARP1 31.19 CDX2 21.45 SMAD4 15.38 PBX3 9.40 ZNF584 14.46 SMAD3 45.27 ZNF195 31.06 NFATC1 21.24 ZNF331 15.03 E2F2 9.23 BCL3 14.43 STAT5B 44.72 BDP1 30.84 SP4 21.14 GABPA 14.12 LHX4 8.47 ZSCAN5B 14.21 TEAD1 43.00 SOX9 30.72 USF1 20.92 NR5A2 13.96 ETV2 8.18 LHX4 13.99 ZNF579 42.94 SP8 30.49 MSX2 20.84 HOXD1 13.67 POU5F1 7.54 E2F3 13.93 ZBTB2 42.28 ZNF121 30.04 PPARG 20.70 SPIC 13.59 MZF1 7.20 RAD21 11.35 ZNF343 41.01 ZNF202 30.01 MYEF2 20.23 ALX1 13.20 ZNF547 6.65 SMAD8 11.21 DOBOX5 39.21 CD59 29.85 MYC_MAX 20.22 TFAP2A 13.18 GTF2I 6.52 E2F2 10.42 NANOG 38.84 RXRB 29.57 ZNF711 19.84 ZBTB7A 13.00 ZNF148 6.33 BCL6 9.96 NFE2L2 38.53 STAT5A 29.31 ZBTB18 19.60 ZIC1 12.85 ELF5 6.19 RPN4 9.81 OBOX2 38.00 SOX11 29.09 HSF2 19.51 ZNF682 12.12 IRF8 5.53 ZBP89 8.73 ZNF652 37.84 WT1 29.06 DNAAF2 19.00 ZNF112 12.10 PSMD9 5.51 IRF8 8.19 ZNF30 37.59 CREM 28.65 IRF3 18.88 ETV5 11.93 IRF9 5.50 ELF5 8.18 MYOG 36.34 ZNF316 28.34 TFAP2E 18.87 ZSCAN5B 11.76 BCL3 5.39 5.77 GABPB1_GABPB2 35.96 HAND1_TCF3 28.07 BCL11A 18.59 ZNF584 11.67 FOXR1 5.10

１１ Supplemental Table S2. Forward-reverse and reverse-forward orientations of DNA binding motif sequences of transcription factors in T cells of four people

Forward-reverse orientation

TF Score TF Score TF Score TF Score TF Score TF Score EGR2 64.94 CDC5L 31.10 SMC3 24.06 PLAG1 17.29 HOXA7 11.58 HOXA2 4.96 RREB 60.13 ZNF75A 31.07 ZNF846 24.01 ZNF253 17.28 GATA4 11.28 ZNF263 4.89 HMGA2 59.06 HBP1 30.92 ZNF786 23.19 POU4F1 16.98 HOXA13 11.22 GABPA 4.81 ZNF701 52.19 GFI1B 30.83 CEBPE 23.12 ELF1 16.84 ZNF676 10.90 ZNF668 4.64 NFYA 48.10 ZNF717 30.82 SOX18 22.95 NFIX 16.54 HNF1A 10.83 HPV16GP4 4.61 BATF 47.08 RREB1 30.81 EMBP1 22.85 INSM1 16.17 NR2C2 10.39 BRCA1 3.48 SP1 44.89 IRF 30.54 ZEB1 22.81 MAF 15.54 ETV3 10.34 FOXF2 3.45 IRF5 44.08 ZFP14 30.34 TP53 22.78 ELF4 15.44 ZBTB7A 10.27 NR0B1 3.12 TBP 43.53 ZNF770 30.25 EGR4 22.52 GLI1 15.33 CEBPZ 10.25 EP300 42.61 EGR1 29.90 FOXJ3 22.21 DDIT3_CEBPA 15.12 ZNF585A 10.18 EGR3 42.12 GATA 29.10 ZBTB33 21.87 THRA 15.05 ZBTB7B 9.83 YBX1 41.49 ZNF124 28.99 ELF3 21.27 FOXN4 14.70 NR2F2 9.65 PAX2 39.35 ZNF681 28.29 SOX5 21.14 ETV4 14.19 TP63 9.57 PDX1 39.00 OTX2 27.70 ZNF534 21.06 ZNF880 14.11 ZNF790 9.21 ZNF582 38.30 HIC1 27.55 SPDEF 20.64 E2F6 14.10 PRDM9 8.80 APEX1 38.21 ZNF546 27.46 GFI1 20.46 ZNF355P 14.02 GLIS2 8.78 HNF1B 37.85 SREBF2 27.22 SOAT1 19.95 TFCP2 13.86 ZNF219 8.78 TAL1 37.82 REL 26.98 DUX1 19.68 TCF7L2 13.76 FOXO3 8.75 NFY 37.47 CTCF 26.87 NFATC2 19.57 E2F4 13.76 PITX2 8.71 P50_P50 37.42 ELF5 26.75 SRP9 19.51 MNX1 13.55 FOXO6 8.57 JDP2 35.17 ZFX 26.74 GATA5 19.50 AR 13.03 BDP1 7.98 ZNF721 35.13 LHX8 26.68 TFAP4 19.20 NRF1 12.53 RFX3 7.91 ZIC1 34.56 ZNF287 26.06 ARID3A 18.83 NFKB1 12.41 ZFP3 7.60 ZNF568 34.07 EBF1 25.20 PRDM15 18.67 TLX1 12.33 BACH1 7.07 KLF1 32.66 BARX2 25.03 DLX3 18.37 NFE2 12.32 DBX1 6.85 ZNF84 32.55 RAD21 24.98 EHF 18.22 12.09 MINI20 6.70 ZNF714 32.33 INSM2 24.72 ZNF639 18.02 RARB 12.07 SOX13 6.59 CUX1 31.87 PCBP1 24.23 TCF4 17.97 FOXA3 12.02 BCL6 6.55 SPI1 31.79 ZNF616 24.19 PITX1 17.72 TBXT 11.91 ELK1 5.34 LHX6 31.31 ZNF117 24.12 HEY1 17.66 MXI1 11.82 MZF1 5.17

Reverse-forward orientation

TF Score TF Score TF Score TF Score TF Score NFE2L2 98.73 ZNF714 29.39 FOS 22.09 PSMD9 16.52 HAND1 10.88 NKX2-1 65.81 NKX2-4 29.21 LHX6 22.02 BCL 16.49 ZNF143 10.38 ZBTB7A 58.99 GFI1 28.72 ZBTB33 21.72 LHX4 16.07 ZBTB41 10.31 THRB 55.52 TCF12 28.16 FOXN4 21.59 GABPA 15.64 SOX2 10.22 ZFP69B 55.25 KLF6 27.51 NR3C1 21.46 NFKB1 15.59 ZNF526 9.51 RELA 54.89 CTCF 27.26 IRF 21.11 ZNF777 15.04 ZBTB18 9.12 GATA4 54.23 MTF1 27.21 HSF1 21.07 SPI1 14.99 ZNF300 8.89 EGR1 49.48 ZNF718 27.15 LBX1 20.95 FOXA2 14.93 ZNF267 8.60 SP2 48.23 MYCN 27.09 RARA 20.81 SPIC 14.74 BCL11B 8.46 PITX3 46.40 RORA 26.43 FOXA1 20.57 EP300 14.55 ZNF256 8.42 KLF8 45.46 ZNF625 26.21 ZNF549 20.37 ZFP2 14.50 YY2 8.22 GTF2I 40.80 CEBPA 26.12 YY1 20.34 ZNF468 14.44 ZNF282 8.18 ZNF658 40.22 PBX3 25.55 POU2F2 19.43 KLF13 14.30 PPARGC1A 7.95 ZNF580 40.00 ZNF880 25.48 ETS1 19.31 MLX 13.79 FOXP3 7.78 ZNF174 39.39 FOXO3 25.45 ZNF341 18.73 BCLAF1 13.73 KLF16 7.15 RREB1 39.23 RFX1 25.44 ZNF257 18.71 TAL1 13.72 ZNF44 5.16 ZNF189 39.06 SIX6 25.34 EHF 18.20 RAD21 13.38 PARP1 4.36 NFY 36.86 CAP1 24.84 ZNF773 18.10 CREB3 13.15 E2F1 3.04 NKX2-5 36.55 ALX1 24.74 NRG2 18.09 FOXJ3 12.92 IRF5 2.74 FOXG1 35.99 ZNF214 24.55 GATA1 18.07 ZNF770 12.79 ETV6 34.88 ZNF410 24.49 BTD 18.07 ZNF219 12.70 ZNF239 34.80 DBP 24.42 REL 17.94 ZNF17 12.61 HOXA10 34.64 HOXB6 24.02 ZNF41 17.66 DMRTA2 12.56 NFYA 33.69 RELB 23.86 ZNF484 17.46 MXI1 12.16 ZNF721 33.08 MYOG 23.34 ZBTB4 17.42 ETV3 12.03 HLTF 32.98 RUNX2 23.16 REST 17.18 ZIC1 11.78 ZNF180 30.49 PPARD 22.89 NR4A1 17.15 ETV1 11.63 ESR1 30.33 ZNF134 22.71 ZNF28 16.95 TEAD1 11.48 FOXA 30.12 ELF3 22.50 SRF 16.81 IRF8 11.39 SMARC 29.78 ZNF592 22.44 ETS2 16.74 MEIS1 11.24

１２ Supplemental Table S3. Forward-reverse and reverse-forward orientations of DNA binding motif sequences of transcription factors in monocytes of four people using H3K27ac histone modification marks

Forward-reverse orientation

TF Score TF Score TF Score TF Score TF Score ZNF658 45.46 RREB1 18.08 PPARGC1A 14.69 THAP1 10.36 KLF7 6.76 ZFP92 36.77 NR2C2 17.84 SIN3A 14.67 HEY2 9.87 ZNF648 6.72 ZIC1 29.92 TP63 17.57 YY1 14.35 CDC42EP3 9.84 ZBTB6 6.62 CTCF 28.04 APEX1 17.45 EBF 14.22 PLAGL1 9.80 SNAI3 6.61 FOS 27.18 POU1F1 17.22 GCM1 14.14 ELF3 9.56 TBX5 6.49 PTF1A 25.83 PBX2 16.97 FOXA1 13.98 NR5A2 9.55 ZNF316 6.41 ZNF579 25.70 KLF14 16.90 USF 13.83 HINFP 9.48 TBX20 6.18 ZNF716 24.39 ZNF304 16.86 EGR2 12.69 KLF5 9.35 SREBF2 5.95 IKZF1 23.84 ZNF236 16.80 FUBP1 12.59 PITX3 9.35 MAZ 5.75 HIC1 23.31 E2F 16.57 ZNF460 12.32 GLI2 9.20 SNAI1 5.64 TP53 23.17 REST 16.50 SIGMAR1 12.24 ZNF177 9.14 ZNF671 5.59 GLI1 23.06 EPAS1 16.48 SULT1A2 12.11 HNF1B 9.09 ZNF775 5.37 ZNF709 22.67 SMC3 16.44 EIF5A2 11.93 HES1 9.06 ENO1 5.23 MINI20 22.33 NFE2 16.30 HIF1A 11.92 TFCP2 8.75 WT1 5.22 ZNF224 22.30 TEF 15.88 SMAD2 11.87 ESR1 8.70 TCF3 5.08 STAT1 22.22 ZNF676 15.85 KLF1 11.83 BBX 8.57 ZNF76 4.60 ETS 22.10 ZNF658B 15.74 ZNF555 11.56 JUND 8.52 TBP 4.08 SRF 22.01 STAT3 15.60 ZNF560 11.53 PKNOX1 8.41 TFAP2A 4.04 NR2F2 21.39 STAT5A 15.55 HNF4A 11.45 E2F6 8.27 YBX1 3.76 ZNF623 21.18 THRA 15.47 MECP2 11.37 ETV4 8.25 FOSB 3.73 ESR2 20.42 ITGAL 15.43 ZNF143 11.36 ETS1 8.21 IRF 2.71 CEBPB 20.38 ZNF131 15.39 TFAP2C 11.13 LHX2 7.96 ZNF219 19.93 ZNF836 15.36 ELK4 11.11 EGR4 7.92 ZNF660 19.38 SP1 15.19 ZNF274 11.04 SMAD 7.90 SP2 18.99 EHF 15.14 RXRB 10.93 ZNF148 7.48 ETV3 18.86 STAT4 15.13 SIX5 10.93 ZNF808 7.39 ZNF391 18.78 DEC 15.13 EGR1 10.85 ZNF99 7.37 RAD21 18.75 ZBTB33 14.92 SPI1 10.84 HAND1 6.98 ELF1 18.55 TBXT 14.88 ZNF426 10.76 ZNF675 6.88 PITX1 18.52 ZNF521 14.76 ZNF91 10.58 CHD2 6.78

Reverse-forward orientation

TF Score TF Score TF Score TF Score RFX5 54.03 SP3 18.75 SOX5 13.59 ATF5 9.05 ZNF701 41.66 SP5 18.61 MAML1_NOTCH2 13.46 PPARG 8.96 PAX5 38.79 TBP 18.38 ETV6 13.10 POU1F1 8.84 CEBPB 38.20 SMAD3 18.38 JDP2 13.08 SOX11 8.73 MSC 37.48 SMAD4 18.15 GLI3 12.94 CTCFL 8.61 ZNF799 35.74 NR2C2 17.89 HNF4A 12.69 ZNF684 8.59 SP8 34.84 TCF7L2 17.72 ETV2 12.41 GTF2IRD1 8.03 SRF 34.79 ETV3 17.68 BCL11A 12.25 POLR3A 7.92 RXRA 32.62 SOX13 17.62 SOX2 12.20 RFX3 7.84 ETV7 32.02 ZNF770 16.87 FLI1 12.10 ZNF668 7.66 KLF16 31.27 NR2F1 16.57 POU3F2 12.06 NKX3-1 7.54 MYF6 29.95 GLI2 16.55 STAT5B 11.64 CNOT3 7.48 ARNTL 28.33 BPTF 16.50 ERG 11.60 TFE3 7.34 ZBTB2 27.77 ZSCAN2 16.49 CCNT2 10.96 ZNF239 7.30 CTCF 27.00 GABPA 16.22 SOX12 10.73 FOXP2 7.24 MECOM 25.23 ETS2 16.08 ETV5 10.70 FOXO1 7.20 SOX9 25.02 NFY 16.03 MGA 10.70 MYC_MAX 6.88 NFE2L2 24.25 ZNF879 16.01 ETS1 10.68 ESRRA 6.67 SP4 23.42 HSF1 16.01 KLF7 10.62 ETS 6.49 ZSCAN4 23.02 THRB 15.94 ELK4 10.50 MSX2 6.49 SREBF1 21.86 MYEF2 15.73 ELF3 10.37 KLF8 5.81 ZBED6 20.75 MAFB 15.47 CREM 10.31 ATF3 5.46 TFAP2C 20.65 ZNF547 14.80 ZNF672 10.17 SMARCC2 5.37 POU5F1 20.42 ZBTB33 14.66 ZEB1 10.01 HDAC1 5.12 OBOX2 20.08 MAML1_NOTCH3 14.55 RELA 9.87 ASH1L 4.67 ZNF449 20.07 GABP 14.44 IRF3 9.85 HSF2 4.59 TRIM28 19.68 APEX1 14.18 ETV4 9.71 MAML1_NOTCH4 4.55 NANOG 19.65 ETV1 13.91 REL 9.70 ZNF33B 3.52 SP1 19.40 NFE2L3 13.78 YY2 9.60 ZNF37A 3.51 ZBTB18 19.20 ZNF721 13.68 ELK3 9.13 ZNF304 2.74

１３ Supplemental Table S4. Forward-reverse and reverse-forward orientations of DNA binding motif sequences of transcription factors in T cells of four people using H3K27ac histone modification marks

Forward-reverse orientation

TF Score TF Score TF Score TF Score SOAT1 59.81 POLR3A 18.20 ZNF263 12.07 MYF6 6.10 RAD21 45.82 ZNF714 17.87 MYOD1 11.98 DDIT3_CEBPA 5.95 CTCF 41.82 KLF5 17.05 NFYA 11.71 ZNF676 5.88 ELF3 40.54 CEBPE 16.95 ZIC3 11.61 DEAF1 5.68 DLX3 36.87 GLI1 16.01 NFKB1 11.49 CUX1 5.38 SMC3 35.58 SRP9 15.81 ZNF73 11.36 TRIM28 5.37 E2F6 30.80 REST 15.75 ZNF486 11.12 ZNF575 5.10 P50_P50 30.16 ZNF250 15.70 ZNF394 10.92 IRF 4.91 ELF1 29.25 LHX6 15.54 EGR1 10.20 MNX1 4.77 EHF 29.20 THRA 15.29 TBX5 10.02 SREBF1 4.68 ZSCAN2 26.99 OTX2 15.26 ZNF75A 9.77 JUN 4.65 RREB1 26.38 DUX1 15.20 ZNF287 9.53 GCM1 4.48 ZNF84 25.96 BATF 15.06 JDP2 9.14 IRF9 3.95 HMGA2 25.64 ZNF595 14.30 ARID3A 9.04 BARX2 3.76 SPI1 24.73 TP53 14.07 FUBP1 8.94 ZNF366 3.56 HNF1B 24.48 FOXO3 13.99 E2F4 8.90 AHR_ARNT 3.50 EP300 24.29 SP1 13.94 RARB 8.80 ZNF717 3.35 ZNF701 24.12 NEUROD1 13.93 ZNF219 8.15 ZNF548 23.57 FGF9 13.88 SPDEF 7.94 ZNF582 22.69 ETV3 13.80 LHX8 7.87 HEY1 22.68 ZACN 13.26 MAF 7.83 MAZ 21.51 E2F1 13.24 VAMP3 7.81 BCL3 21.38 NR3C1 12.74 ZNF790 7.73 SOX18 21.14 MYCN 12.71 GC 7.42 ZSCAN18 20.88 ZNF639 12.55 NFIA 7.37 ZIC1 20.61 TFCP2 12.50 SPZ1 7.35 ELF4 19.85 FOXF2 12.49 SMARCC2 7.23 UF1H3BETA 18.63 BACH1 12.34 ZNF658B 7.08 ZNF436 18.48 GATA2 12.33 SMAD3 6.55 ZNF880 18.26 GFI1B 12.24 ZNF586 6.22

Reverse-forward orientation

TF Score TF Score TF Score TF Score NKX2-1 51.66 RREB1 18.21 NFKB2 12.36 STAT1 7.29 NFE2L2 45.80 SRF 18.16 PARP1 12.35 SOX1 7.00 CTCF 45.77 ELF3 18.04 SP4 12.34 AR 6.90 PAX4 38.26 ZNF235 17.66 KLF6 12.29 ZNF681 6.84 ZNF491 37.25 ZNF281 17.58 IRF 12.29 PBX2 6.68 ZBTB7A 36.37 SRY 17.35 PROX1 12.15 NFKB1 6.65 YY1 35.85 ZNF239 17.30 MYOD1 11.89 ZNF256 6.61 SOX17 34.63 FOXN3 16.98 LBX1 11.57 ZNF8 6.59 ZNF366 33.53 FOXJ3 16.42 PPARD 11.18 EP300 6.47 ETS1 32.36 ZNF718 16.09 ZNF777 10.86 TBX2 6.33 DBP 29.96 NR2C1 16.06 TGIF1 10.53 GABPA 6.11 ZNF174 29.77 ZNF132 15.89 ZNF678 10.13 E2F4 5.54 ETV6 28.41 BHLHE40 15.81 FOS 9.83 FOXK1 4.72 ZIC1 27.88 FOXA3 15.69 TP73 9.56 GFI1 4.62 ZNF579 26.75 CTCFL 15.63 EGR1 9.47 NR0B1 4.58 NRL 25.27 ZNF551 15.58 REST 9.26 ZNF440 4.08 KLF3 25.06 CEBPA 15.48 LHX4 9.20 JDP2 4.06 ZIC3 24.64 PSMD9 15.44 ONECUT2 9.00 BHLHE41 4.00 ZNF468 24.16 TFAP2C 14.84 BCLAF1 8.93 SPDEF 3.28 RARA 24.04 ELF2 14.71 RFX4 8.92 LHX6 3.04 ZNF880 23.00 SP1 14.20 HAND1 8.85 MAZ 22.26 NKX2-4 14.19 TBX5 8.79 ESR1 22.05 PBX3 14.11 YBX1 8.76 RFX1 21.70 ZNF335 14.05 E2F 8.58 ZNF549 21.44 MAFA 13.71 GATA 7.80 ZNF155 20.52 TEAD1 13.53 ZBTB1 7.78 GFI1B 20.39 ZBTB11 13.40 LEF1 7.76 SP2 18.89 RXRA 13.30 MEF2A 7.65 EHF 18.86 RELA 12.73 RUNX2 7.61 ZFP69B 18.44 EDF1 12.48 MEIS1 7.52

１４ Supplemental Table S5. Biased orientation of DNA binding motif sequences of transcription factors found in both monocytes and T cells. FR: Forward-reverse orientation, RF: Reverse- forward orientation.

FR and RF (61) FR and RF (61) FR (31) RF (34) FR and RF (84) FR and RF (84) FR and RF (84) ALX1 PITX1 CEBPZ ALX1 ALX1 MYOG SPI1 CEBPZ POU2F2 CTCF CTCF BCL6 MZF1 SPIC CTCF PRDM15 EGR2 EP300 BDP1 NFE2 SRF EGR2 PRDM9 EHF ETS2 CEBPZ NFE2L2 TBP EHF PSMD9 ETV4 ETV3 CTCF NFKB1 TCF12 EP300 RAD21 GLI1 ETV6 DBP NFY TEAD1 ETS2 REST GLIS2 GABPA EBF1 NKX2-5 THRB ETV3 RREB1 HIC1 GTF2I EGR2 NR2C2 TP53 ETV4 SMC3 HOXA7 HSF1 EHF NR2F2 TP63 ETV6 SOX2 MINI20 IRF8 ELF5 NR3C1 YBX1 GABPA SP1 NFE2 KLF16 EP300 PARP1 YY1 GLI1 SP2 NFKB1 LHX4 ETS2 PBX3 ZBTB18 GLIS2 SPI1 NR2C2 MYOG ETV3 PITX1 ZBTB33 GTF2I SPIC NR2F2 NFE2L2 ETV4 PITX3 ZBTB7A HIC1 SRF PITX1 NFY ETV6 PLAG1 ZBTB7B HOXA7 TBP PRDM15 PARP1 FOS POU2F2 ZIC1 HSF1 TEAD1 PRDM9 PBX3 FOXA1 PPARGC1A ZNF143 IRF8 THRB RAD21 POU2F2 GABPA PRDM15 ZNF214 KLF16 TP53 RREB1 PSMD9 GLI1 PRDM9 ZNF219 LHX4 TP63 SMC3 RAD21 GLIS2 PSMD9 ZNF263 MINI20 YBX1 SP1 REST GTF2I RAD21 ZNF28 MYOG ZBTB18 SPI1 SOX2 HIC1 RELA ZNF676 NFE2 ZBTB33 TBP SP2 HNF1B REST ZNF721 NFE2L2 ZBTB7A TP53 SPI1 HOXA7 RFX3 ZNF770 NFKB1 ZIC1 TP63 SPIC HSF1 RREB1 NFY ZNF219 YBX1 SRF IRF8 RUNX2 NR2C2 ZNF263 ZBTB33 TEAD1 KLF16 SMC3 NR2F2 ZNF28 ZIC1 THRB KLF6 SOX2 PARP1 ZNF676 ZNF219 ZBTB18 LHX4 SP1 PBX3 ZNF721 ZNF263 ZBTB7A MINI20 SP2 ZNF770 ZNF676 ZIC1 ZNF28 ZNF721 ZNF770

Using H3K27ac histone modification marks

FR and RF (40) FR and RF (40) FR (28) RF (34) FR and RF (58) FR and RF (58) CTCF TBX5 CTCF CTCF RREB1 CTCFL TFAP2C CTCFL CTCFL RXRA E2F6 TFCP2 ELF3 E2F SMAD3 EGR1 THRA ETS1 E2F6 SMARCC2 EHF TP53 ETV6 EGR1 SMC3 ELF1 ZIC1 GABPA EHF SP1 ELF3 ZNF219 JDP2 ELF1 SP2 ETS1 ZNF239 NFE2L2 ELF3 SP4 ETV3 ZNF658B RELA ESR1 SPI1 ETV6 ZNF676 RXRA ETS1 SREBF1 FUBP1 SP1 ETV3 SRF GABPA SP4 ETV6 STAT1 GCM1 SRF FOS TBX5 GLI1 TFAP2C FUBP1 TFAP2C HNF1B ZNF239 GABPA TFCP2 IRF GCM1 THRA JDP2 GLI1 TP53 KLF5 HAND1 TRIM28 MAZ HNF1B YBX1 NFE2L2 IRF YY1 RAD21 JDP2 ZIC1 RELA KLF5 ZNF219 REST MAZ ZNF239 RREB1 MYF6 ZNF579 RXRA NFE2L2 ZNF658B SMC3 PBX2 ZNF676 SP1 POLR3A ZNF701 SP4 RAD21 ZSCAN2 SPI1 RELA SRF REST

１５ The results of the two analyses of biased orientation of DNA motif sequences using only open chromatin regions and open chromatin regions overlapped with H3K27ac histone modification marks were merged in each cell type of monocytes and T cells, and biased orientation of DNA motif sequences found in both cell types in common were listed.

FR and RF (101) FR and RF (101) FR and RF (101) FR and RF (101) FR (57) FR (57) RF (53) RF (53) ALX1 HSF1 REST ZIC3 APEX1 PITX1 ALX1 REST APEX1 IRF RREB1 ZNF219 CEBPZ PRDM15 CTCF RXRA CEBPZ IRF8 RXRA ZNF239 CTCF PRDM9 CTCFL SOX2 CTCF JDP2 SMARCC2 ZNF263 E2F6 RAD21 ELF2 SP1 CTCFL KLF1 SMC3 ZNF28 EGR1 REST ELF3 SP2 E2F6 KLF16 SOX2 ZNF366 EGR2 RREB1 EP300 SP4 EGR1 KLF5 SP1 ZNF579 EGR4 SMARCC2 ETS1 SPI1 EGR2 KLF8 SP2 ZNF658B EHF SMC3 ETS2 SPIC EGR4 LHX4 SP4 ZNF676 ELF1 SP1 ETV1 SRF EHF MAZ SPI1 ZNF721 ELF3 SPI1 ETV3 STAT1 ELF1 MINI20 SPIC ZNF770 ETV3 SREBF2 ETV6 TEAD1 ELF2 MYOG SREBF2 ETV4 TBP GABPA TFAP2C ELF3 NFE2 SRF FUBP1 TBX5 GTF2I THRB EP300 NFE2L2 STAT1 GATA2 TBXT HSF1 YY2 ETS1 NFKB1 TBP GCM1 TFCP2 IRF8 ZBTB18 ETS2 NFKB2 TBX5 GLI1 THRA JDP2 ZBTB33 ETV1 NFY TBXT GLIS2 TP53 KLF16 ZBTB7A ETV3 NR2C2 TEAD1 HIC1 TP63 KLF8 ZIC1 ETV4 NR2F2 TFAP2C HNF1B YBX1 LHX4 ZNF239 ETV6 NR3C1 TFCP2 HOXA7 ZBTB33 MYOG ZNF28 FUBP1 PARP1 THRA IRF ZIC1 NFE2L2 ZNF579 GABPA PBX3 THRB KLF1 ZIC3 NFKB2 ZNF721 GATA2 PITX1 TP53 KLF5 ZNF219 NFY ZNF770 GCM1 POU2F2 TP63 MAZ ZNF263 PARP1 GLI1 PRDM15 YBX1 MINI20 ZNF366 PBX3 GLIS2 PRDM9 YY2 NFE2 ZNF658B POU2F2 GTF2I PSMD9 ZBTB18 NFKB1 ZNF676 PSMD9 HIC1 RAD21 ZBTB33 NR2C2 RAD21 HNF1B REL ZBTB7A NR2F2 REL HOXA7 RELA ZIC1 NR3C1 RELA

FR and RF (144) FR and RF (144) FR and RF (144) FR and RF (144) FR and RF (144) ALX1 FUBP1 NFE2 SMAD3 YY2 APEX1 GABPA NFE2L2 SMARCC2 ZBTB18 BCL3 GATA2 NFKB1 SMC3 ZBTB33 BCL6 GCM1 NFKB2 SOX13 ZBTB7A BDP1 GLI1 NFY SOX2 ZBTB7B CEBPZ GLIS2 NKX2-5 SOX5 ZEB1 CTCF GTF2I NR2C2 SP1 ZIC1 CTCFL HAND1 NR2F2 SP2 ZIC3 DBP HIC1 NR3C1 SP4 ZNF143 E2F HNF1B PARP1 SPI1 ZNF214 E2F6 HOXA7 PBX2 SPIC ZNF219 EBF1 HSF1 PBX3 SREBF1 ZNF239 EGR1 IRF PITX1 SREBF2 ZNF263 EGR2 IRF8 PITX3 SRF ZNF28 EGR4 IRF9 PLAG1 STAT1 ZNF366 EHF JDP2 POLR3A TBP ZNF579 ELF1 KLF1 POU2F2 TBX5 ZNF658 ELF2 KLF16 PPARGC1A TBXT ZNF658B ELF3 KLF3 PRDM15 TCF12 ZNF668 ELF5 KLF5 PRDM9 TCF7L2 ZNF676 EP300 KLF6 PROX1 TEAD1 ZNF701 ESR1 KLF8 PSMD9 TFAP2C ZNF721 ETS1 LHX4 RAD21 TFCP2 ZNF770 ETS2 MAFA REL THRA ZSCAN2 ETV1 MAZ RELA THRB ETV3 MEF2A REST TP53 ETV4 MINI20 RFX3 TP63 ETV6 MYF6 RREB1 TRIM28 FOS MYOG RUNX2 YBX1 FOXA1 MZF1 RXRA YY1

１６ Supplemental Table S6. Forward-reverse and reverse-forward orientations of DNA binding motif sequences of transcription factors in H1-hESC, iPS, Huvec, and Mcf7

H1-hESC

Forward-reverse orientation Reverse-forward orientation

TF Score TF Score TF Score TF Score SPI1 29.28 GLI1 1.59 RXRA 21.14 FOX 1.84 ZNF521 14.82 ZIC1 1.57 ZNF30 13.98 ETV6 1.81 HMBOX1 13.16 FOS 1.56 ATF3 12.99 SOX9 1.76 CTCF 11.49 IKZF1 1.54 ZNF584 12.21 SP4 1.54 ZNF93 10.81 RFX3 8.86 EP300 1.52 REST 10.20 ZSCAN2 8.67 SPIC 1.50 FUBP1 8.68 IRF4 8.30 POU5F1 1.32 SMC3 7.52 ZNF670 7.67 BBX 7.52 BCL11A 7.61 STAT3 6.40 GTF2I 7.56 E2F5 5.92 ZNF195 7.28 RAD21 5.67 CDX2 6.73 NR2F6 5.21 HSF1 6.47 ZNF143 5.14 CD59 6.40 EBF 5.11 CTCF 6.29 HOMEZ 4.53 MZF1 6.09 SIRT6 3.97 MYC_MAX 4.56 KLF14 3.59 MYF6 4.44 ZNF670 3.15 PAX5 3.92 E2F 3.07 TFAP2E 3.68 MAZ 2.98 ZNF202 3.37 ZNF92 2.97 GABPB1_GABPB2 2.92 SULT1A2 2.38 RBAK 2.81 ETS 2.00 ISL1 2.46 EGR2 1.91 GABPA 2.41 SRF 1.84 ZIC2 2.39 E2F3 1.77 ZBTB2 2.16 HES1 1.72 CEBPZ 2.04 STAT5A 1.62 NFE2L2 1.93 ZNF836 1.60 NKX3-1 1.87

iPS cells

Forward-reverse orientation Reverse-forward orientation

TF Score TF Score TF Score TF Score ZIC3 19.32 XRCC4 5.38 CTCF 35.80 GTF2I 2.15 ZNF521 18.93 PAX5 4.72 ATF3 23.50 SOX9 2.06 TFE3 16.63 STAT3 4.54 ZNF670 16.91 ZNF148 1.98 ZNF317 16.43 MLXIPL 4.37 IRF4 16.73 SMAD3 1.35 NKX2-5 16.25 DNAAF2 4.14 TBP 15.60 HES1 15.34 PLAGL1 4.11 DNAAF2 14.39 ZBTB24 14.21 BBX 3.68 THRB 13.58 SMC3 13.76 E2F 3.49 ZIC2 12.85 FOS 13.69 ZNF263 3.36 NKX3-1 10.23 RAD21 13.05 SP1 3.27 POU3F2 10.18 ZNF836 11.64 PARG 3.17 SMAD4 9.37 TBX5 11.48 ZNF219 3.14 ZBTB7B 8.44 CTCF 11.24 KLF6 2.84 IRF8 8.19 STAT1 11.19 ETS 2.80 IRF3 7.66 RUNX2 10.28 GLI1 2.65 ZNF343 7.11 WT1 10.27 ZNF28 2.59 HSF1 6.28 ZIC1 9.60 SMARCC2 2.36 ZNF112 5.95 MAX 8.55 GATA6 2.04 TP53 5.10 KLF3 8.29 SMAD2 1.94 RXRA 4.94 KLF14 8.25 HNF4A 1.88 MYF6 4.74 ZNF143 7.81 GLIS2 1.83 SP1 4.05 E2F5 7.66 FOXO4 1.78 ZNF641 4.00 SIRT6 7.56 HOXB1 1.75 ZIC1 3.93 EN1 7.49 TP53 1.75 BCL6 3.65 YY1 7.02 SRF 1.62 FOXR1 3.04 STAT5B 6.73 EP300 2.97 MAZ 6.39 KLF16 2.82 ZNF148 6.20 ZBTB2 2.55 TCF3 5.73 WT1 2.48 EGR2 5.45 ZNF331 2.38

１７ Huvec cells

Forward-reverse orientation Reverse-forward orientation

TF Score TF Score TF Score EGR2 23.96 TFE3 1.63 ZNF202 11.95 CEBPZ 8.55 REST 1.58 CTCF 11.10 XRCC4 8.13 MYB 1.44 PBX3 5.07 SLC25A20 7.27 CEBPG 1.43 RBAK 5.02 ZNF648 6.83 ZBTB24 1.40 OBOX2 3.23 NFIB 5.75 SMC3 1.40 TFAP2E 2.99 STAT4 5.37 E2F 1.37 PAX6 2.70 MINI20 5.11 MSX2 2.61 SULT1A2 5.06 SMAD4 2.52 XBP1 4.90 BDP1 2.51 HOMEZ 4.85 GABPB1_GABPB2 2.50 TBX5 4.69 NANOG 2.34 PAX8 4.47 ZSCAN2 1.85 KLF14 3.94 ETS2 1.82 MAFA 3.56 FOXP2 1.75 TP63 3.35 STAT5A 1.51 CTCF 3.32 LHX4 1.46 RAD21 3.11 RXRA 1.41 GLI2 2.95 ISL1 1.40 E2F3 2.40 ASCL2 1.30 ZNF33B 2.26 YBX1 2.12 E2F8 2.01 FOSB 2.01 KLF5 1.96 ZBTB6 1.87 PITX1 1.86 SRF 1.78 ZNF460 1.78 SETDB1 1.67

Mcf7 cells

Forward-reverse orientation Reverse-forward orientation

TF Score TF Score TF Score RAD21 16.21 STAT3 1.94 CTCF 19.09 SMC3 15.63 TBX5 1.75 SMAD3 9.28 CTCF 15.12 ZNF148 1.52 RXRA 9.21 E2F 10.14 KLF6 1.51 ZBTB2 7.39 SLC25A20 9.62 EGR2 1.51 PLAG1 7.27 HOXA7 8.29 DNAAF2 5.81 STAT5B 7.55 ZIC2 5.50 REST 7.25 SMAD4 3.87 SIRT6 7.05 WT1 3.87 KLF3 6.53 TP53 3.44 YY1 5.30 MZF1 3.41 PLAGL1 4.97 ZSCAN2 2.53 ZNF219 4.91 ATF2_ATF4 2.39 STAT1 4.43 ZNF672 1.82 SNTB1 4.42 ASCL2 1.77 ETS 3.16 SP2 1.62 XRCC4 3.15 PBX3 1.57 ZBTB6 3.12 RAD21 1.48 DBP 2.53 NR2F1 1.42 SETDB1 2.53 MYF6 1.33 RREB1 2.50 E2F5 2.38 KLF5 2.33 SPEF1 2.22 ZNF143 2.20 ZNF460 2.19 FOS 2.18 GATA2 1.97 MAZ 1.95 PARG 1.94

１８ Supplemental Table S7. Biased orientation of repeat DNA sequences in T cells. Score: –log10 (p-value).

Forward-reverse (FR) orientation Repeat DNA seq. Score HAL1 15.58 MLT1B 13.73 MIRb 9.81

Reverse-forward (RF) orientation Repeat DNA seq. Score MIR3 35.41 Tigger3a 13.16

Using H3K27ac histone modification marks

Forward-reverse (FR) orientation Repeat DNA seq. Score MIRb 8.19

Reverse-forward (RF) orientation Repeat DNA seq. Score MIR3 14.35

１９ Supplemental Table S8. Co-location of biased orientation of DNA motif sequences in monocytes

Motif 1 Motif 2 # both # motif 1 # motif 2 # others p-value BRF1 SMARCC2 4800 3746 1168 16381 0 SMAD2 ZNF263 7427 1578 1805 15285 0 ETS2 RREB1 4789 922 4347 16037 0 SMARCC2 ZNF263 7354 1192 1893 15656 0 ETS2 MAZ 4778 933 3183 17201 0 RREB1 SP1 7208 1957 1165 15765 0 MLXIPL RREB1 4776 802 4360 16157 0 SIRT6 ZNF263 7126 1154 2121 15694 0 KLF3 ZNF219 4739 2266 1070 18020 0 MAZ SP1 7052 909 1321 16813 0 ETS2 SMARCC2 4730 981 3816 16568 0 MAZ ZNF263 7022 999 2225 15849 0 SMAD2 XRCC4 4717 4288 1049 16041 0 SP1 ZNF263 7009 1364 2223 15499 0 PLAGL1 ZNF219 4678 3033 1131 17253 0 SMAD2 SP1 6925 2080 1448 15642 0 HIC1 RREB1 4672 662 4464 16297 0 MAZ RREB1 6920 967 2245 15963 0 HIC1 SMAD2 4660 674 4345 16416 0 SIRT6 SMAD2 6766 1514 2239 15576 0 SMARCC2 XRCC4 4654 3892 1112 16437 0 SIRT6 SMARCC2 6668 1612 1878 15937 0 SMARCC2 ZNF219 4652 3894 1157 16392 0 PLAGL1 SMAD2 6637 1074 2368 16016 0 MLXIPL ZNF263 4628 950 4604 15913 0 MAZ SMAD2 6627 1334 2378 15756 0 FOSB ZNF263 4613 1002 4619 15861 0 PARG SMAD2 6602 1012 2403 16078 0 ETS2 SIRT6 4609 1102 3671 16713 0 PLAGL1 ZNF263 6571 1140 2661 15723 0 HIC1 SP1 4579 755 3794 16967 0 EGR2 RREB1 6565 787 2600 16143 0 EGR2 KLF3 4557 1117 2448 17973 0 KLF6 RREB1 6563 932 2573 16027 0 MLXIPL SP1 4557 1021 3816 16701 0 MAZ SMARCC2 6562 1459 1984 16090 0 FOSB RREB1 4537 1078 4599 15881 0 RREB1 ZNF263 6551 1607 2681 15256 0 CTCF SMAD2 4527 781 4478 16309 0 KLF6 SP1 6541 954 1832 16768 0 SMAD2 ZNF143 4523 1130 4482 15960 0 PLAGL1 RREB1 6496 1215 2640 15744 0 MAZ SP2 4506 3455 946 17188 0 EGR2 SP1 6492 860 1881 16862 0 MLXIPL PLAGL1 4505 1073 3206 17311 0 KLF6 SMAD2 6491 1004 2514 16086 0 SP2 ZNF263 4466 4766 986 15877 0 PARG ZNF263 6390 1224 2842 15639 0 KLF6 MLXIPL 4463 3032 1115 17485 0 PLAGL1 SP1 6318 1393 2055 16329 0 HIC1 KLF6 4450 884 3045 17716 0 KLF6 ZNF263 6304 1191 2928 15672 0 HIC1 ZNF263 4444 890 4788 15973 0 EGR2 SMAD2 6270 1082 2735 16008 0 SMAD2 SP2 4443 4562 1009 16081 0 EGR2 ZNF263 6253 1099 2979 15764 0 EGR2 SP2 4385 2967 1067 17676 0 EGR2 MAZ 6219 1133 1742 17001 0 CTCF RREB1 4379 929 4757 16030 0 PARG RREB1 6219 1395 2917 15564 0 PARG SP1 4379 1016 3994 16706 0 RREB1 SMAD2 6213 2923 1245 15714 0 HIC1 PLAGL1 4359 975 3352 17409 0 KLF3 RREB1 6159 846 3006 16084 0 CTCF ZNF263 4357 951 4875 15912 0 KLF6 MAZ 6146 1349 1815 16785 0 PARG SIRT6 4326 1069 3954 16746 0 KLF3 SP1 6092 913 2281 16809 0 CTCF SP1 4321 987 4052 16735 0 SP1 ZNF148 6052 2321 651 17071 0 PARG SMARCC2 4321 1074 4225 16475 0 RREB1 ZNF148 6030 3135 673 16257 0 HIC1 MAZ 4285 1049 3676 17085 0 EGR2 KLF6 6012 1340 1483 17260 0 RREB1 WT1 4252 4913 449 16481 0 PITX3 SMAD2 6010 890 2995 16200 0 SP1 WT1 4146 4227 555 17167 0 KLF3 ZNF263 5902 1103 3330 15760 0 PITX1 SMAD2 4029 760 4976 16330 0 KLF3 SMAD2 5872 1133 3133 15957 0 ETS RREB1 4018 519 5118 16440 0 MAZ ZNF148 5870 2091 833 17301 0 E2F RREB1 3994 413 5142 16546 0 ELF2 ZNF263 5853 1018 3379 15845 0 EGR2 WT1 3985 3367 716 18027 0 ELF2 SMAD2 5820 1051 3185 16039 0 ZBTB6 ZNF263 3972 694 5260 16169 0 KLF3 MAZ 5810 1195 2151 16939 0 SMAD2 ZBTB6 3968 5037 698 16392 0 FOXO4 RREB1 5764 674 3401 16256 0 RREB1 YY1 3948 402 5217 16528 0 ZNF148 ZNF263 5710 993 3537 15855 0 E2F SP1 3913 494 4460 17228 0 SETDB1 ZNF263 5697 869 3535 15994 0 HES1 SMAD2 3911 445 5094 16645 0 PITX3 RREB1 5688 1212 3448 15747 0 MAZ WT1 3898 4063 803 17331 0 PITX3 ZNF263 5666 1234 3566 15629 0 E2F SMAD2 3896 511 5109 16579 0 FOXO4 ZNF263 5642 796 3590 16067 0 WT1 ZNF148 3894 2809 807 18585 0 FOXO4 SMAD2 5605 833 3400 16257 0 SMAD2 YY1 3885 465 5120 16625 0 FOXO4 SP1 5601 837 2772 16885 0 RREB1 ZBTB6 3883 5282 783 16147 0 ELF2 RREB1 5548 1323 3588 15636 0 KLF6 WT1 3876 3619 825 17775 0 SETDB1 SMAD2 5545 1021 3460 16069 0 SMAD2 WT1 3876 5129 825 16265 0 SMAD2 ZNF148 5543 3462 1160 15930 0 WT1 ZNF263 3869 5363 832 16031 0 FOXO4 MAZ 5536 902 2351 17306 0 SP1 YY1 3863 487 4510 17235 0 PITX3 SP1 5535 1365 2838 16357 0 PITX1 RREB1 3861 928 5275 16031 0 ELF2 SP1 5533 1338 2840 16384 0 HES1 RREB1 3856 500 5309 16430 0 EGR2 ZNF148 5531 1821 1172 17571 0 KLF6 ZNF143 3852 486 3643 18114 0 KLF6 ZNF148 5435 2060 1268 17332 0 SP1 ZNF143 3850 488 4523 17234 0 SETDB1 SIRT6 5423 1143 2857 16672 0 ETS SP1 3845 692 4528 17030 0 RREB1 ZNF219 5374 3791 435 16495 0 ETS SMAD2 3819 718 5186 16372 0 SMARCC2 ZNF148 5367 3179 1336 16213 0 E2F KLF6 3815 592 3680 18008 0 SP1 ZNF219 5352 3021 457 17265 0 CTCF RAD21 3804 1504 225 20562 0 SETDB1 SMARCC2 5315 1251 3231 16298 0 ATF3 SMAD2 3786 692 5219 16398 0 FOXO4 SMARCC2 5274 1164 3272 16385 0 KLF6 YY1 3777 573 3718 18027 0 EGR2 FOXO4 5231 2121 1207 17536 0 E2F ZNF263 3751 656 5481 16207 0 FOXO4 KLF6 5229 1209 2266 17391 0 E2F EGR2 3746 661 3606 18082 0 FOXO4 PLAGL1 5172 1266 2539 17118 0 ZNF143 ZNF263 3738 600 5494 16263 0 REST RREB1 5163 852 4002 16078 0 SP1 ZBTB6 3735 4638 931 16791 0 MAZ ZNF219 5131 2830 678 17456 0 HES1 SP1 3732 624 4641 17098 0 BRF1 SMAD2 5127 3878 841 16249 0 ETS ZNF263 3716 821 5516 16042 0 SIRT6 XRCC4 5121 3159 645 17170 0 HES1 KLF6 3705 651 3790 17949 0 EGR2 SMARCC2 5078 1230 3468 16319 0 CTCF KLF6 3695 852 3800 17748 0 BRF1 ZNF263 5035 933 4212 15915 0 E2F MAZ 3694 713 4267 17421 0 REST SMAD2 5034 981 3971 16109 0 YY1 ZNF263 3694 656 5538 16207 0 ETS2 ZNF263 5017 694 4215 16169 0 PTF1A SMAD2 3692 690 5313 16400 0 ZNF219 ZNF263 4998 811 4234 16052 0 EGR2 ZNF143 3684 654 3668 18089 0 EGR2 ZNF219 4974 2378 835 17908 0 ETS KLF6 3665 872 3830 17728 0 SMAD2 ZNF219 4955 4050 854 16236 0 HES1 ZNF263 3665 691 5567 16172 0 KLF6 ZNF219 4909 2586 900 17700 0 EGR2 YY1 3651 699 3701 18044 0 ETS2 SMAD2 4908 803 4097 16287 0 PLAGL1 YY1 3651 699 4060 17685 0 REST SP1 4906 1109 3467 16613 0 ETS MAZ 3636 901 4325 17233 0 SP1 SP2 4897 3476 555 17167 0 E2F PLAGL1 3635 772 4076 17612 0 MLXIPL SMAD2 4894 684 4111 16406 0 ATF3 ZNF263 3627 851 5605 16012 0 XRCC4 ZNF263 4874 892 4358 15971 0 ATF3 RREB1 3616 862 5520 16097 0 RREB1 SP2 4866 4299 586 16344 0 MAZ YY1 3613 737 4348 17397 0 RREB1 ZNF143 4857 796 4279 16163 0 PLAGL1 ZNF143 3612 726 4099 17658 0 REST ZNF263 4840 1175 4392 15688 0 HES1 PLAGL1 3601 755 4110 17629 0 ZNF148 ZNF219 4839 1864 970 18422 0 MYOG SMAD2 3601 752 5404 16338 0 RAD21 RREB1 4836 1044 4300 15915 0 MAZ ZNF143 3584 754 4377 17380 0 ETS2 SP1 4831 880 3542 16842 0 EGR2 HES1 3576 3776 780 17963 0 RAD21 SMAD2 4826 1054 4179 16036 0 PARG ZNF143 3558 780 4056 17701 0 FOSB SMAD2 4820 795 4185 16295 0 PTF1A ZNF263 3532 850 5700 16013 0 BRF1 RREB1 4815 4350 1153 15777 0 MYOG RREB1 3530 823 5606 16136 0 BRF1 SIRT6 4808 3472 1160 16655 0 PARG YY1 3506 844 4108 17637 0

２０ HES1 MAZ 3499 857 4462 17277 0 FUBP1 PLAGL1 2451 460 5260 17924 0 HES1 PARG 3491 865 4123 17616 0 NFKB2 ZNF263 2442 521 6790 16342 0 SMAD2 TBP 3450 344 5555 16746 0 KLF16 SP1 2428 5945 488 17234 0 RREB1 TBP 3418 376 5718 16583 0 PROX1 SP1 2428 424 5945 17298 0 SP1 TBP 3334 460 5039 17262 0 FUBP1 PARG 2427 484 5187 17997 0 KLF5 RREB1 3315 5850 471 16459 0 SP1 SP3 2420 5953 544 17178 0 KLF6 TBP 3308 486 4187 18114 0 NFKB2 RREB1 2401 562 6735 16397 0 FOS RREB1 3300 238 5865 16692 0 PROX1 ZNF263 2399 453 6833 16410 0 RREB1 RUNX2 3299 5837 358 16601 0 FUBP1 MAZ 2391 520 5496 17688 0 CEBPZ SMAD2 3297 497 5708 16593 0 EGR2 SIN3A 2389 542 4963 18201 0 KLF5 SP1 3287 5086 499 17223 0 KLF6 PROX1 2388 5107 464 18136 0 RUNX2 SMAD2 3261 396 5744 16694 0 PLAGL1 SIN3A 2376 555 5335 17829 0 FOS SP1 3258 280 5115 17442 0 PSMD9 RREB1 2372 210 6793 16720 0 PLAGL1 TBP 3225 569 4486 17815 0 KLF16 SP2 2370 546 3082 20097 0 GABPB1_GABPB2 ZNF263 3199 652 6048 16196 0 PSMD9 SP1 2365 217 6008 17505 0 TBP ZNF263 3197 597 6035 16266 0 FUBP1 PITX3 2348 563 4552 18632 0 CEBPZ RREB1 3195 599 5941 16360 0 PLAGL1 PROX1 2325 5386 527 17857 0 GABPB1_GABPB2 SMAD2 3186 665 5819 16425 0 EGR2 PROX1 2293 5059 559 18184 0 RUNX2 SP1 3176 481 5197 17241 0 MAZ PROX1 2287 5674 565 17569 0 RREB1 SMAD4 3162 5974 310 16649 0 PARG PROX1 2287 565 5327 17916 0 SP1 SP4 3157 5216 342 17380 0 MAZ PSMD9 2274 308 5687 17826 0 KLF6 RUNX2 3156 4339 501 18099 0 PSMD9 ZNF148 2270 312 4433 19080 0 EGR2 TBP 3145 649 4207 18094 0 KLF6 PSMD9 2259 323 5236 18277 0 FOS SMAD2 3145 393 5860 16697 0 PSMD9 ZNF263 2251 331 6996 16517 0 EN1 SMAD2 3133 525 5872 16565 0 EGR2 PSMD9 2250 332 5102 18411 0 PARG TBP 3130 664 4484 17817 0 PSMD9 SMAD2 2241 341 6764 16749 0 RREB1 SP4 3121 6044 378 16552 0 NR2C2 ZNF263 2236 551 7011 16297 0 GABPB1_GABPB2 RREB1 3118 733 6018 16226 0 RREB1 TRIM28 2196 6940 301 16658 0 FOS KLF6 3118 420 4377 18180 0 SMAD2 TRIM28 2172 6833 325 16765 0 POU6F1 SMAD2 3114 482 5891 16608 0 KLF3 PSMD9 2155 427 4850 18663 0 EN1 SP1 3112 546 5261 17176 0 PSMD9 ZNF219 2151 431 3658 19855 0 EGR2 RUNX2 3099 4253 558 18185 0 PSMD9 SMARCC2 2144 438 6402 17111 0 RXRA SMAD2 3098 5907 681 16409 0 PLAGL1 PSMD9 2123 459 5588 17925 0 CEBPZ ZNF263 3095 699 6137 16164 0 SP1 TRIM28 2070 6303 427 17295 0 EGR2 FOS 3091 447 4261 18296 0 TRIM28 ZNF263 2050 7182 447 16416 0 KLF5 ZNF148 3090 3613 696 18696 0 KLF14 RREB1 2049 7087 340 16619 0 SMAD4 SP1 3090 5283 382 17340 0 KLF6 TRIM28 2049 5446 448 18152 0 FOS MAZ 3087 451 4874 17683 0 HOXA7 RREB1 2043 252 7122 16678 0 RUNX2 ZNF263 3083 574 6149 16289 0 KLF14 SP1 2041 6332 348 17374 0 MAZ TBP 3081 713 4880 17421 0 PLAGL1 TRIM28 2019 5692 478 17906 0 NR3C1 ZNF263 3079 545 6168 16303 0 KLF3 TBP 1982 361 5023 18729 0 EN1 ZNF263 3079 579 6153 16284 0 EBF1 RREB1 1979 7157 494 16465 0 RREB1 RXRA 3073 6063 706 16253 0 TBP ZNF219 1971 372 3838 19914 0 PITX3 TBP 3060 734 3840 18461 0 HOXA7 SP1 1963 332 6410 17390 0 KLF5 MAZ 3060 4901 726 17408 0 ATF3 SP1 1959 267 6414 17455 0 EN1 RREB1 3059 599 6077 16360 0 TBP ZNF148 1948 395 4755 18997 0 CEBPZ SP1 3057 737 5316 16985 0 RREB1 SP8 1932 7233 308 16622 0 FOS ZNF263 3052 486 6180 16377 0 HOXA7 SMAD2 1906 389 7099 16701 0 BDP1 RREB1 3050 730 6115 16200 0 HOXA7 MAZ 1899 396 6062 17738 0 PLAGL1 RUNX2 3037 4674 620 17764 0 HOXA7 ZNF263 1898 397 7334 16466 0 POU6F1 ZNF263 3035 561 6212 16287 0 SP3 SP8 1890 1074 350 22781 0 MAZ RUNX2 3028 4933 629 17505 0 HOXA7 KLF6 1885 410 5610 18190 0 NR3C1 SMAD2 3014 610 5991 16480 0 EGR2 HOXA7 1864 431 5488 18312 0 SMAD2 SMAD4 2986 6019 486 16604 0 ATF3 KLF6 1862 364 5633 18236 0 FOS PLAGL1 2967 571 4744 17813 0 KLF16 SP8 1862 1054 378 22801 0 EGR2 SP4 2952 4400 547 18196 0 SP2 SP8 1851 389 3601 20254 0 FOS KLF3 2948 590 4057 18500 0 SP1 SP8 1850 6523 390 17332 0 EN1 KLF6 2944 714 4551 17886 0 RREB1 ZIC1 1841 7295 210 16749 0 POLR3A RREB1 2942 6223 731 16199 0 ATF3 EGR2 1840 386 5512 18357 0 PARG RUNX2 2936 4678 721 17760 0 SP1 ZIC1 1833 6540 218 17504 0 FOS ZNF148 2934 604 3769 18788 0 SMAD2 SMAD3 1823 7182 397 16693 0 FOS ZNF219 2933 605 2876 19681 0 GLI1 RREB1 1817 314 7319 16645 0 KLF6 SMAD4 2932 4563 540 18060 0 DNAAF2 RREB1 1816 7349 259 16671 0 EN1 PLAGL1 2931 727 4780 17657 0 SMAD2 TP53 1806 415 7199 16675 0 EGR2 SMAD4 2930 4422 542 18201 0 ATF3 MAZ 1804 422 6083 17786 0 EN1 MAZ 2928 730 5033 17404 0 RREB1 SMAD3 1792 7344 428 16531 0 SMAD4 ZNF263 2915 6317 557 16306 0 SMAD2 ZIC1 1789 7216 262 16828 0 NR3C1 SIRT6 2913 711 5367 17104 0 DNAAF2 SP1 1783 6590 292 17430 0 MAZ SMAD4 2908 5053 564 17570 0 DNAAF2 SMAD2 1779 7226 296 16794 0 MAZ SP4 2904 5057 595 17539 0 EGR2 ZIC1 1748 5604 303 18440 0 POU6F1 RREB1 2898 698 6238 16261 0 GLI1 SMAD2 1742 389 7263 16701 0 SP4 ZNF263 2892 6340 607 16256 0 GLI1 SP1 1733 398 6640 17324 0 SMAD2 SP4 2888 6117 611 16479 0 KLF6 ZIC1 1728 5767 323 18277 0 ETV5 SMAD2 2860 612 6145 16478 0 ZIC1 ZNF263 1721 330 7511 16533 0 SP4 ZNF148 2855 3848 644 18748 0 GLI1 ZNF263 1709 422 7523 16441 0 KLF6 SP4 2850 4645 649 17951 0 KLF3 ZIC1 1698 5307 353 18737 0 FOS SMARCC2 2839 699 5707 16850 0 MAZ ZIC1 1697 6264 354 17780 0 ETV5 ZNF263 2835 637 6412 16211 0 PLAGL1 ZIC1 1695 6016 356 18028 0 SP2 SP4 2817 2635 682 19961 0 ISL1 SMAD2 1691 352 7314 16738 0 PLAGL1 SMAD4 2799 4912 673 17711 0 DNAAF2 KLF6 1682 5813 393 18207 0 PPARG ZNF263 2741 629 6491 16234 0 ISL1 ZNF263 1679 364 7568 16484 0 PPARG SMAD2 2711 659 6294 16431 0 DNAAF2 PLAGL1 1664 6047 411 17973 0 FUBP1 SMAD2 2671 240 6334 16850 0 DNAAF2 EGR2 1662 5690 413 18330 0 FUBP1 RREB1 2633 278 6503 16681 0 ISL1 RREB1 1656 387 7480 16572 0 SIN3A SMAD2 2592 339 6413 16751 0 SP2 ZIC1 1642 409 3810 20234 0 RREB1 SIN3A 2589 342 6547 16617 0 IKZF1 RREB1 1559 283 7606 16647 0 FUBP1 KLF6 2567 344 4928 18256 0 TFAP2A TFAP2B 1534 96 150 24315 0 FUBP1 SP1 2543 368 5830 17354 0 IKZF1 ZNF263 1522 320 7710 16543 0 KLF16 RREB1 2536 6629 380 16550 0 KLF14 SP2 1518 283 3934 20360 0 PROX1 SMAD2 2534 318 6471 16772 0 IKZF1 SP1 1509 333 6864 17389 0 RREB1 SP3 2530 6635 434 16496 0 RFTN1 RREB1 1509 148 7627 16811 0 KLF16 SP3 2513 403 451 22728 0 TFAP2A TFAP2E 1499 131 69 24396 0 SIN3A SP1 2507 424 5866 17298 0 TFAP2B TFAP2E 1496 188 72 24339 0 FUBP1 ZNF263 2493 418 6739 16445 0 IKZF1 MAZ 1492 350 6395 17858 0 PROX1 RREB1 2485 367 6651 16592 0 KLF14 SP4 1490 311 2009 22285 0 KLF6 SIN3A 2479 452 5016 18148 0 KLF14 KLF16 1485 316 1431 22863 0 EGR2 FUBP1 2477 4875 434 18309 0 RFTN1 SP1 1482 175 6891 17547 0 SIN3A ZNF263 2466 465 6766 16398 0 RREB1 ZNF28 1473 7692 331 16599 0 SP2 SP3 2464 500 2988 20143 0 MYF6 RREB1 1471 7694 330 16600 0 NFKB2 SMAD2 2453 510 6552 16580 0 NFE2 SMAD2 1471 210 7534 16880 0

２１ MYF6 SMAD2 1463 7542 338 16752 0 NFE2 RREB1 1460 221 7676 16738 0 RFTN1 SMAD2 1445 212 7560 16878 0 KLF14 SMAD2 1442 7563 359 16731 0 NKX2-5 ZNF263 1423 345 7824 16503 0 NFE2 SP1 1420 261 6953 17461 0 EGR2 RFTN1 1406 251 5946 18492 0 KLF6 RFTN1 1398 259 6097 18341 0 RFTN1 ZNF263 1385 272 7847 16591 0 KLF6 NFE2 1385 296 6110 18304 0 KLF3 RFTN1 1381 276 5624 18814 0 RREB1 TFAP2B 1375 309 7761 16650 0 NFE2 ZNF263 1374 307 7858 16556 0 SMAD2 TFAP2B 1374 310 7631 16780 0 MAZ RFTN1 1370 287 6517 17921 0 NFE2 PLAGL1 1369 312 6342 18072 0 PLAGL1 RFTN1 1367 290 6344 18094 0 RFTN1 ZNF148 1360 297 5343 19095 0 NFE2 PARG 1351 330 6263 18151 0 RFTN1 SP2 1335 322 4117 20321 0 RFTN1 ZNF219 1329 328 4480 19958 0 RREB1 TFAP2A 1326 304 7810 16655 0 DBP SMAD2 1322 288 7683 16802 0 SMAD2 TFAP2A 1320 310 7685 16780 0 DBP ZNF263 1296 314 7951 16534 0 RREB1 TFAP2E 1264 304 7872 16655 0 CTCF SMC3 1259 178 1977 22681 0 GTF2I ZNF263 1256 297 7991 16551 0 DNAAF2 ZNF263 1231 8001 216 16647 0 CTCF RXRA 1220 259 2559 22057 0 RAD21 RXRA 1206 239 2573 22077 0 RAD21 SMC3 1193 244 2836 21822 0 DNAAF2 PARG 1186 6428 261 18220 0 DNAAF2 PITX3 1166 5734 281 18914 0 RREB1 ZIC2 1160 185 7976 16774 0 RREB1 ZNF676 1136 8000 161 16798 0 SMAD2 ZIC2 1131 214 7874 16876 0 SP1 ZNF676 1119 7254 178 17544 0 SP1 ZIC2 1111 234 7262 17488 0 KLF6 ZIC2 1098 247 6397 18353 0 ZIC2 ZNF263 1096 249 8151 16599 2.35E-287 SMAD2 ZNF676 1069 7936 228 16862 6.00E-303 ZNF263 ZNF676 1062 8170 235 16628 2.99E-282 KLF6 ZNF676 1047 6448 250 18350 0 SMAD2 ZNF716 1046 7959 261 16829 7.20E-276 SMAD2 SULT1A2 967 107 8038 16983 0 RREB1 ZNF521 955 8181 236 16723 6.03E-245 RXRA SMC3 944 2835 218 22098 0 RREB1 ZNF770 932 8233 133 16797 2.76E-292 RREB1 SULT1A2 921 153 8215 16806 4.00E-277 SULT1A2 ZNF263 911 163 8321 16700 5.70E-262 KLF6 SULT1A2 895 179 6600 18421 0 RREB1 ZIC3 892 8244 142 16817 8.15E-272 SP1 SULT1A2 890 184 7483 17538 1.09E-289 PAX5 SMAD2 888 8117 219 16871 6.06E-234 PLAGL1 SULT1A2 881 193 6830 18191 1.48E-323 PARG SULT1A2 874 200 6740 18281 1.48E-322 SMAD2 ZIC3 865 8140 169 16921 9.77E-252 PITX3 SULT1A2 864 210 6036 18985 0 ZIC3 ZNF263 848 186 8384 16677 2.96E-224 PLAGL1 ZIC3 844 6867 190 18194 2.21E-306 SP1 ZIC3 842 7531 192 17530 4.32E-263 KLF6 ZIC3 830 6665 204 18396 2.75E-305 RREB1 ZNF202 804 8361 182 16748 2.79E-212 CREM SMAD2 753 170 8252 16920 1.46E-205 PAX8 RREB1 737 144 8428 16786 1.68E-206 PAX8 SMAD2 713 168 8292 16922 1.26E-190 HOMEZ RREB1 659 95 8506 16835 5.06E-204 BBX RREB1 653 132 8512 16798 5.57E-180 RREB1 ZNF316 641 8495 113 16846 4.55E-187 SMAD2 ZNF112 639 8366 135 16955 9.46E-179 HOMEZ SMAD2 636 118 8369 16972 4.03E-187 E2F3 SMAD2 634 8371 119 16971 9.93E-186 HOMEZ ZNF263 630 124 8602 16739 5.81E-173 E2F3 RREB1 627 8509 126 16833 4.04E-174 RREB1 ZBTB7B 623 86 8513 16873 3.98E-196 SMAD2 ZNF316 620 8385 134 16956 1.12E-171 HOMEZ SP1 615 139 7758 17583 3.35E-191 E2F2 SMAD2 612 8393 109 16981 1.44E-182 HOMEZ MAZ 612 142 7275 18066 2.99E-209 SP1 ZNF316 608 7765 146 17576 3.68E-184 E2F2 RREB1 603 8562 118 16812 4.34E-168 SP1 ZBTB7B 591 118 7782 17604 1.12E-192 SMAD2 ZBTB7B 584 125 8421 16965 3.43E-162 ZBTB7B ZNF263 571 138 8661 16725 5.99E-143 PLAGL1 ZBTB7B 569 140 7142 18244 3.37E-197 GCM1 RREB1 265 62 8900 16868 3.66E-68 ETS2 FLI1 251 7 24 25813 0 SP1 ZBTB7A 246 49 8127 17673 7.64E-80 GATA6 SMAD2 232 8773 44 17046 2.18E-67 GATA6 RREB1 225 8911 51 16908 3.52E-59 ETV3 FLI1 223 582 52 25238 0 GATA6 ZNF263 222 9025 54 16794 3.36E-55 ETS2 ETV3 221 37 584 25253 0 ETV2 FLI1 210 32 65 25788 0 ETS2 ETV2 201 41 57 25796 0 STAT1 STAT5B 118 17 82 25878 0 STAT3 STAT5B 113 22 611 25349 0 ALX1 LBX2 22 2 2 26069 0

２２ Supplemental Table S9. Top 30 of c o-locations of biased orientation of DNA binding motif sequences of transcription factors in T cells. Co-locations of DNA motif sequence of CTCF with another biased orientation of DNA motif sequence were shown in a separate table. Co-locations of twelve pairs of DNA motif sequences were found in both monocytes and T cells, which were shown in a right table. All co-locations of biased orientation of DNA motif sequences in T cells were shown in the next page. Motif 1,2: DNA binding motif sequences of transcription factors. # both: the number of open chromatin regions including both Motif 1 and Motif 2. # motif 1: the number of open chromatin regions including Motif 1. # motif 2: the number of open chromatin regions including Motif 2. # others: the number of open chromatin regions not including Motif 1 and Motif 2. Open chromatin regions overlapped with histone modification marks (H3K27ac) were used (Total 30,647 regions).

Motif 1 Motif 2 # both # motif 1 # motif 2 # others p-value Motif 1 Motif 2 CTCF NR0B1 2112 5641 958 21936 0 CTCF KLF6 CTCF RAD21 2051 4040 1019 23537 0 CTCF RAD21 CTCF ZNF219 1805 4110 648 24084 0 CTCF SMC3 CTCF EGR2 1758 3894 695 24300 0 EGR2 KLF6 CTCF KLF6 1697 837 756 27357 0 EGR2 PSMD9 CTCF MZF1 1631 3783 822 24411 0 EGR2 SP2 CTCF SMC3 935 2135 586 26991 0 EGR2 TBP CTCF SP2 916 1537 337 27857 0 EGR2 ZNF219 CTCF TCF12 556 269 1897 27925 0 FOS SP1 KLF6 ZNF219 PSMD9 ZNF219 Motif 1 Motif 2 # both # motif 1 # motif 2 # others p-value TBP ZNF219 NR0B1 ZNF219 4407 3346 1508 21386 0 NR0B1 POU4F1 4401 3352 1263 21631 0 EGR2 NR0B1 4337 1315 3416 21579 0 NR0B1 RAD21 4322 1769 3431 21125 0 EP300 NR0B1 4301 2356 3452 20538 0 MZF1 ZNF219 4274 1140 1641 23592 0 MTF1 NR0B1 4148 989 3605 21905 0 MZF1 NR0B1 4140 1274 3613 21620 0 EGR2 ZNF219 4124 1528 1791 23204 0 BDP1 NR0B1 3955 1382 3798 21512 0 HAND1 NR0B1 3945 1136 3808 21758 0 EGR2 MZF1 3853 1799 1561 23434 0 EP300 ZNF219 3586 3071 2329 21661 0 EP300 MZF1 3501 3156 1913 22077 0 EP300 POU4F1 3475 3182 2189 21801 0 NR0B1 TEAD1 3417 4336 1224 21670 0 MTF1 RAD21 3294 2797 1843 22713 0 MYOG NR0B1 3252 1354 4501 21540 0 HAND1 RAD21 3201 2890 1880 22676 0 NR0B1 ZBTB33 3130 4623 891 22003 0 MTF1 POU4F1 3129 2008 2535 22975 0 ALX1 NR0B1 3087 1090 4666 21804 0 NR0B1 PPARD 3068 4685 1118 21776 0 EGR3 EGR4 3063 427 685 26472 0 HAND1 MTF1 3062 2019 2075 23491 0 MYOG RAD21 3043 3048 1563 22993 0 SOAT1 ZNF219 2999 1862 2916 22870 0 EGR2 EGR4 2986 2666 762 24233 0 NR0B1 SOAT1 2964 1897 4789 20997 0 FOXF2 NR0B1 2876 1016 4877 21878 0

２３ Motif 1 Motif 2 # both # motif 1 # motif 2 # others p-value NR0B1 TCF12 1708 1102 6045 21792 0 NR0B1 ZNF219 4407 3346 1508 21386 0 CTCF KLF6 1697 837 756 27357 0 NR0B1 POU4F1 4401 3352 1263 21631 0 NR0B1 ZNF180 1672 6081 944 21950 0 EGR2 NR0B1 4337 1315 3416 21579 0 EGR1 NR0B1 1670 6083 605 22289 0 NR0B1 RAD21 4322 1769 3431 21125 0 EGR2 GTF2I 1667 3985 1076 23919 0 EP300 NR0B1 4301 2356 3452 20538 0 MZF1 ZNF180 1659 3755 957 24276 0 MZF1 ZNF219 4274 1140 1641 23592 0 EP300 ZNF658 1650 5007 1047 22943 0 MTF1 NR0B1 4148 989 3605 21905 0 EGR1 ZNF219 1634 4281 641 24091 0 MZF1 NR0B1 4140 1274 3613 21620 0 MZF1 ZNF658 1632 3782 1065 24168 0 EGR2 ZNF219 4124 1528 1791 23204 0 CTCF MZF1 1631 3783 822 24411 0 BDP1 NR0B1 3955 1382 3798 21512 0 MZF1 TBP 1629 719 3785 24514 0 HAND1 NR0B1 3945 1136 3808 21758 0 SOX13 ZNF219 1629 773 4286 23959 0 EGR2 MZF1 3853 1799 1561 23434 0 ZNF219 ZNF341 1618 4297 790 23942 0 EP300 ZNF219 3586 3071 2329 21661 0 RAD21 SOX13 1616 786 4475 23770 0 EP300 MZF1 3501 3156 1913 22077 0 EGR2 SOX13 1612 790 4040 24205 0 EP300 POU4F1 3475 3182 2189 21801 0 NR0B1 ZNF134 1602 6151 573 22321 0 NR0B1 TEAD1 3417 4336 1224 21670 0 NR0B1 NR2F2 1598 6155 769 22125 0 MTF1 RAD21 3294 2797 1843 22713 0 DBX1 NR0B1 1595 503 6158 22391 0 MYOG NR0B1 3252 1354 4501 21540 0 EP300 ZNF180 1594 5063 1022 22968 0 HAND1 RAD21 3201 2890 1880 22676 0 KLF6 RAD21 1594 4497 940 23616 0 NR0B1 ZBTB33 3130 4623 891 22003 0 NR0B1 TP53 1583 6170 725 22169 0 MTF1 POU4F1 3129 2008 2535 22975 0 ETS2 NR0B1 1582 724 6171 22170 0 ALX1 NR0B1 3087 1090 4666 21804 0 EGR2 ZNF180 1578 4074 1038 23957 0 NR0B1 PPARD 3068 4685 1118 21776 0 BTD EGR2 1575 4077 490 24505 0 EGR3 EGR4 3063 427 685 26472 0 MTF1 SOX13 1570 832 3567 24678 0 HAND1 MTF1 3062 2019 2075 23491 0 NR0B1 NR2C2 1554 6199 644 22250 0 MYOG RAD21 3043 3048 1563 22993 0 RAD21 TBP 1547 801 4544 23755 0 SOAT1 ZNF219 2999 1862 2916 22870 0 E2F6 EP300 1542 933 5115 23057 0 EGR2 EGR4 2986 2666 762 24233 0 BTD NR0B1 1538 6215 527 22367 0 NR0B1 SOAT1 2964 1897 4789 20997 0 KLF6 POU4F1 1534 1000 4130 23983 0 FOXF2 NR0B1 2876 1016 4877 21878 0 E2F6 POU4F1 1526 949 4138 24034 0 EGR2 EGR3 2864 2788 626 24369 0 BTD ZNF219 1516 4399 549 24183 0 EGR4 NR0B1 2857 4896 891 22003 0 EGR1 MZF1 1511 3903 764 24469 0 NR0B1 RELB 2825 4928 1189 21705 0 PSMD9 RAD21 1503 913 4588 23643 0 EP300 TEAD1 2810 3847 1831 22159 0 POU4F1 PSMD9 1498 918 4166 24065 0 NFATC2 NR0B1 2805 1305 4948 21589 0 POU4F1 SOX13 1495 907 4169 24076 0 DBP NR0B1 2762 893 4991 22001 0 EGR2 ZNF134 1493 4159 682 24313 0 EP300 NFATC2 2684 3973 1426 22564 0 NR0B1 ZNF580 1480 6273 490 22404 0 EGR3 NR0B1 2671 5082 819 22075 0 BTD KLF6 1476 1058 589 27524 0 GLIS2 NR0B1 2638 952 5115 21942 0 ZNF134 ZNF219 1475 4440 700 24032 0 EGR2 ZBTB33 2594 3058 1427 23568 0 EP300 HEY1 1472 2077 880 26218 0 RAD21 ZBTB33 2582 3509 1439 23117 0 MZF1 ZNF341 1463 3951 945 24288 0 GLIS2 ZNF219 2549 1041 3366 23691 0 EP300 PSMD9 1451 965 5206 23025 0 ALX1 POU4F1 2513 1664 3151 23319 0 EGR2 ZNF580 1449 4203 521 24474 0 EGR4 ZNF219 2506 3409 1242 23490 0 POU4F1 TBP 1440 908 4224 24075 0 EGR2 GLIS2 2494 1096 3158 23899 0 MTF1 TBP 1438 910 3699 24600 0 FOXF2 RAD21 2470 3621 1422 23134 0 ZNF219 ZNF580 1416 4499 554 24178 0 ZBTB33 ZNF219 2429 3486 1592 23140 0 FOXP3 NR0B1 1416 723 6337 22171 0 EGR3 ZNF219 2416 3499 1074 23658 0 BTD MZF1 1392 4022 673 24560 0 NR0B1 OTX2 2413 5340 755 22139 0 NR0B1 TFAP4 1389 6364 628 22266 0 NR0B1 REST 2362 791 5391 22103 0 EGR2 MTF1 1389 860 4263 24135 0 FOXF2 MTF1 2356 1536 2781 23974 0 APEX1 NR0B1 1388 281 6365 22613 0 POU4F1 ZNF219 2343 3321 1526 23457 0 RAD21 ZNF134 1378 4713 797 23759 0 EGR4 MZF1 2341 3073 1407 23826 0 RAD21 TFAP4 1378 4713 639 23917 0 GLIS2 MZF1 2314 1276 3100 23957 0 EGR1 EGR4 1374 901 2374 25998 0 FOXA3 NR0B1 2275 1081 5478 21813 0 DBX1 RAD21 1374 724 4717 23832 0 EGR4 RAD21 2258 3833 1490 23066 0 NR0B1 ZNF880 1363 6390 568 22326 0 DBP POU4F1 2209 1446 3455 23537 0 MNX1 NR0B1 1346 261 6407 22633 0 EGR3 MZF1 2207 3207 1283 23950 0 EBF1 NR0B1 1346 815 6407 22079 0 NR0B1 SIX6 2199 547 5554 22347 0 EP300 NR2C2 1325 5332 873 23117 0 EP300 OTX2 2181 4476 987 23003 0 DBX1 ZNF219 1296 802 4619 23930 0 EGR3 RAD21 2157 3934 1333 23223 0 MINI20 NR0B1 1288 6465 711 22183 0 RAD21 REST 2137 1016 3954 23540 0 MYOG TFAP4 1283 3323 734 25307 0 CTCF NR0B1 2112 5641 958 21936 0 DBX1 EGR2 1271 827 4381 24168 0 IRF5 NR0B1 2106 1213 5647 21681 0 NR0B1 ZNF790 1266 6487 331 22563 0 EP300 IRF5 2094 4563 1225 22765 0 MZF1 ZNF580 1262 4152 708 24525 0 CTCF RAD21 2051 4040 1019 23537 0 NR0B1 NRF1 1248 6505 500 22394 0 OTX2 POU4F1 2045 1123 3619 23860 0 NKX2-5 NR0B1 1247 557 6506 22337 0 FOXA3 RAD21 2040 4051 1316 23240 0 GLIS2 ZNF580 1241 2349 729 26328 0 EGR2 SIX6 2026 720 3626 24275 0 NR0B1 THRB 1236 6517 769 22125 0 SIX6 ZNF219 2021 725 3894 24007 0 APEX1 MTF1 1231 438 3906 25072 0 KLF6 NR0B1 1986 548 5767 22346 0 ZNF219 ZNF468 1222 4693 526 24206 0 NR0B1 PSMD9 1971 445 5782 22449 0 NR0B1 RFX1 1209 6544 413 22481 0 GTF2I NR0B1 1962 781 5791 22113 0 NR0B1 ZNF468 1209 6544 539 22355 0 PSMD9 ZNF219 1959 457 3956 24275 0 RAD21 ZNF580 1206 4885 764 23792 0 EGR2 PSMD9 1958 458 3694 24537 0 ZNF219 ZNF880 1204 4711 727 24005 0 KLF6 ZNF219 1947 587 3968 24145 0 EGR3 ZNF580 1184 2306 786 26371 0 NR0B1 SOX13 1922 480 5831 22414 0 EGR4 ZNF580 1184 2564 786 26113 0 MZF1 SIX6 1919 827 3495 24406 0 MNX1 MTF1 1169 438 3968 25072 0 EGR2 KLF6 1913 3739 621 24374 0 APEX1 RAD21 1168 501 4923 24055 0 E2F6 NR0B1 1912 563 5841 22331 0 MNX1 RAD21 1154 453 4937 24103 0 NR0B1 TBP 1877 471 5876 22423 0 NR0B1 REL 1137 6616 653 22241 4.64E-321 GTF2I ZNF219 1824 919 4091 23813 0 REL RELB 1133 2881 657 25976 0 TBP ZNF219 1819 529 4096 24203 0 EGR2 ZNF468 1124 4528 624 24371 0 MZF1 PSMD9 1814 602 3600 24631 0 MZF1 ZNF468 1120 4294 628 24605 0 EGR1 EGR2 1809 3843 466 24529 0 KLF6 SP2 1118 1416 135 27978 0 EP300 GTF2I 1806 4851 937 23053 0 EP300 NKX2-5 1112 5545 692 23298 0 CTCF ZNF219 1805 4110 648 24084 0 EP300 ZNF174 1103 5554 710 23280 0 GTF2I MZF1 1798 945 3616 24288 0 NRF1 RAD21 1091 5000 657 23899 0 NR0B1 ZNF658 1779 5974 918 21976 0 NR0B1 ZBTB7A 1089 6664 546 22348 0 EGR2 TBP 1771 577 3881 24418 0 APEX1 HAND1 1078 591 4003 24975 0 E2F6 ZNF219 1768 707 4147 24025 0 MTF1 ZNF790 1072 4065 525 24985 0 CTCF EGR2 1758 3894 695 24300 0 APEX1 POU4F1 1066 603 4598 24380 0 RAD21 SIX6 1747 999 4344 23557 0 RAD21 RFX1 1065 5026 557 23999 0 KLF6 MZF1 1739 795 3675 24438 0 MTF1 NRF1 1055 4082 693 24817 0 E2F6 EGR2 1739 736 3913 24259 0 HAND1 MNX1 1053 554 4028 25012 0 E2F6 MZF1 1735 740 3679 24493 0 MZF1 ZNF721 1045 4369 620 24613 0 ZNF180 ZNF219 1733 4182 883 23849 0 ZNF219 ZNF721 1044 4871 621 24111 0 ZNF219 ZNF658 1733 4182 964 23768 0 ESR1 NR0B1 1039 583 6714 22311 1.49E-297 POU4F1 SIX6 1710 1036 3954 23947 0 RAD21 ZNF790 1024 5067 573 23983 0

２４ APEX1 EGR2 1018 651 4634 24344 0 CUX1 ZNF219 338 225 5577 24507 2.54E-134 EGR2 ZBTB7A 1010 4642 625 24370 0 NFKB1 P50_P50 318 180 478 29671 0 ZBTB7A ZNF219 1008 4907 627 24105 0 NR0B1 ZNF239 306 7447 114 22780 2.67E-112 MTF1 RFX1 1004 4133 618 24892 0 ELK1 NR0B1 291 7462 179 22715 3.35E-75 MNX1 POU4F1 992 615 4672 24368 0 SP2 ZBTB7A 287 0 966 29394 0 HAND1 RFX1 981 4100 641 24925 0 PBX3 SP1 267 59 511 29810 0 SP2 ZNF219 964 4951 289 24443 0 FOS NFYA 264 70 307 30006 0 POU4F1 ZNF790 959 4705 638 24345 0 NFY PBX3 261 65 287 30034 0 NR0B1 SOX18 944 6809 521 22373 1.03E-272 FOS NFY 260 74 288 30025 0 CTCF SMC3 935 2135 586 26991 0 RAD21 ZNF239 260 5831 160 24396 3.71E-104 NR0B1 SP2 932 6821 321 22573 0 FOS SP1 257 77 521 29792 0 BTD SP2 925 1140 328 28254 0 NFYA PBX3 257 69 314 30007 0 NR0B1 ZIC1 920 329 6833 22565 0 FOS PBX3 246 88 80 30233 0 CTCF SP2 916 1537 337 27857 0 CEBPE NR0B1 228 143 7525 22751 4.99E-58 EGR2 SP2 903 4749 350 24645 0 IRF NFYA 222 54 349 30022 0 NR0B1 PBX3 891 6862 524 22370 8.66E-244 IRF NFY 219 57 329 30042 0 MZF1 SP2 855 4559 398 24835 0 IRF SP1 210 66 568 29803 0 EHF ELF3 836 11 148 29652 0 KLF6 ZBTB7A 204 83 2330 28030 0 RAD21 ZIC1 817 432 5274 24124 0 NR0B1 YY2 190 7563 100 22794 5.63E-56 MYC NR0B1 788 260 6965 22634 3.46E-312 BTD ZBTB7A 188 99 1877 28483 0 KLF16 NR0B1 786 6967 243 22651 4.15E-321 TCF12 ZBTB7A 185 640 102 29720 0 NR0B1 ZNF117 764 6989 467 22427 4.60E-201 HOXA10 NR0B1 151 68 7602 22826 8.65E-50 EGR1 EGR3 764 238 1511 28134 0 LHX6 LHX8 108 16 53 30470 0 EHF ELF4 753 172 231 29491 0 LHX8 NFYA 105 56 466 30020 0 ELF1 ELF4 744 181 55 29667 0 DUX1 NFY 104 53 391 30099 0 KLF6 TCF12 709 116 1825 27997 0 LHX8 NFY 99 62 449 30037 0 NR0B1 PARP1 690 7063 406 22488 4.61E-187 TP53 TP63 90 59 430 30068 0 ELF4 ETS1 686 239 128 29594 0 LHX6 NFYA 65 38 506 30038 0 SP2 TCF12 686 139 567 29255 0 LHX6 NFY 62 41 486 30058 0 MYC RAD21 679 5412 369 24187 2.92E-300 NKX2-1 NKX2-4 62 44 28 30513 0 KLF16 MTF1 672 4465 357 25153 0 FOXA FOXA1 54 27 38 30528 0 ELF3 ELF4 669 178 256 29544 0 NKX2-1 NKX2-5 43 63 25 30516 0 ETS1 GABPA 668 1417 440 28122 0 ZNF253 ZNF681 29 8 159 30451 0 KLF16 RAD21 668 5423 361 24195 2.55E-296 BCLAF1 ELF4 667 258 171 29551 0 MTF1 MYC 660 4477 388 25122 0 ETV1 ETV4 656 55 0 29936 0 EHF GABPA 651 333 1434 28229 0 BCLAF1 ETV3 637 182 201 29627 0 BCLAF1 ETV1 633 78 205 29731 0 BCLAF1 ETV4 632 24 206 29785 0 BCLAF1 EHF 629 355 209 29454 0 EHF ELF1 624 360 175 29488 0 ETV1 ETV3 622 89 197 29739 0 ELF4 GABPA 622 303 1463 28259 0 EGR2 KLF16 621 5031 408 24587 1.04E-271 ELF4 ETV1 609 316 102 29620 0 ELF1 ETS1 605 209 194 29639 0 BCLAF1 ETS1 601 237 213 29596 0 TCF12 ZNF219 589 236 5326 24496 1.98E-322 ETV3 ETV4 587 232 69 29759 0 EHF ETS1 587 397 227 29436 0 BCLAF1 GABPA 586 252 151 29658 0 ETV3 GABPA 582 237 1503 28325 0 BCLAF1 ELF1 580 258 219 29590 0 HOXA7 NR0B1 573 307 7180 22587 7.82E-167 ELF4 ETV4 573 352 83 29639 0 ELF1 ELF3 573 274 226 29574 0 BCLAF1 ELF3 571 276 267 29533 0 ETS1 ETV1 569 142 245 29691 0 ELF4 ETV3 568 357 251 29471 0 BTD TCF12 561 264 1504 28318 0 CTCF TCF12 556 269 1897 27925 0 ELF3 GABPA 555 292 1530 28270 0 FOXN4 NR0B1 545 7208 163 22731 3.89E-224 EHF ETV3 541 278 443 29385 0 EGR2 TCF12 541 284 5111 24711 1.36E-273 TBP ZBTB7B 538 184 1810 28115 0 MZF1 TCF12 537 288 4877 24945 2.42E-286 ETS1 ETV4 534 122 280 29711 0 BCL NFKB1 534 328 611 29174 0 ETS1 ETV3 532 287 576 29252 0 ELF1 GABPA 523 276 214 29634 0 ELF1 ETV1 522 189 277 29659 0 NR0B1 TLX1 521 7232 290 22604 5.96E-147 ELF3 ETS1 506 341 308 29492 0 ETV6 GABPA 504 275 233 29635 0 EHF ETV1 494 217 490 29446 0 ZBTB7B ZNF219 488 234 5427 24498 4.79E-242 ELF1 ETV3 488 73 311 29775 0 ETV1 GABPA 487 224 1598 28338 0 ELF1 ETV4 486 170 313 29678 0 NR0B1 ZBTB7B 474 248 7279 22646 4.19E-140 NFY NFYA 468 103 80 29996 0 ETV4 GABPA 458 198 1627 28364 0 EHF ETV4 457 199 527 29464 0 NR0B1 ZNF44 451 7302 282 22612 5.05E-115 CEBPZ NR0B1 448 279 7305 22615 1.16E-114 NFY SP1 443 105 335 29764 0 NFYA SP1 438 133 340 29736 0 ELF3 ETV1 436 411 275 29525 0 FOXN4 MTF1 435 4702 273 25237 8.75E-227 CUX1 NR0B1 434 129 7319 22765 1.97E-178 KLF8 NR0B1 432 7321 252 22642 5.69E-117 FOXN4 HAND1 431 4650 277 25289 6.78E-225 FOXN4 RAD21 430 5661 278 24278 1.10E-166 FOXN4 POU4F1 425 5239 283 24700 5.55E-182 ELF3 ETV4 399 448 257 29543 0 NFKB1 REL 361 163 784 29339 0 CUX1 POU4F1 349 214 5315 24769 4.28E-158

２５ Supplemental Table S10. Comparison of enhancer-promoter interactions (EPI) with chromatin interactions in monocytes. TF: DNA binding motif sequence of a transcription factor. Score: – log10 (p-value). Score 1: Comparison of EPA shortened at the genomic locations of FR or RF orientation of DNA motif sequence with EPA not shortened. Score 2: Comparison of EPA shortened at the genomic locations of FR or RF orientation of DNA motif sequence with EPA shortened at the genomic locations of any orientation of DNA binding sequence.

Forward-reverse Reverse-forward orientation

TF Score 1 Score 2 TF Score 1 Score 2 BRF1 3.21 5.75 ATF3 29.41 5.12 CTCF 6.09 6.80 BDP1 13.04 6.13 E2F 19.43 3.24 CTCF 11.59 8.71 E2F5 10.58 2.02 DNAAF2 19.53 1.95 EGR2 4.28 10.11 E2F2 3.90 1.74 ETS 7.66 5.74 EBF1 2.45 5.28 FOS 28.64 3.75 FOXP2 3.11 3.04 FOSB 7.98 1.99 IRF4 9.16 1.71 FOXO4 7.98 5.84 IRF8 3.67 3.29 GCM1 2.51 3.47 KLF16 6.94 2.53 GTF3C2 20.26 4.66 PAX5 47.18 3.82 IRF7 16.36 2.03 POLR3A 24.37 7.71 KLF14 18.52 8.08 RAD21 4.14 2.23 KLF3 6.42 6.43 RXRA 14.78 5.39 KLF5 8.64 2.69 SMAD4 19.98 2.50 MAZ 1.82 4.55 SP1 8.87 5.20 NR3C1 6.39 4.50 SP3 5.83 2.84 PARG 5.38 4.21 SP4 12.56 3.60 PITX3 10.31 5.62 SP8 7.80 2.75 PLAGL1 11.50 5.42 TFAP2A 4.62 3.59 POU6F1 31.28 7.60 TFAP2B 6.97 2.24 PTF1A 8.91 4.50 TRIM28 1.74 2.43 RAD21 9.28 5.16 ZNF202 18.81 2.19 RFTN1 42.64 6.22 RREB1 7.47 6.40 RUNX2 2.97 1.68 SETDB1 1.63 2.08 SMAD2 4.10 3.48 SMC3 10.24 6.21 SP1 20.98 4.64 SPI1 3.86 1.71 TFAP2A 5.10 1.63 TFE3 94.90 3.64 YY1 13.88 7.04 ZBTB6 15.08 3.93 ZIC1 5.37 1.63 ZNF148 14.51 4.47 ZNF219 15.44 7.99 ZNF28 11.88 3.36 ZNF460 14.14 1.63

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