Table 10 Summary of the top 10-ranked upstream regulators (TF) out of the 72 identified using the ChEA3 tool and significantly associated (FDR cutoff ≤0.05) with our differentially expressed gene (DEG) list obtained in RNAseq data from liver tissue of 4-d old Holstein calves (n = 6/group) born to cows randomly assigned to receive a basal control (CON) diet from − 28 ± 2 d to parturition [1.47 Mcal/kg dry matter (DM) and 15.3% crude protein (CP)] with no added Met or CON plus ethyl cellulose Met (MET, Mepron®, Evonik Nutrition & Care GmbH, Germany)

MYC

Activated

1

4.11E-09

1.26E-06

POP1, GMFG, SMC4, KRTCAP2, CDK5RAP3, IER2, CLPP, DDIT3, UBA52, RPL28, NPRL2, ABCB8, ANAPC11, BLOC1S6, PRKAR2A, TOE1, NR1D2, NFATC4, MRPL38, ABCC10, CYB561D2, MCEE, GSTO1, SUMF1, RNF167, TUT1, SF3B5, RIDA, PSMB2, BID, SF3A2, TARBP2, LAMTOR2, HSPA1A, STK16, MAP 2 K3, CNPY3, LENG1, SNRPA, ENY2, INO80E, GOT1, DHCR24, FOXN2, G6PC3, TMEM11, RAD9A, BMPR2, ZC3H3, MRPL4, NGRN, GPX1, REXO4, EVC, SNRPA1, ZBTB44, MRM1, NCLN, POLR2I, POLR2J, ATOX1, KLF5, KLF9, POLR3H, EIF4A2, SMARCB1, NUBP1, NUBP2, SNRPD1, RPL36AL, PDK1, ALG5, MRPS18B, MRPS18A, ALG3, IMP4, SNX4, PTDSS2, VAT1, ALDH6A1, CALM3, SUGP1, FKBP11, SLC44A4, GRIK5, GUK1, SEC61B, PRMT6, TMED9, NME1, APRT, RPUSD4, KIF2C, YAP1, NEDD8, NT5C, PES1, NPM3, GEMIN2, NR3C1, CHCHD1, ZGPAT, DPM2, DOK2, CCNE2, CCNB1, SHARPIN, DHRS7B, RHBDD3, NONO, DLG1, NABP2, COPE, CHD9, DDX41, YWHAG, PEX1, EEF1D, DOCK1, PFDN6, PNKP, PSMB10, TBRG4, PRRG4, RMND5A, MAPK6, SLC50A1, WEE1

E2F1

Activated

2

7.28E-08

7.45E-06

SMC4, SMC2, MYC, MPV17, CDK5RAP3, IER2, VPS18, AARSD1, RNF125, CLPP, DDIT3, RPL28, RPN1, ABCB8, ANAPC11, BLOC1S6, MCTS1, TOE1, MCAT, VANGL1, ADI1, MMS19, MRPL38, ING1, NUDC, ANXA4, SUMF1, CDC42EP5, TUT1, SF3B5, AHNAK, RNF138, BID, SF3A2, TARBP2, DCBLD2, SNX15, ATCAY, STK16, CNPY2, LENG1, UTRN, ENY2, FECH, FOXO4, ATXN7, AMDHD2, EIF2B4, GOT1, DHCR24, FOXN2, TMEM11, RAD9A, MRPL4, NGRN, GPX1, REXO4, COASY, SNRPA1, TSSC4, GTF3C5, HM13, MRM1, SH3BP2, POLR2G, FNIP1, KCNJ2, FOXJ3, GFER, ATOX1, KLF5, KLF9, SLC25A30, POLR3H, EIF4A2, SMARCB1, NUBP1, NUBP2, SNRPD1, RPL36AL, EIF2D, TNS3, PDK1, CPT1A, ACTN2, MRPS18B, MRPS18A, ALG3, IMP4, PLPP3, PTDSS2, RACGAP1, VAT1, EAF2, FKBP11, INTS11, MRPS11, CITED4, ROBO1, ACADM, PRMT6, ZFX, ZDHHC17, NME1, APRT, KIF2C, YAP1, UQCR11, TYMS, NT5C, PES1, SCAND1, YIPF1, ITCH, GEMIN2, CHCHD1, HIST1H2AC, ZGPAT, ACYP2, ALDH3A2, DPM2, CCNE2, RPP21, COX19, DPP4, SHARPIN, DHRS7B, ECT2, KLHL26, NONO, HSPA2, TJAP1, BRWD1, PICALM, DDX41, ADGRE5, ARHGEF10, TSFM, PEX1, ETV5, TRAPPC6A, EEF1D, CAT, PFDN6, PNKP, PPP2R3C, TAF10, WEE1, CDK2AP2

CREB1

Activated

3

2.87E-07

2.20E-05

KRTCAP2, IER2, CHID1, VPS18, BIN3, BIN1, DDIT3, FDX2, PRKD2, UBA52, EXD2, CDCA2, ANAPC11, BLOC1S6, MCTS1, IRF2BP2, TYSND1, NR1D2, FOSL2, MMS19, ING1, CYB561D2, EMD, TUT1, PPARA, SF3B5, PSMB2, TARBP2, SNX15, LAMTOR2, CHPF, LTN1, GOLIM4, FADS2, STK16, MAP 2 K3, CNPY3, SNRPA, ENY2, RLF, EIF2B4, GOT1, TMEM11, CPD, ZC3H3, MRPL4, DAD1, TSSC4, HM13, CXXC1, NCLN, SEC11C, SPAG9, OXR1, KLF6, KLF5, KLF9, TRMT61A, EIF4A2, PANK3, JMJD1C, TXNDC16, NUBP2, EFR3A, GOLPH3L, PREB, APOB, ZRANB1, EAF2, NDUFAF3, CALM3, SUGP1, GUK1, TMED9, KIF2C, AMIGO1, RTL6, CHCHD1, ALG12, BRMS1, SHARPIN, ANKZF1, CBX8, RHBDD3, DENND4A, NONO, NABP2, GMPPA, YWHAG, YWHAZ, ETV5, EEF1D, HLF, NR2C2, PSMB10, MAPK6, TAF10, WEE1, CDK2AP2, RBM42

PPARG

Inhibited

4

5.64E-07

3.46E-05

ZC3H12D, SCP2, MYC, NAMPT, WDR91, IER2, CHID1, AARSD1, HDHD5, RNF125, BIN3, CLPP, DDIT3, PRKD2, RPL28, RPN1, MRPL16, PRKAR2A, IRF2BP2, RMDN2, FOSL2, FERMT1, PAH, MTMR10, EEA1, GSTO1, ANXA5, SUMF1, KAT2B, HEATR5A, AEBP2, TUT1, PLCB1, AHNAK, BID, RNLS, BBOX1, TARBP2, LAMTOR5, UHRF1BP1L, MYLK4, FADS2, CDH2, ZBTB39, UTRN, ENY2, AMDHD2, GOT1, FOXN2, CDK1, MDM2, SERINC5, NGRN, GPX1, PIK3CA, MET, GTF3C5, ROCK2, GLRX, MRM1, FNIP1, POLR2J, CYB5A, FOXJ3, DDHD2, PTPN12, CDC42BPA, KBTBD11, BICC1, KLF6, NAGK, KLF9, SLC25A30, PANK3, SMARCB1, TNS3, CPT1A, ECH1, MRPS18B, MRPS18A, PREB, PLPP3, CFTR, STK38L, PCK1, ZRANB1, MYO5C, CUTC, IDE, ROBO1, ACADM, ZDHHC17, RPUSD4, CD47, C1QB, SH3BGRL, KLB, GEMIN2, SSC4D, SELENOP, COX19, COBLL1, ACBD5, CRIM1, HOOK3, ARHGAP25, TJAP1, DLG1, GCLM, PICALM, CHD9, TNFAIP3, PPP1R9B, ADGRE5, YWHAG, ARHGEF10, PEX1, YWHAZ, ACOX1, CAT, KDM7A, USP12, NR2C2, PSMB10, RMND5A, TNKS2, MAPK6, TMEM30B, CMTM4

KLF1

Activated

6

9.92E-07

4.19E-05

SPI1, KRTCAP2, MYC, AARSD1, CLPP, RPN1, TYSND1, VANGL1, ADI1, MRPL38, EMD, GSTO1, TUT1, SNX15, SMCHD1, SNRPA, FECH, CORO1A, EIF2B4, GOT1, DHCR24, COPS9, SORD, SNRPA1, HM13, CXXC1, NCLN, SEC11C, NUBP2, SNRPD1, SOX6, PDK1, ECH1, IMP4, PREB, SYMPK, CALM3, IDE, RAC2, TMED9, UQCR11, NEDD8, NT5C, CHCHD1, HIST1H2AC, CYBA, BRMS1, RPP21, PPIH, RPS19BP1, ACBD5, NABP2, GCLM, PPP1R9B, YWHAG, TRAPPC6A, CAT, PFDN6, TBRG4, TAF10

SPI1

Activated

5

9.49E-07

4.19E-05

SPI1, GMFG, SLC4A4, SCP2, PSMD4, NAMPT, CDK5RAP3, IER2, RNF125, PRKD2, RPL28, EXD2, CFP, BLOC1S6, WDR70, MCTS1, NR1D2, NFATC4, FERMT1, PYGL, ING1, PQBP1, EEA1, TRMT112, MRPL42, GSTO1, ANXA4, GMIP, SUMF1, RNF167, TUT1, PPARA, FAM214A, APOLD1, BID, PET100, LAPTM5, PSMB8, LAMTOR2, GOLIM4, MYLK4, PYCARD, ATCAY, STK16, MAP 2 K3, TPM1, CNPY3, CLIP1, CORO1A, YBEY, AMDHD2, MAP 3 K20, GOT1, CYBRD1, DHCR24, FOXN2, BFSP1, G6PC3, CPD, CCDC22, SERINC5, NGRN, PSTPIP1, SORD, DAD1, ROCK2, UNC93B1, CXXC1, GLRX, HSD17B11, HECTD1, SH3BP2, POLR2G, PTPN18, PTPN12, OXR1, FBXL12, SLC25A30, PANK3, JMJD1C, MRPS18B, MAP 7, STK38L, ASL, CD14, STK11IP, STAG2, NDUFAF3, RAC2, TMED9, ZFX, ZDHHC17, VAV1, C1QB, TOR4A, AIF1, PES1, C1QC, WASHC4, NR3C1, EME2, KNTC1, ZGPAT, ACYP2, CYBA, TYROBP, RPS19BP1, CCNB1, CBX8, ACBD5, HOOK3, ARHGAP25, BRWD1, PICALM, CHD9, PPP1R9B, GMPPA, CNPPD1, YWHAZ, ETV5, CAT, PNKP, USP12, TBRG4, STOM, TAF10, SLC50A1, BUD13

ZFX

Activated

7

1.23E-06

4.19E-05

NCKAP1, PSMD4, NAMPT, IER2, AARSD1, HDHD5, CLPP, UBA52, RPL28, RPN1, ABCB8, ANAPC11, PRKAR2A, TTPA, TOE1, MCAT, NR0B2, VANGL1, ADI1, MRPL38, EEA1, EMD, NUDC, GSTO1, SUMF1, AHNAK, PSMB2, RNF138, SC5D, BID, SF3A2, TARBP2, DCBLD2, STK16, ZBTB39, CNPY2, CNPY3, LENG1, CLIP1, FKBP9, SNRPA, ENY2, FECH, ATXN7, NEK9, FOXN2, BFSP1, G6PC3, MDM2, RAD9A, ISY1, MRPL4, REXO4, COASY, EVC, SNRPA1, GTF3C5, ZBTB44, FNIP1, FOXJ3, ATOX1, SLC25A30, POLR3H, EIF4A2, PANK3, SMARCB1, SNRPD1, FBXO3, TNS3, PDK1, MRPS18A, NEIL2, FNDC4, SNX4, PTDSS2, STK38L, RAC2, PRMT6, ZFX, ZDHHC17, VAV1, AMIGO1, PES1, SCAND1, ITCH, GEMIN2, RTL6, ZGPAT, CYBA, ALDH3A2, DPM2, CCNE2, RHBDD3, KLHL26, NONO, TJAP1, NABP2, GCLM, BRWD1, CHD9, ADGRE5, ETV5, TRAPPC6A, LATS2, ACOX1, EEF1D, ZMYND11, CLN5, TBRG4, MARVELD2, MAPK6, TMEM30B, CMTM4, WEE1, CDK2AP2, BUD13

CEBPB

Activated

8

1.79E-06

5.00E-05

MYC, CHID1, AARSD1, BIN3, RUFY3, FDX2, CFP, NR2C2AP, TOE1, TYSND1, RMDN2, MCAT, ABCC10, CYB561D2, EMD, PCMTD1, GMIP, RNF167, PLCB1, PDF, PSMB8, LAMTOR5, CHPF, MPV17L2, STK16, ZBTB39, CNPY2, INSIG2, FBXO48, FOXO4, RLF, IP6K2, BCL3, RAD9A, COPS9, NGRN, CXXC1, MRM1, POLR2G, FOXJ3, PTPN12, OXR1, GFER, KBTBD11, FBXL12, KLF6, SLC25A30, NUBP2, RPL36AL, ECH1, IMP4, PREB, SNX4, STK38L, B4GALNT1, ZRANB1, FKBP11, IDE, GUK1, STBD1, SEC61B, PRMT6, TMED9, CYBA, CBX8, RHBDD3, PICALM, ARHGEF10, TSFM, EEF1D, NR2C2, MAPK6, LUM, TAF10, SLC50A1, MAPK12, CDK2AP2, BUD13

HNF4A

Inhibited

9

3.65E-06

9.34E-05

NCKAP1, ZC3H12D, KRTCAP2, SCP2, PSMD4, MYC, RUFY3, CDCA2, NPRL2, MRPL16, WDR70, PRKAR2A, TTPA, IRF2BP2, TYSND1, NR0B2, FOSL2, FERMT1, ADI1, PAH, MMS19, HRG, MYOM1, MTMR10, PYGL, ABCC10, EEA1, MRPL42, NUDC, GSTO1, ANXA4, ANXA5, SUMF1, HEATR5A, TUT1, PPARA, PLCB1, RAPGEF5, SF3B5, AHNAK, PDF, CHN2, BID, KIDINS220, BBOX1, DCBLD2, GATM, AADAC, SLMAP, SNX15, LAMTOR5, UHRF1BP1L, CHPF, GOLIM4, PLOD2, IL1RAP, MYLK4, PYCARD, CDH2, MAP 2 K3, CNPY3, CLIP1, UTRN, CALCRL, INSIG2, AMDHD1, ATXN7, AMDHD2, ANKRD29, EIF2B4, GOT1, DHCR24, FOXN2, TMEM11, CPD, ALB, SLCO1A2, BCL3, SERINC5, ZNF771, ISY1, ZC3H3, MRPL4, PSTPIP1, REXO4, COASY, EVC, PCCA, DAD1, MET, TSSC4, GTF3C5, ROCK2, UNC93B1, HM13, GLRX, HSD17B11, HECTD1, NCLN, SH3BP2, FNIP1, POLR2I, SEC11C, SPAG9, CYB5A, METAP1D, SLC35A3, FOXJ3, PTPN12, CDC42BPA, OXR1, BICC1, ATOX1, FBXL12, KLF6, POLR3H, EIF4A2, JMJD1C, TXNDC16, SOX6, TNS3, CPT1A, ACTN2, GOLPH3L, MRPS18A, PLPP3, SNX4, RACGAP1, HLTF, STK38L, SYMPK, ASL, STXBP5, CD14, PCK1, APOB, STK11IP, ALDH6A1, STAG2, MYO5C, CALM3, CUTC, SUGP1, ROBO2, ROBO1, SH3PXD2B, ACADM, TMED9, ZFX, NME1, MICU3, YAP1, UQCR11, NEDD8, AIF1, PES1, SCAND1, IL33, YIPF1, ITCH, KLB, SSC4D, NR3C1, SRP14, SBF2, ZGPAT, IL11RA, LMO7, ACYP2, ALDH3A2, BRMS1, SELENOP, PPIH, COX19, DPP4, SHARPIN, COBLL1, DHRS7B, ACBD5, TCAF1, ARHGEF37, DENND4A, NONO, CRIM1, HOOK3, TJAP1, DLG1, DLG5, COPE, PICALM, CHD9, DOCK7, TNFAIP3, GMPPA, YWHAG, PEX1, YWHAZ, LATS2, RABEP2, ACOX1, ALDH1A1, CAT, DOCK1, HLF, PSMB10, PRRG4, TNKS2, MARVELD2, PPP2R3C, STOM, CMTM4, ATP2B1, WEE1, RBM42, SNTB1

FOXO1

Inhibited

10

7.35E-06

1.73E-04

GMFG, ZC3H12D, IER2, VPS18, HDHD5, RNF125, BIN1, UBA52, RPN1, MCTS1, IRF2BP2, NR1D2, FOSL2, MMS19, MTMR10, PYGL, ING1, PCMTD1, AEBP2, AHNAK, LAPTM5, LAMTOR5, FADS2, SMCHD1, TPM1, UTRN, IP6K2, GOT1, RAD9A, ISY1, PTPN21, PSTPIP1, DAD1, HM13, GLRX, MRM1, HECTD1, PTPN18, FOXJ3, KBTBD11, KLF6, NAGK, TRMT61A, TXNDC16, PDK1, MRPS18A, PLPP3, NEIL1, ZRANB1, STK11IP, STAG2, GUK1, SH3PXD2B, RAC2, ACADM, ZFX, CD47, PTGER3, SH3BGRL, SSC4D, NR3C1, SRP14, GPRIN3, TYROBP, CCNE2, RPP21, COBLL1, ECT2, ACBD5, DENND4A, ARHGAP25, GCLM, PICALM, TNFAIP3, PPP1R9B, ADGRE5, USP12, MAPK6, SNTB1