Table S1: The 69 genes, which were up-regulated at all three time points, were analyzed by using Enrichr KEGG program. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION5/ CCL22;TNFSF12;CXCL11;CCL2;CCL5 HSA04620 TOLL LIKE RECEPTOR SIGNALING PATHWAY3/ CXCL11;CCL5;SPP1 HSA00380 TRYPTOPHAN METABOLISM2/ CYP1B1;ABP1 HSA00363 BISPHENOL A DEGRADATION1/ DHRS7 HSA00626 NAPHTHALENE AND ANTHRACENE DEGRADATION1/ DHRS7 HSA00642 ETHYLBENZENE DEGRADATION1/ DHRS7 HSA00960 ALKALOID BIOSYNTHESIS II1/ ABP1 HSA AND 2 METHYLNAPHTHALENE DEGRADATION1/ DHRS7 HSA00361 GAMMA HEXACHLOROCYCLOHEXANE DEGRADATION1/ DHRS7 HSA00632 BENZOATE DEGRADATION VIA COA LIGATION1/ DHRS7 HSA00903 LIMONENE AND PINENE DEGRADATION1/ DHRS7 HSA00410 BETA ALANINE METABOLISM1/ ABP1 HSA04510 FOCAL ADHESION2/ SPP1;FIGF HSA00360 PHENYLALANINE METABOLISM1/ ABP1 HSA05219 BLADDER CANCER1/ FIGF HSA05010 ALZHEIMERS DISEASE1/ APOE HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS1/ ABP1 HSA00340 HISTIDINE METABOLISM1/ ABP1 HSA04150 MTOR SIGNALING PATHWAY1/ FIGF HSA01510 NEURODEGENERATIVE DISEASES1/ APOE

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes response to external stimulus (GO: )10/ E E SPP1;BLNK;CCL22;CXCL11;SCUBE1;CCL2;CCL5;PTAFR;TPM1;ANXA1 response to wounding (GO: )8/ E E CXCL11;SCUBE1;CCL5;BLNK;PTAFR;TPM1;CCL22;ANXA1 defense response (GO: )9/ E E LGALS3BP;BLNK;WAS;CCL22;CXCL11;SCUBE1;CCL5;PTAFR;ANXA1 inflammatory response (GO: )7/ E E CXCL11;SCUBE1;CCL5;BLNK;PTAFR;CCL22;ANXA1 immune response (GO: )8/ E GEM;WAS;CCL22;CCL2;CCL5;PTAFR;BLNK;CD274 immune system process (GO: )9/ E GEM;WAS;CCL22;CCL2;CCL5;PTAFR;BLNK;KLF6;CD274 signal transduction (GO: )19/ E GEM;MARK1;CCL2;CCL5;APOE;STK17B;GNB4;CCL22;RRAD;CXCL11;TA CSTD2;BLNK;IRF9;TNFSF12;PTAFR;ANXA1;LGALS3BP;CD274;RGS19 response to chemical stimulus (GO: )10/ E SPP1;GNB4;CCL22;CXCL11;CCL2;CCL5;PTAFR;APOE;ABCG1;TPM1 chemotaxis (GO: )5/ E CXCL11;CCL2;CCL5;PTAFR;CCL22 locomotory behavior (GO: )5/ E CXCL11;CCL2;CCL5;PTAFR;CCL22 cell communication (GO: )19/ E GEM;MARK1;CCL2;CCL5;APOE;STK17B;GNB4;CCL22;RRAD;CXCL11;TA CSTD2;BLNK;IRF9;TNFSF12;PTAFR;ANXA1;LGALS3BP;CD274;RGS19 response to stress (GO: )11/ E WAS;CCL22;CXCL11;CCL5;PTAFR;ANXA1;APOE;LGALS3BP;BLNK;SCUBE 1;TPM1 intracellular signaling cascade (GO: )9/ MARK1;GNB4;RRAD;CCL2;PTAFR;APOE;STK17B;BLNK;RGS19 behavior (GO: )5/ CXCL11;CCL2;CCL5;PTAFR;CCL22 cell motion (GO: )5/ TNFSF12;CCL2;CCL5;TPM1;ANXA1 cell surface receptor linked signal transduction (GO: )9/ GEM;CCL2;PTAFR;ANXA1;APOE;TACSTD2;CD274;RGS19;IRF9 B cell activation (GO: )2/ KLF6;BLNK cell differentiation (GO: )4/ SCUBE1;BLNK;KLF6;ANXA1 response to oxidative stress (GO: )3/ APOE;CCL5;TPM1 reverse cholesterol transport (GO: )2/ ABCG1;APOE Table S2: The 69 genes, which were up-regulated at all three time points, were further analyzed by using Enrichr GO Biological Process program.

Table S3: The 1583 genes, which were up-regulated at late stage (12 weeks), were analyzed further by using Enrichr KEGG program. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA00190 OXIDATIVE PHOSPHORYLATION27/ E COX6C;COX7B;COX7C;ATP6V0B;COX6B2;COX8A;PPA1;ATP5E;UQCRQ;NDUFS4;AT P5L;COX17;ATP5H;NDUFB11;COX4I1;NDUFC1;NDUFA11;ATP6V1F;UQCRH;NDUFB 6;NDUFB7;NDUFB8;ATP5G2;ATP5G1;NDUFA2;NDUFA6;NDUFA7 HSA05131 PATHOGENIC ESCHERICHIA COLI INFECTION EPEC13/538.88E ACTG1;CDC42;TUBA1A;TUBA1B;TUBA1C;ARHGEF2;ARPC5L;NCK1;ARPC5;ACTB;HC LS1;FYN;YWHAQ HSA05130 PATHOGENIC ESCHERICHIA COLI INFECTION EHEC13/538.88E ACTG1;CDC42;TUBA1A;TUBA1B;TUBA1C;ARHGEF2;ARPC5L;NCK1;ARPC5;ACTB;HC LS1;FYN;YWHAQ HSA03020 RNA POLYMERASE8/ POLR2H;POLR2F;POLR2E;POLR3K;POLR1D;POLR2K;ZNRD1;POLR2D HSA00240 PYRIMIDINE METABOLISM15/ DTYMK;NT5M;NT5C;POLR1D;POLR2H;POLR2F;POLR2E;POLR2K;UPP1;ZNRD1;POL A2;POLR2D;TK2;POLR3K;DUT HSA04120 UBIQUITIN MEDIATED PROTEOLYSIS9/ FZR1;ANAPC11;RBX1;ANAPC5;CDC26;UBE2C;TCEB2;TCEB1;UBE2E2 HSA04110 CELL CYCLE17/ PKMYT1;TGFB1;ANAPC5;MAD2L1;FZR1;ANAPC11;RBX1;CDC26;PCNA;E2F1;MCM7 ;CDK4;MCM3;CCND2;BUB1B;YWHAH;YWHAQ HSA04130 SNARE INTERACTIONS IN VESICULAR TRANSPORT8/ STX8;STX6;VTI1B;BNIP1;VAMP5;VAMP4;BET1L;VAMP2 HSA04660 T CELL RECEPTOR SIGNALING PATHWAY14/ NFKB1;CDC42;BCL10;CD3D;CDK4;NCK1;LCK;ICOS;ZAP70;NFATC4;ITK;LAT;NRAS;FY N HSA04670 LEUKOCYTE TRANSENDOTHELIAL MIGRATION16/ NCF2;NCF1;NCF4;THY1;SIPA1;ITGB2;MYL9;RAC2;ITK;CDC42;CXCR4;MSN;VASP;CL DN16;MAPK11;MAPK12 HSA05110 CHOLERA INFECTION8/ ARF6;ARF5;ATP6V0B;ACTG1;ACTG2;SEC61A2;ATP6V1F;SEC61B HSA00532 CHONDROITIN SULFATE BIOSYNTHESIS6/ B3GALT6;UST;DSE;B3GAT3;CHPF;CHST12 HSA04662 B CELL RECEPTOR SIGNALING PATHWAY10/ NFKB1;BCL10;LYN;CD72;RAC2;CD22;NFATC4;NRAS;CD79B;CD79A HSA04370 VEGF SIGNALING PATHWAY10/ CDC42;MAPKAPK2;RAC2;PLA2G12A;NFATC4;SPHK1;MAPK11;BAD;NRAS;MAPK12 HSA04810 REGULATION OF ACTIN CYTOSKELETON23/ MYH9;PFN1;RAC2;ARHGEF1;ARHGEF6;NRAS;PDGFB;TIAM1;RRAS;ARPC1B;SSH3;A RPC4;ITGB2;ARPC5;MYL9;ITGAX;PIP4K2B;CDC42;GSN;MSN;LIMK1;RRAS2;ARPC5L

TermOverlapP-valueAdjusted P-valueZ-scoreCombined Score RNA processing (GO: )62/ E E RNA splicing (GO: )47/ E E RNA metabolic process (GO: )89/ E E nucleobase, nucleoside, nucleotide and nucleic acid metabolic process (GO: )134/ E E nuclear mRNA splicing, via spliceosome (GO: )32/ E E mRNA processing (GO: )37/ E E RNA splicing, via transesterification reactions (GO: )32/ E E mRNA metabolic process (GO: )39/ E E metabolic process (GO: )311/ E RNA elongation (GO: )15/469.21E transcription initiation from RNA polymerase II promoter (GO: )17/601.36E spliceosomal snRNP biogenesis (GO: )10/242.87E RNA elongation from RNA polymerase II promoter (GO: )14/452.36E transcription initiation (GO: )17/674.11E Ras protein signal transduction (GO: )18/798.39E positive regulation of fibroblast proliferation (GO: )6/ small GTPase mediated signal transduction (GO: )19/ negative regulation of ubiquitin-protein ligase activity during mitotic cell cycle (GO: )13/ myeloid cell differentiation (GO: )8/ negative regulation of ubiquitin-protein ligase activity (GO: )13/ Table S4: The 1583 genes, which were up-regulated at late stage (12 weeks), were analyzed further by using Enrichr GO Biological Process.

Table S5: The 313 genes, which were up-regulated transiently at the middle stage (8 weeks), were analyzed further by using Enrichr KEGG program. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA00512 O GLYCAN BIOSYNTHESIS3/ ST3GAL1;GALNT10;WBSCR17 HSA04514 CELL ADHESION MOLECULES7/ MPZL1;CD40;PDCD1LG2;CLDN6;SELP;SELL;PECAM 1 HSA04620 TOLL LIKE RECEPTOR SIGNALING PATHWAY5/ TLR6;MAP3K8;CD40;IRAK4;TICAM2 HSA00340 HISTIDINE METABOLISM3/ MAOB;HAL;ALDH3B1 HSA00533 KERATAN SULFATE BIOSYNTHESIS2/ CHST1;ST3GAL1 HSA00604 GLYCOSPHINGOLIPID BIOSYNTHESIS GANGLIOSERIES2/ ST3GAL1;ST3GAL5 HSA04660 T CELL RECEPTOR SIGNALING PATHWAY4/ MAP3K8;PRKCQ;CARD11;GRAP2 HSA04662 B CELL RECEPTOR SIGNALING PATHWAY3/ BTK;CARD11;PLCG2 HSA04370 VEGF SIGNALING PATHWAY3/ NOS3;SH2D2A;PLCG2 HSA04110 CELL CYCLE4/ ESPL1;CDC20;CDC6;CCNB1 HSA04520 ADHERENS JUNCTION3/ FGFR1;TCF7L1;SNAI1 HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 14/ ST3GAL1;WBSCR17;CHST1;GALNT10 HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION7/ CD40;CCR4;XCR1;CCL20;IL18R1;CXCR3;IFNGR1 HSA00360 PHENYLALANINE METABOLISM2/ MAOB;ALDH3B1 HSA00530 AMINOSUGARS METABOLISM2/ HK2;GFPT2 HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS2/ ARG2;MAOB HSA00330 ARGININE AND PROLINE METABOLISM2/ ARG2;NOS3 HSA04512 ECM RECEPTOR INTERACTION3/ ITGB5;FNDC5;ITGA3 HSA01430 CELL COMMUNICATION4/ KRT35;GJA5;GJC1;KRT7 HSA04670 LEUKOCYTE TRANSENDOTHELIAL MIGRATION3/ PLCG2;CLDN6;PECAM1

Table S6: The 313 genes, which were up-regulated transiently at the middle stage (8 weeks), were analyzed further by using Enrichr GO Biological Process program. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes inflammatory response (GO: )9/ S1PR3;CD40;CCR4;AFAP1L2;AGER;MMP25;XCR1;NLRP3;CC L20 microtubule cytoskeleton organization (GO: )5/ NUSAP1;ESPL1;NDC80;UNC84B;SPAG5 defense response (GO: )12/ S1PR3;CD40;CCR4;AFAP1L2;AGER;MMP25;XCR1;CCL20;SEL P;TLR6;PGLYRP2;NLRP3 response to wounding (GO: )9/ S1PR3;CD40;CCR4;AFAP1L2;AGER;MMP25;XCR1;NLRP3;CC L20 spindle organization (GO: )3/ NDC80;UNC84B;SPAG5 response to external stimulus (GO: )12/ S1PR3;CD40;PITPNM1;CCR4;AFAP1L2;AGER;MMP25;XCR1; CCL20;PGLYRP2;NLRP3;PLP2 positive regulation of NF-kappaB transcription factor activity (GO: )3/ AGT;NPM1;CARD11 chromosome organization (GO: )9/ ESPL1;NDC80;CHAF1A;NPM1;NFE2;DKC1;NUSAP1;TCF7L1; TEP1 cytokinesis (GO: )3/ NUSAP1;ESPL1;RACGAP1 organelle organization (GO: )16/ ESPL1;UNC84B;SPAG5;NDC80;DKC1;NUSAP1;SASS6;PLD2;N EK3;CHAF1A;NOS3;NPM1;NFE2;TCF7L1;RACGAP1;TEP1 microtubule-based process (GO: )5/ NUSAP1;ESPL1;UNC84B;SPAG5;NDC80 positive regulation of transcription factor activity (GO: )3/ AGT;NPM1;CARD11 regulation of mitotic cell cycle (GO: )5/ ESPL1;AFAP1L2;GAS1;CDC6;NUSAP1 defense response to bacterium (GO: )3/ TLR6;PGLYRP2;SELP positive regulation of cytokine production (GO: )3/ AFAP1L2;AGT;CARD11 regulation of cytokine production (GO: )5/ TLR6;AFAP1L2;NLRP3;CARD11;AGT cell cycle (GO: )3/ CDC20;NDC80;SPAG5 cell division (GO: )3/ NUSAP1;ESPL1;RACGAP1 signal transduction (GO: )39/ BTK;NDC80;MPZL1;PLD2;CD33;PTGES;AGT;LRRN2;FGFR1;D DR2;NLRP3;PECAM1;LTBP2;SPAG5;GNB5;CCL20;CAPN5;PL P2;S1PR3;XCR1;IL18R1;IFNGR1;PTN;P2RX4;AGER;RIN1;IRA K4;CORO2A;NPM1;PRKCQ;GRAP2;ANGPT2;RASD1;SGSM3; PRKAR1B;SH2D2A;STAT2;TLR6;GSG2 positive regulation of DNA binding (GO: )3/ AGT;NPM1;CARD11

Table S7: The 486 genes, which were down-regulated at the late stage (12 weeks), were analyzed further by using Enrichr KEGG program. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA01032 GLYCAN STRUCTURES DEGRADATION4/ ARSB;HPSE2;HYAL1;NEU1 HSA00071 FATTY ACID METABOLISM5/ EHHADH;ACOX3;CPT1A;ALDH2;ALDH9A1 HSA04520 ADHERENS JUNCTION7/ EGFR;CTNNA3;CTNNA2;PARD3;SORBS1;PVRL3;MET HSA00310 LYSINE DEGRADATION5/ EHHADH;PIPOX;SHMT2;ALDH2;ALDH9A1 HSA03320 PPAR SIGNALING PATHWAY6/ EHHADH;ACOX3;PDPK1;SLC27A2;SORBS1;CPT1A HSA04530 TIGHT JUNCTION9/ MYH15;INADL;MPDZ;CTNNA3;CTNNA2;PPP2R1B;MPP5; PARD3;EXOC4 HSA05213 ENDOMETRIAL CANCER5/ PDPK1;EGFR;PIK3CB;CTNNA3;CTNNA2 HSA04070 PHOSPHATIDYLINOSITOL SIGNALING SYSTEM6/ PLCB1;PIK3CB;PI4KA;DGKG;INPP5B;DGKQ HSA00531 GLYCOSAMINOGLYCAN DEGRADATION3/ ARSB;HYAL1;HPSE2 HSA00640 PROPANOATE METABOLISM4/ EHHADH;ACSS2;ALDH2;ALDH9A1 HSA00770 PANTOTHENATE AND COA BIOSYNTHESIS3/ COASY;ENPP3;PANK3 HSA00380 TRYPTOPHAN METABOLISM5/ EHHADH;AFMID;CAT;ALDH9A1;ALDH2 HSA00561 GLYCEROLIPID METABOLISM5/ GPAM;ALDH9A1;DGKG;DGKQ;ALDH2 HSA00650 BUTANOATE METABOLISM4/ EHHADH;BDH2;ALDH2;ALDH9A1 HSA04012 ERBB SIGNALING PATHWAY5/ GAB1;EGFR;PIK3CB;ERBB3;ABL2 HSA05215 PROSTATE CANCER5/ PDPK1;CREB3L2;EGFR;AR;PIK3CB HSA00562 INOSITOL PHOSPHATE METABOLISM4/ PLCB1;PIK3CB;PI4KA;INPP5B HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 16/ MGAT3;XYLT1;FUT8;STT3B;HS6ST1;C1GALT1 HSA00230 PURINE METABOLISM6/ PDE4D;ENPP3;PDE8A;ADK;PDE9A;ADCY9 HSA04650 NATURAL KILLER CELL MEDIATED CYTOTOXICITY1/ PIK3CB

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes retinoid metabolic process (GO: )3/ ALDH8A1;CYP26B1;BCO2 vitamin A metabolic process (GO: )3/ ALDH8A1;CYP26B1;BCO2 vitamin metabolic process (GO: )5/ ALDH8A1;AFMID;CYP26B1;BCO2;NMNAT1 positive regulation of transferase activity (GO: )9/ ALS2;EGFR;PIK3CB;SERINC1;PDPK1;ERN1;MAP3K13;PRK D3;PARD3 positive regulation of kinase activity (GO: )8/ ALS2;EGFR;PIK3CB;PDPK1;ERN1;MAP3K13;PRKD3;PARD 3 positive regulation of protein kinase activity (GO: )8/ ALS2;EGFR;PIK3CB;PDPK1;ERN1;MAP3K13;PRKD3;PARD 3 induction of apoptosis by intracellular signals (GO: )4/ CUL3;DYRK2;CIDEB;HIPK2 cellular aldehyde metabolic process (GO: )3/ ALDH8A1;ALDH9A1;BCO2 protein amino acid N-linked glycosylation (GO: )4/ FUT8;STT3A;ALK;MAGT1 exocytosis (GO: )3/ SNAP29;LIN7A;MIA3 nucleotide metabolic process (GO: )6/ AFMID;PDE8A;ADK;NMNAT1;COASY;ENPP3 DNA damage response, signal transduction (GO: )5/ FOXN3;HIPK2;HUS1;DYRK2;CIDEB regulation of protein kinase activity (GO: )10/ ALS2;PIK3CB;DUSP16;PDPK1;MAP3K13;PARD3;EGFR;CD K5RAP1;ERN1;PRKD3 metabolic process (GO: )81/ ALDH8A1;SLC3A1;MARS2;NR2E3;FBXO10;BMPR2;CAT;S NRNP200;ERN1;WWP1;FBXL5;NEK4;HUS1;PDPK1;ADK; MAP3K13;STT3A;FECH;CSNK1G3;ALDH2;ALK;HS6ST1;AT XN1;ATXN3;DDAH1;TNKS;TRPS1;SIK2;FBXL21;SHMT2;AC OX3;PPM1B;A1CF;COL4A3BP;SERINC1;GYS2;SLC27A2;D ARS;POR;SRR;PTPN4;CYP26B1;BDH2;CUL3;PIK3CB;RREB 1;PDSS1;ASAH2;PI4KA;IDE;PNPLA8;ABL2;COASY;NCOR1; BCO2;TRIOBP;FUT8;ACSS2;AOAH;PRKD3;UBE3A;UBE4A; UBE4B;FAH;XYLT1;SORD;CPT1A;NMNAT1;DYRK2;AFMID ;PDE8A;GPAM;ALDH9A1;XYLB;ORC3L;ENPP3;ALOX12B;S UFU;SEPSECS;CPOX;MAGT1 epidermal growth factor receptor signaling pathway (GO: )3/ EGFR;REPS2;GAB1 lipid metabolic process (GO: )16/ ALDH8A1;PDSS1;ASAH2;PI4KA;CPT1A;PNPLA8;ACOX3;G PAM;SERINC1;BCO2;ALOX12B;SLC27A2;ACSS2;AOAH;CY P26B1;BDH2 brain development (GO: )4/ SHROOM4;UBE3A;CDK5RAP1;ALK cofactor metabolic process (GO: )6/ AFMID;CPOX;FECH;NMNAT1;COASY;PDSS1 carboxylic acid transport (GO: )4/ SERINC1;SLC22A6;SLC3A1;SLC16A2 secretion by cell (GO: )5/ HNF1A;SNAP29;MIA3;SYN3;LIN7A Table S8: The 486 genes, which were down-regulated at the late stage (12 weeks), were analyzed further by using Enrichr GO Biological Process.

Table S9: The 54 genes, which were down-regulated transiently at 8 weeks of age, were analyzed further by using Enrichr KEGG program. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA05060 PRION DISEASE1/ HSPD1 HSA00100 BIOSYNTHESIS OF STEROIDS1/ NQO1 HSA05010 ALZHEIMERS DISEASE1/ MAPT HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS1/ NAGS HSA00512 O GLYCAN BIOSYNTHESIS1/ GALNT14 HSA00252 ALANINE AND ASPARTATE METABOLISM1/ ASPA HSA01510 NEURODEGENERATIVE DISEASES1/ MAPT HSA00600 SPHINGOLIPID METABOLISM1/ SPTLC1 HSA00340 HISTIDINE METABOLISM1/ ASPA HSA00510 N GLYCAN BIOSYNTHESIS1/ DHDDS HSA00280 VALINE LEUCINE AND ISOLEUCINE DEGRADATION1/ IVD HSA00650 BUTANOATE METABOLISM1/ AACS HSA00310 LYSINE DEGRADATION1/ TMLHE HSA04940 TYPE I DIABETES MELLITUS1/ HSPD1 HSA00564 GLYCEROPHOSPHOLIPID METABOLISM1/ LYPLA1 HSA04640 HEMATOPOIETIC CELL LINEAGE1/ TFRC HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 11/ GALNT14 HSA04080 NEUROACTIVE LIGAND RECEPTOR INTERACTION1/ GRIK2 HSA04010 MAPK SIGNALING PATHWAY1/ MAPT

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes protein folding (GO: )2/ CCT6B;HSPD1 regulation of protein complex assembly (GO: )1/ MAPT positive regulation of T cell mediated immunity (GO: )1/ HSPD1 B cell activation (GO: )1/ HSPD1 anatomical structure development (GO: )4/ SH3GL2;FHL1;KLK7;AQP4 adaptive immune response (GO: )1/ HSPD1 regulation of macrophage activation (GO: )1/ HSPD1 regulation of interleukin-6 production (GO: )1/ HSPD1 positive regulation of programmed cell death (GO: )2/ GRIK2;HSPD1 Wnt receptor signaling pathway through beta-catenin (GO: )1/ PTPRU positive regulation of cytoskeleton organization (GO: )1/ MAPT sphingolipid biosynthetic process (GO: )1/ SPTLC1 positive regulation of innate immune response (GO: )1/ HSPD1 protein complex assembly (GO: )2/ CCT6B;HSPD1 positive regulation of T cell activation (GO: )1/ HSPD1 xenobiotic metabolic process (GO: )1/ NQO1 positive regulation of protein polymerization (GO: )1/ MAPT mononuclear cell proliferation (GO: )1/ HSPD1 response to toxin (GO: )1/ NQO1 mitochondrial membrane organization (GO: )1/ LETM1 negative regulation of transcription (GO: )2/ PTPRU;MLX Table S10: The 54 genes, which were down-regulated transiently at 8 weeks of age, were analyzed further by using Enrichr GO Biological Process.

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA00564 GLYCEROPHOSPHOLIPID METABOLISM3/ LYPLA1;CHPT1;DGKB HSA00150 ANDROGEN AND ESTROGEN METABOLISM2/ SRD5A2;HSD3B2 HSA04080 NEUROACTIVE LIGAND RECEPTOR INTERACTION3/ MCHR1;GHR;P2RY1 HSA00410 BETA ALANINE METABOLISM1/ CNDP1 HSA00565 ETHER LIPID METABOLISM1/ CHPT1 HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS1/ NAGS HSA00120 BILE ACID BIOSYNTHESIS1/ SRD5A2 HSA00601 GLYCOSPHINGOLIPID BIOSYNTHESIS LACTOSERIES1/ B3GALT2 HSA00340 HISTIDINE METABOLISM1/ CNDP1 HSA00440 AMINOPHOSPHONATE METABOLISM1/ CHPT1 HSA00512 O GLYCAN BIOSYNTHESIS1/ GALNT11 HSA00380 TRYPTOPHAN METABOLISM1/ AFMID HSA00561 GLYCEROLIPID METABOLISM1/ DGKB HSA04012 ERBB SIGNALING PATHWAY1/ NRG4 HSA00140 C21 STEROID HORMONE METABOLISM1/ HSD3B2 HSA04070 PHOSPHATIDYLINOSITOL SIGNALING SYSTEM1/ DGKB HSA00620 PYRUVATE METABOLISM1/ ACOT12 HSA05215 PROSTATE CANCER1/ SRD5A2 HSA00280 VALINE LEUCINE AND ISOLEUCINE DEGRADATION1/ DBT HSA04610 COMPLEMENT AND COAGULATION CASCADES1/ C4A HSA00630 GLYOXYLATE AND DICARBOXYLATE METABOLISM1/ AFMID HSA00240 PYRIMIDINE METABOLISM1/ UPP2 HSA01031 GLYCAN STRUCTURES BIOSYNTHESIS 21/ B3GALT2 HSA00232 CAFFEINE METABOLISM1/ NAT2 HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 11/ GALNT11 HSA00230 PURINE METABOLISM1/ AMPD1 HSA04530 TIGHT JUNCTION1/ RAB3B HSA04630 JAK STAT SIGNALING PATHWAY1/ GHR HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION1/ GHR Table S11: 84 genes which were down-regulated between 4-8 weeks but no changes between 8-12 weeks further analyzed for Enrichr KEGG.

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes excretion (GO: )3/414.12E AQP4;AQP1;KCNK5 secretion (GO: )4/ E AQP4;AQP1;KCNK5;SYN3 lipid metabolic process (GO: )5/ GHR;NR1H4;CHPT1;ACOT12;SRD5A2 cation transport (GO: )3/ AQP1;KCNK5;KCNC1 fatty acid metabolic process (GO: )2/ ACOT12;GHR cellular amino acid and derivative metabolic process (GO: )3/ BPHL;CHPT1;GHR cellular amino acid derivative metabolic process (GO: )2/ GHR;CHPT1 potassium ion transport (GO: )2/ KCNC1;KCNK5 cofactor metabolic process (GO: )2/ AFMID;ACOT12 steroid metabolic process (GO: )2/ SRD5A2;NR1H4 ion transport (GO: )3/ AQP1;KCNK5;KCNC1 regulation of growth (GO: )2/ CHPT1;GHR metabolic process (GO: )14/ C4A;GHR;MMP10;NR2E3;NR1H4;CHPT1;AC OT12;B3GALT2;BPHL;UPP2;SRD5A2;GLYCTK ;AFMID;MCHR1 second-messenger-mediated signaling (GO: )2/ P2RY1;MCHR1 transport (GO: )6/ GHR;KCNK5;KCNC1;AQP4;AQP1;SYN3 response to chemical stimulus (GO: )4/ GHR;BPHL;HSPB7;ANGPTL7 regulation of multicellular organism growth (GO: )1/ GHR cellular amine metabolic process (GO: )2/ CHPT1;GHR positive regulation of growth (GO: )1/ GHR male gonad development (GO: )1/ SRD5A2 positive regulation of JAK-STAT cascade (GO: )1/ GHR positive regulation of tyrosine phosphorylation of STAT protein (GO: )1/ GHR gonad development (GO: )1/ SRD5A2 organic cation transport (GO: )1/ AQP1 phosphatidylcholine metabolic process (GO: )1/ CHPT1 Table S12: 84 genes which were down-regulated between 4-8 weeks but no changes between 8-12 weeks further analyzed for Enrichr Go Biological Process.

Table S13: 240 genes which were up-regulated between 4-8 weeks but no changes between 8-12 weeks further analyzed for Enrichr KEGG. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION18/ E E CCR7;CCR4;CCR2;CXCL5;CCR1;CCL24;CCL22;C D27;CCL17;CCL3;CCL2;CCL5;CXCR6;LTB;TNFSF 13B;TNFRSF4;IL2RG;IL2RA HSA04640 HEMATOPOIETIC CELL LINEAGE11/884.37E E CD8A;CD3G;CD3D;CD3E;CD37;ITGB3;CD2;CD2 2;CD4;IL2RA;CD14 HSA04660 T CELL RECEPTOR SIGNALING PATHWAY10/934.09E E CD8A;CD3G;CD3D;CD3E;CD247;ICOS;CD4;CD2 8;CTLA4;LAT HSA04514 CELL ADHESION MOLECULES11/ E PDCD1LG2;ICOS;CD8A;VCAM1;CD2;CD22;CD4; CD6;SELPLG;CD28;CTLA4 HSA04610 COMPLEMENT AND COAGULATION CASCADES6/ F10;F7;C1QA;C1QB;C3AR1;C6 HSA04670 LEUKOCYTE TRANSENDOTHELIAL MIGRATION7/ MMP9;MMP2;NCF2;NCF1;THY1;RAC2;VCAM1 HSA04512 ECM RECEPTOR INTERACTION6/ COL1A2;COL1A1;COL3A1;ITGB3;COL6A2;COL6 A1 HSA04110 CELL CYCLE7/ CCNA2;ESPL1;CDC20;MCM5;MCM6;SFN;CCNB 2 HSA04510 FOCAL ADHESION8/ RAC2;PARVG;COL3A1;COL6A2;COL6A1;COL1A 2;COL1A1;ITGB3 HSA01430 CELL COMMUNICATION6/ KRT19;COL1A2;COL1A1;COL3A1;COL6A2;COL6 A1 HSA04612 ANTIGEN PROCESSING AND PRESENTATION4/ CD8A;CTSS;CD74;CD4 HSA04650 NATURAL KILLER CELL MEDIATED CYTOTOXICITY5/ CD48;RAC2;TYROBP;LAT;CD247 HSA04662 B CELL RECEPTOR SIGNALING PATHWAY3/ LILRB3;RAC2;CD22 HSA05210 COLORECTAL CANCER3/ RAC2;TCF7;BIRC5 HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS2/ ARG1;ALDH1B1

Table S14: 240 genes which were up-regulated between 4-8 weeks but no changes between weeks further analyzed by GO Biological Process TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes immune system process (GO: )37/ E E NCF2;NCF1;PDCD1LG2;TCF7;RGS1;CCL24;CCL22;CTLA4;PGLYR P1;PGLYRP2;CCL2;CCL5;ICOS;IGJ;LAT;NFIL3;VCAM1;CD2;CD4;C FP;CD3G;CD3E;CCR4;CCR2;CD74;CLEC7A;CCR1;CD27;CD28;FO XP3;CORO1A;CD8A;CTSS;CTSE;TNFRSF4;IL2RG;IL2RA defense response (GO: )29/ E E AIF1;CD48;CFP;NCF2;NCF1;CCR7;CCR4;LILRB3;CCR2;TYROBP;C LEC7A;NFAM1;KLRG1;PLA2G7;CCR1;GPR68;CCL24;CCL22;LSP1 ;PGLYRP1;PGLYRP2;C3AR1;CCL3;PTPRCAP;CCL5;CORO1A;HP;R NASE6;KCNN4 immune response (GO: )29/ E E NCF2;NCF1;PDCD1LG2;TCF7;RGS1;CCL24;CCL22;CTLA4;PGLYR P1;PGLYRP2;CCL2;CCL5;ICOS;IGJ;LAT;NFIL3;CD4;CFP;CCR4;CCR 2;CCR1;CD27;CD28;CORO1A;CD8A;CTSS;TNFRSF4;IL2RG;IL2RA response to stress (GO: )34/ E E AIF1;CCNA2;NCF2;NCF1;SERPINH1;KLRG1;GPR68;CCL24;CCL22 ;LSP1;PGLYRP1;PGLYRP2;C3AR1;CCL3;CCL5;HP;RNASE6;CD48; CFP;CCR7;CCR4;LILRB3;CCR2;TYROBP;CLEC7A;NFAM1;PLA2G7 ;CCR1;COL3A1;SFN;MAP4K1;PTPRCAP;CORO1A;KCNN4 response to external stimulus (GO: )21/ E E AIF1;CCR7;CCR4;CCR2;NFAM1;KLRG1;PLA2G7;CXCL5;CCR1;CO L3A1;GPR68;CCL24;CCL22;CCL17;PGLYRP1;PGLYRP2;C3AR1;CC L3;CCL2;CCL5;CORO1A inflammatory response (GO: )14/ E E AIF1;CCR7;CCR4;CCR2;C3AR1;CCL3;CCL5;NFAM1;KLRG1;PLA2 G7;CCR1;GPR68;CCL24;CCL22 response to wounding (GO: )15/ E E AIF1;CCR7;CCR4;CCR2;C3AR1;CCL3;CCL5;NFAM1;KLRG1;PLA2 G7;CCR1;COL3A1;GPR68;CCL24;CCL22 chemotaxis (GO: )12/ E E CCR7;CCR4;CCR2;CCL3;CCL2;CCL5;CORO1A;CXCL5;CCR1;CCL24 ;CCL22;CCL17 T cell activation (GO: )8/399.15E E CD8A;TNFRSF4;CD2;CD28;CD3G;CD3E;FOXP3;CLEC7A locomotory behavior (GO: )12/ E E CCR7;CCR4;CCR2;CCL3;CCL2;CCL5;CORO1A;CXCL5;CCR1;CCL24 ;CCL22;CCL17

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION4/ IL7R;CCL8;CXCR4;PF4 HSA05214 GLIOMA2/ E2F1;IGF1 HSA05218 MELANOMA2/ E2F1;IGF1 HSA04730 LONG TERM DEPRESSION2/ PLA2G2D;IGF1 HSA05215 PROSTATE CANCER2/ E2F1;IGF1 HSA04080 NEUROACTIVE LIGAND RECEPTOR INTERACTION3/ C5AR1;P2RY10;PTGER4 HSA04630 JAK STAT SIGNALING PATHWAY2/ SOCS3;IL7R HSA00591 LINOLEIC ACID METABOLISM1/ PLA2G2D HSA00565 ETHER LIPID METABOLISM1/ PLA2G2D HSA05219 BLADDER CANCER1/ E2F1 HSA00860 PORPHYRIN AND CHLOROPHYLL METABOLISM1/ ALAS2 HSA04930 TYPE II DIABETES MELLITUS1/ SOCS3 HSA04150 MTOR SIGNALING PATHWAY1/ IGF1 HSA00260 GLYCINE SERINE AND THREONINE METABOLISM1/ ALAS2 HSA05131 PATHOGENIC ESCHERICHIA COLI INFECTION EPEC1/ TUBB2B HSA00562 INOSITOL PHOSPHATE METABOLISM1/ PIP4K2A HSA05223 NON SMALL CELL LUNG CANCER1/ E2F1 HSA05130 PATHOGENIC ESCHERICHIA COLI INFECTION EHEC1/ TUBB2B HSA00590 ARACHIDONIC ACID METABOLISM1/ PLA2G2D HSA00592 ALPHA LINOLENIC ACID METABOLISM1/ PLA2G2D HSA04662 B CELL RECEPTOR SIGNALING PATHWAY1/ CD79B HSA00601 GLYCOSPHINGOLIPID BIOSYNTHESIS LACTOSERIES1/ B3GALT1 HSA04370 VEGF SIGNALING PATHWAY1/ PLA2G2D HSA01031 GLYCAN STRUCTURES BIOSYNTHESIS 21/ B3GALT1 HSA04115 P53 SIGNALING PATHWAY1/ IGF1 HSA04610 COMPLEMENT AND COAGULATION CASCADES1/ C5AR1 HSA00564 GLYCEROPHOSPHOLIPID METABOLISM1/ PLA2G2D HSA05212 PANCREATIC CANCER1/ E2F1 HSA04664 FC EPSILON RI SIGNALING PATHWAY1/ PLA2G2D HSA04920 ADIPOCYTOKINE SIGNALING PATHWAY1/ SOCS3 Table S15: 66 genes which were up-regulated between 4-8 weeks and between 8-12 weeks further analyzed for Enrichr KEGG.

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes immune response (GO: )7/ IL7R;POU2AF1;PTGER4;C5AR1;LAX1;CD79B;CXCR4 immune system process (GO: )7/ IL7R;POU2AF1;PTGER4;C5AR1;LAX1;CD79B;CXCR4 defense response (GO: )6/ S100A8;S100A9;C5AR1;PLA2G2D;TPSAB1;CXCR4 response to chemical stimulus (GO: )8/ GNG2;RTP4;FHL2;CYGB;CCL8;ALAS2;C5AR1;CXCR4 cell communication (GO: )17/ E IL7R;IGF1;CCL8;CD53;C5AR1;STK17B;IL1RL1;GPR176;PLEK;CX CR4;GNG2;FHL2;S100A9;LAX1;SOCS3;PTGER4;LPAR1 intracellular signaling cascade (GO: )8/ GNG2;FHL2;IGF1;PTGER4;STK17B;LAX1;PLEK;SOCS3 signal transduction (GO: )16/ E IL7R;IGF1;CCL8;CD53;C5AR1;STK17B;IL1RL1;GPR176;PLEK;CX CR4;GNG2;FHL2;LAX1;SOCS3;PTGER4;LPAR1 response to external stimulus (GO: )6/ S100A8;S100A9;C5AR1;PLA2G2D;CCL8;CXCR4 inflammatory response (GO: )4/ S100A8;S100A9;PLA2G2D;CXCR4 response to virus (GO: )3/ ISG20;CXCR4;CCL8 cytosolic calcium ion homeostasis (GO: )3/ LPAR1;CXCR4;C5AR1 elevation of cytosolic calcium ion concentration (GO: )3/ LPAR1;CXCR4;C5AR1 regulation of MAP kinase activity (GO: )3/ CXCR4;C5AR1;LAX1 response to wounding (GO: )4/ S100A8;S100A9;PLA2G2D;CXCR4 homeostatic process (GO: )5/ LPAR1;C5AR1;IGF1;ALAS2;CXCR4 calcium ion homeostasis (GO: )3/ LPAR1;CXCR4;C5AR1 cellular calcium ion homeostasis (GO: )3/ LPAR1;CXCR4;C5AR1 cellular metal ion homeostasis (GO: )3/ LPAR1;C5AR1;CXCR4 metal ion homeostasis (GO: )3/ LPAR1;C5AR1;CXCR4 G-protein coupled receptor protein signaling pathway (GO: )5/ LPAR1;GPR176;PLEK;CXCR4;PTGER4 response to stress (GO: )8/ CYGB;TPSAB1;ALAS2;S100A8;S100A9;C5AR1;PLA2G2D;CXCR4 cell proliferation (GO: )4/ ISG20;IGF1;TGFBI;E2F1 chemotaxis (GO: )3/ C5AR1;CCL8;CXCR4 locomotory behavior (GO: )3/ C5AR1;CCL8;CXCR4 cellular cation homeostasis (GO: )3/ LPAR1;C5AR1;CXCR4 Table S16: 66 genes which were up-regulated between 4-8 weeks and between 8-12 weeks further analyzed by GO Biological Process

Table S17: 63 genes which were no changes between 4-8 weeks but up- regulated between 8-12 weeks further analyzed for Enrichr KEGG TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA04350 TGF BETA SIGNALING PATHWAY2/ TGFB3;DCN HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION2/ CCL28;TGFB3 HSA04710 CIRCADIAN RHYTHM1/ PER1 HSA05217 BASAL CELL CARCINOMA1/ PTCH2 HSA00272 CYSTEINE METABOLISM1/ CDO1 HSA04610 COMPLEMENT AND COAGULATION CASCADES1/ KNG1 HSA00430 TAURINE AND HYPOTAURINE METABOLISM1/ CDO1 HSA05212 PANCREATIC CANCER1/ TGFB3 HSA04340 HEDGEHOG SIGNALING PATHWAY1/ PTCH2 HSA05211 RENAL CELL CARCINOMA1/ TGFB3 HSA05210 COLORECTAL CANCER1/ TGFB3 HSA05220 CHRONIC MYELOID LEUKEMIA1/ TGFB3 HSA04620 TOLL LIKE RECEPTOR SIGNALING PATHWAY1/ TLR7 HSA04110 CELL CYCLE1/ TGFB3 HSA00190 OXIDATIVE PHOSPHORYLATION1/ COX7B2 HSA01430 CELL COMMUNICATION1/ KRT23 HSA04010 MAPK SIGNALING PATHWAY1/ TGFB3

TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes response to external stimulus (GO: )7/ E CTGF;TPST1;CCL28;PER1;CDO1;LYVE1;KNG1 response to wounding (GO: )5/ E CTGF;CDO1;TPST1;LYVE1;KNG1 negative regulation of coagulation (GO: )2/ KNG1;TMPRSS6 negative regulation of blood coagulation (GO: )2/ KNG1;TMPRSS6 regulation of blood coagulation (GO: )2/ KNG1;TMPRSS6 cell-matrix adhesion (GO: )2/ LYVE1;FBLN5 cell-substrate adhesion (GO: )2/ LYVE1;FBLN5 response to stress (GO: )7/ CTGF;TGFB3;CDO1;LYVE1;KNG1;TPST1;TLR7 inflammatory response (GO: )3/ CDO1;TPST1;KNG1 anatomical structure morphogenesis (GO: )4/ TGFB3;LYVE1;GCM1;DCN defense response (GO: )4/ TPST1;TLR7;CDO1;KNG1 anatomical structure development (GO: )6/ CTGF;IGF2;TGFB3;PTCH2;GATA6;GREM1 sulfur metabolic process (GO: )2/ CDO1;TPST1 regulation of gene-specific transcription (GO: )2/ TGFB3;IGF2 epidermis development (GO: )2/ CTGF;PTCH2 response to hormone stimulus (GO: )2/ TGFB3;RERG oxidation reduction (GO: )2/ LOXL1;CDO1 small GTPase mediated signal transduction (GO: )2/ NGF;RERG organ morphogenesis (GO: )2/ TGFB3;DCN tissue development (GO: )2/ CTGF;PTCH2 cell adhesion (GO: )3/ FBLN5;LYVE1;ISLR positive regulation of MAPKKK cascade (GO: )1/ IGF2 positive regulation of mitosis (GO: )1/ IGF2 regulation of bone mineralization (GO: )1/ TGFB3 regulation of protein kinase B signaling cascade (GO: )1/ IGF2 Table S18: 63 genes which were no changes between 4-8 weeks but up-regulated between 8-12 weeks further analyzed for Enrichr GO Biological Process