1. 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 INTERACTION5/2570.0054074920.221707182-2.1146323683.185477479CCL22;TNFSF12;CXCL11;CCL2;CCL5 HSA04620 TOLL LIKE RECEPTOR SIGNALING PATHWAY3/1020.0113786480.233262286-1.9094844652.779429865CXCL11;CCL5;SPP1 HSA00380 TRYPTOPHAN METABOLISM2/600.0319424210.351419898-1.8014140381.883871028CYP1B1;ABP1 HSA00363 BISPHENOL A DEGRADATION1/140.0666724870.351419898-1.1521199291.204856469DHRS7 HSA00626 NAPHTHALENE AND ANTHRACENE DEGRADATION1/180.0837273150.351419898-1.0868595511.136608896DHRS7 HSA00642 ETHYLBENZENE DEGRADATION1/150.0709641670.351419898-1.0441830941.091978989DHRS7 HSA00960 ALKALOID BIOSYNTHESIS II1/210.096324230.351419898-0.9766721681.021377852ABP1 HSA00624 1 AND 2 METHYLNAPHTHALENE DEGRADATION1/250.1128650650.351419898-0.8607285940.900127138DHRS7 HSA00361 GAMMA HEXACHLOROCYCLOHEXANE DEGRADATION1/230.1046308330.351419898-0.8241749530.861900309DHRS7 HSA00632 BENZOATE DEGRADATION VIA COA LIGATION1/280.1250820210.351419898-0.80421930.841031216DHRS7 HSA00903 LIMONENE AND PINENE DEGRADATION1/290.1291187960.351419898-0.7275102980.760810976DHRS7 HSA00410 BETA ALANINE METABOLISM1/250.1128650650.351419898-0.7195335970.752469154ABP1 HSA04510 FOCAL ADHESION2/2000.2359755390.368831805-0.7272012060.725321066SPP1;FIGF HSA00360 PHENYLALANINE METABOLISM1/300.1331379220.351419898-0.3873235990.405052749ABP1 HSA05219 BLADDER CANCER1/420.1800170480.368831805-0.3652242050.364279937FIGF HSA05010 ALZHEIMERS DISEASE1/280.1250820210.351419898-0.3426763330.358361821APOE HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS1/300.1331379220.351419898-0.2860827750.299177779ABP1 HSA00340 HISTIDINE METABOLISM1/410.1762041080.368831805-0.2944413060.293680043ABP1 HSA04150 MTOR SIGNALING PATHWAY1/480.2025459170.368831805-0.2595591590.258888082FIGF HSA01510 NEURODEGENERATIVE DISEASES1/380.1646642480.368831805-0.2469975250.246358926APOE

2. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes response to external stimulus (GO:0009605)10/3523.87E-064.63E-04 - 2.35832182918.10742232SPP1;BLNK;CCL22;CXCL11;SCUBE1;CCL2;CCL5;PTAFR;TPM1;ANXA1 response to wounding (GO:0009611)8/1832.03E-064.63E-04 - 2.33149809217.90146708CXCL11;SCUBE1;CCL5;BLNK;PTAFR;TPM1;CCL22;ANXA1 defense response (GO:0006952)9/3091.07E-056.42E-04-2.3940718117.59818208LGALS3BP;BLNK;WAS;CCL22;CXCL11;SCUBE1;CCL5;PTAFR;ANXA1 inflammatory response (GO:0006954)7/1485.89E-064.69E-04-2.238930317.16044732CXCL11;SCUBE1;CCL5;BLNK;PTAFR;CCL22;ANXA1 immune response (GO:0006955)8/4216.51E-040.014135982 - 3.07265931113.08655372GEM;WAS;CCL22;CCL2;CCL5;PTAFR;BLNK;CD274 immune system process (GO:0002376)9/5528.44E-040.016819192 - 3.03397317912.39449234GEM;WAS;CCL22;CCL2;CCL5;PTAFR;BLNK;KLF6;CD274 signal transduction (GO:0007165)19/17227.25E-050.003466427 - 2.16567737412.26776281 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:0042221)10/5662.13E-040.0072661 - 2.27793931311.21779327SPP1;GNB4;CCL22;CXCL11;CCL2;CCL5;PTAFR;APOE;ABCG1;TPM1 chemotaxis (GO:0006935)5/1101.75E-040.006989813 - 2.16895023210.76515396CXCL11;CCL2;CCL5;PTAFR;CCL22 locomotory behavior (GO:0007626)5/1202.59E-040.007479845 - 2.12840722610.41970952CXCL11;CCL2;CCL5;PTAFR;CCL22 cell communication (GO:0007154)19/18962.82E-040.007479845 - 2.12046826810.38084401 GEM;MARK1;CCL2;CCL5;APOE;STK17B;GNB4;CCL22;RRAD;CXCL11;TA CSTD2;BLNK;IRF9;TNFSF12;PTAFR;ANXA1;LGALS3BP;CD274;RGS19 response to stress (GO:0006950)11/7675.74E-040.013729963 - 2.1789465619.343703663 WAS;CCL22;CXCL11;CCL5;PTAFR;ANXA1;APOE;LGALS3BP;BLNK;SCUBE 1;TPM1 intracellular signaling cascade (GO:0007242)9/586 0.00128645 1 0.021961548 - 2.149756451 8.208763665MARK1;GNB4;RRAD;CCL2;PTAFR;APOE;STK17B;BLNK;RGS19 behavior (GO:0007610)5/183 0.00165965 70.026443876 - 2.1026534377.638373683CXCL11;CCL2;CCL5;PTAFR;CCL22 cell motion (GO:0006928)5/208 0.00286694 20.034259955 - 2.0817021477.023201129TNFSF12;CCL2;CCL5;TPM1;ANXA1 cell surface receptor linked signal transduction (GO:0007166)9/689 0.00387996 40.04415768 - 2.0932730326.530987593GEM;CCL2;PTAFR;ANXA1;APOE;TACSTD2;CD274;RGS19;IRF9 B cell activation (GO:0042113)2/22 0.00547392 10.054511129-1.885683075.486112781KLF6;BLNK cell differentiation (GO:0030154)4/156 0.00625192 20.059768379 - 1.8991238825.350360957SCUBE1;BLNK;KLF6;ANXA1 response to oxidative stress (GO:0006979)3/73 0.00518822 40.053912419 - 1.7871444195.219166583APOE;CCL5;TPM1 reverse cholesterol transport (GO:0043691)2/13 0.00213808 10.028388959 - 1.4504494895.166145682ABCG1;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.

3. 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 PHOSPHORYLATION27/1281.87E-050.002693769-1.84932996610.94214161 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-040.042624639-1.9740911676.228894881 ACTG1;CDC42;TUBA1A;TUBA1B;TUBA1C;ARHGEF2;ARPC5L;NCK1;ARPC5;ACTB;HC LS1;FYN;YWHAQ HSA05130 PATHOGENIC ESCHERICHIA COLI INFECTION EHEC13/538.88E-040.042624639-1.7967856785.669438828 ACTG1;CDC42;TUBA1A;TUBA1B;TUBA1C;ARHGEF2;ARPC5L;NCK1;ARPC5;ACTB;HC LS1;FYN;YWHAQ HSA03020 RNA POLYMERASE8/230.0014423720.051925376-1.3753385284.0681794POLR2H;POLR2F;POLR2E;POLR3K;POLR1D;POLR2K;ZNRD1;POLR2D HSA00240 PYRIMIDINE METABOLISM15/890.0089007470.213617921-1.6087632982.483232774 DTYMK;NT5M;NT5C;POLR1D;POLR2H;POLR2F;POLR2E;POLR2K;UPP1;ZNRD1;POL A2;POLR2D;TK2;POLR3K;DUT HSA04120 UBIQUITIN MEDIATED PROTEOLYSIS9/400.0087258180.213617921-1.5433901532.38232499FZR1;ANAPC11;RBX1;ANAPC5;CDC26;UBE2C;TCEB2;TCEB1;UBE2E2 HSA04110 CELL CYCLE17/1150.0166246980.265995173-1.4143876591.873041211 PKMYT1;TGFB1;ANAPC5;MAD2L1;FZR1;ANAPC11;RBX1;CDC26;PCNA;E2F1;MCM7 ;CDK4;MCM3;CCND2;BUB1B;YWHAH;YWHAQ HSA04130 SNARE INTERACTIONS IN VESICULAR TRANSPORT8/360.0139483070.264588246-1.2814714041.703819324STX8;STX6;VTI1B;BNIP1;VAMP5;VAMP4;BET1L;VAMP2 HSA04660 T CELL RECEPTOR SIGNALING PATHWAY14/930.025045070.337071699-1.3845660061.505659615 NFKB1;CDC42;BCL10;CD3D;CDK4;NCK1;LCK;ICOS;ZAP70;NFATC4;ITK;LAT;NRAS;FY N HSA04670 LEUKOCYTE TRANSENDOTHELIAL MIGRATION16/1150.0310328880.372394656-1.2972298831.281405086 NCF2;NCF1;NCF4;THY1;SIPA1;ITGB2;MYL9;RAC2;ITK;CDC42;CXCR4;MSN;VASP;CL DN16;MAPK11;MAPK12 HSA05110 CHOLERA INFECTION8/410.0257485330.337071699-0.9787407731.064341063ARF6;ARF5;ATP6V0B;ACTG1;ACTG2;SEC61A2;ATP6V1F;SEC61B HSA00532 CHONDROITIN SULFATE BIOSYNTHESIS6/220.0146993470.264588246-0.6556282970.871710565B3GALT6;UST;DSE;B3GAT3;CHPF;CHST12 HSA04662 B CELL RECEPTOR SIGNALING PATHWAY10/640.0444025820.491843985-1.1631317180.825350957NFKB1;BCL10;LYN;CD72;RAC2;CD22;NFATC4;NRAS;CD79B;CD79A HSA04370 VEGF SIGNALING PATHWAY10/700.0690517040.662896356-1.1084402160.455720371CDC42;MAPKAPK2;RAC2;PLA2G12A;NFATC4;SPHK1;MAPK11;BAD;NRAS;MAPK12 HSA04810 REGULATION OF ACTIN CYTOSKELETON23/2120.0988542890.749211456-1.1115296860.320936431 MYH9;PFN1;RAC2;ARHGEF1;ARHGEF6;NRAS;PDGFB;TIAM1;RRAS;ARPC1B;SSH3;A RPC4;ITGB2;ARPC5;MYL9;ITGAX;PIP4K2B;CDC42;GSN;MSN;LIMK1;RRAS2;ARPC5L

4. TermOverlapP-valueAdjusted P-valueZ-scoreCombined Score RNA processing (GO:0006396)62/2601.22E-104.60E-08-2.263730238.24720548 RNA splicing (GO:0008380)47/1607.81E-114.60E-08-2.23579822337.77527643 RNA metabolic process (GO:0016070)89/4985.40E-091.35E-06-2.29867660531.05989575 nucleobase, nucleoside, nucleotide and nucleic acid metabolic process (GO:0006139)134/8941.33E-082.51E-06-2.23868410828.87098666 nuclear mRNA splicing, via spliceosome (GO:0000398)32/1054.30E-085.38E-06-2.1265873425.79957197 mRNA processing (GO:0006397)37/1332.83E-084.26E-06-2.06802300825.57224641 RNA splicing, via transesterification reactions (GO:0000375)32/1065.16E-085.55E-06-2.10992707825.53425968 mRNA metabolic process (GO:0016071)39/1602.36E-072.22E-05-2.17096462323.26699146 metabolic process (GO:0008152)311/28815.94E-050.004961003-2.03149463310.77940993 RNA elongation (GO:0006354)15/469.21E-050.006922161-1.9634743499.76441151 transcription initiation from RNA polymerase II promoter (GO:0006367)17/601.36E-040.00930723-1.770257828.2794316 spliceosomal snRNP biogenesis (GO:0000387)10/242.87E-040.016574142-1.9951163198.179800302 RNA elongation from RNA polymerase II promoter (GO:0006368)14/452.36E-040.014760225-1.8745687757.902843073 transcription initiation (GO:0006352)17/674.11E-040.022068841-1.7457875616.657715462 Ras protein signal transduction (GO:0007265)18/798.39E-040.042077832-1.9699182046.241162277 positive regulation of fibroblast proliferation (GO:0048146)6/140.00435210.204548711-1.7857271142.833858098 small GTPase mediated signal transduction (GO:0007264)19/1050.0059698730.249408015-1.9660677432.730209676 negative regulation of ubiquitin-protein ligase activity during mitotic cell cycle (GO:0051436)13/620.0077136210.292225444-1.8252177052.24543704 myeloid cell differentiation (GO:0030099)8/280.0077719530.292225444-1.7880750042.199742987 negative regulation of ubiquitin-protein ligase activity (GO:0051444)13/640.0096207940.344516056-1.81839181.937704821 Table S4: The 1583 genes, which were up-regulated at late stage (12 weeks), were analyzed further by using Enrichr GO Biological Process.

5. 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 BIOSYNTHESIS3/310.0235154190.64023378-1.8684117180.833165681ST3GAL1;GALNT10;WBSCR17 HSA04514 CELL ADHESION MOLECULES7/1340.0139305020.64023378-1.8104293420.80731007 MPZL1;CD40;PDCD1LG2;CLDN6;SELP;SELL;PECAM 1 HSA04620 TOLL LIKE RECEPTOR SIGNALING PATHWAY5/1020.0451812110.64023378-1.7403665930.776067557TLR6;MAP3K8;CD40;IRAK4;TICAM2 HSA00340 HISTIDINE METABOLISM3/410.0457309840.64023378-1.4880509050.663554469MAOB;HAL;ALDH3B1 HSA00533 KERATAN SULFATE BIOSYNTHESIS2/160.0419039050.64023378-1.3055860120.582189379CHST1;ST3GAL1 HSA00604 GLYCOSPHINGOLIPID BIOSYNTHESIS GANGLIOSERIES2/160.0419039050.64023378-1.2168413650.542616199ST3GAL1;ST3GAL5 HSA04660 T CELL RECEPTOR SIGNALING PATHWAY4/930.1008236410.773476397-1.4993733040.385129214MAP3K8;PRKCQ;CARD11;GRAP2 HSA04662 B CELL RECEPTOR SIGNALING PATHWAY3/640.1233880410.773476397-1.1631317180.298762158BTK;CARD11;PLCG2 HSA04370 VEGF SIGNALING PATHWAY3/700.1485603580.773476397-1.1084402160.284714092NOS3;SH2D2A;PLCG2 HSA04110 CELL CYCLE4/1150.1726666070.773476397-0.9119460470.234242575ESPL1;CDC20;CDC6;CCNB1 HSA04520 ADHERENS JUNCTION3/750.1707048060.773476397-0.8964562880.230263874FGFR1;TCF7L1;SNAI1 HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 14/1170.1799393870.773476397-0.8849108030.227298299ST3GAL1;WBSCR17;CHST1;GALNT10 HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION7/2570.2069103740.799003684-0.9905433770.222267754CD40;CCR4;XCR1;CCL20;IL18R1;CXCR3;IFNGR1 HSA00360 PHENYLALANINE METABOLISM2/300.1154920990.773476397-0.7588240320.194911636MAOB;ALDH3B1 HSA00530 AMINOSUGARS METABOLISM2/290.1095241410.773476397-0.7303001760.187584994HK2;GFPT2 HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS2/300.1154920990.773476397-0.6786635170.174321596ARG2;MAOB HSA00330 ARGININE AND PROLINE METABOLISM2/350.1464631030.773476397-0.5344686230.137283677ARG2;NOS3 HSA04512 ECM RECEPTOR INTERACTION3/870.227193010.799003684-0.5468809130.122714456ITGB5;FNDC5;ITGA3 HSA01430 CELL COMMUNICATION4/1380.2616245390.845248509-0.4902090680.082416204KRT35;GJA5;GJC1;KRT7 HSA04670 LEUKOCYTE TRANSENDOTHELIAL MIGRATION3/1150.3676794030.868766705-0.1793082230.025225198PLCG2;CLDN6;PECAM1

6. 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:0006954)9/1480.0013102280.36305485-2.26760162.29753701 S1PR3;CD40;CCR4;AFAP1L2;AGER;MMP25;XCR1;NLRP3;CC L20 microtubule cytoskeleton organization (GO:0000226)5/470.0017538880.36305485-2.0402985212.067233222NUSAP1;ESPL1;NDC80;UNC84B;SPAG5 defense response (GO:0006952)12/3090.0079051440.484995848-2.3797347671.722011652 S1PR3;CD40;CCR4;AFAP1L2;AGER;MMP25;XCR1;CCL20;SEL P;TLR6;PGLYRP2;NLRP3 response to wounding (GO:0009611)9/1830.0051048070.484995848-2.2888517051.656247309 S1PR3;CD40;CCR4;AFAP1L2;AGER;MMP25;XCR1;NLRP3;CC L20 spindle organization (GO:0007051)3/170.0043528540.484995848-2.2361100081.618082629NDC80;UNC84B;SPAG5 response to external stimulus (GO:0009605)12/3520.0198446720.484995848-2.2185630681.605385401 S1PR3;CD40;PITPNM1;CCR4;AFAP1L2;AGER;MMP25;XCR1; CCL20;PGLYRP2;NLRP3;PLP2 positive regulation of NF-kappaB transcription factor activity (GO:0051092)3/270.0137138380.484995848-2.1808219431.578075359AGT;NPM1;CARD11 chromosome organization (GO:0051276)9/2250.017368480.484995848-2.1785747911.576449286 ESPL1;NDC80;CHAF1A;NPM1;NFE2;DKC1;NUSAP1;TCF7L1; TEP1 cytokinesis (GO:0000910)3/290.0163500690.484995848-2.065100791.494337803NUSAP1;ESPL1;RACGAP1 organelle organization (GO:0006996)16/5530.0297949330.484995848-2.0210950381.462494583 ESPL1;UNC84B;SPAG5;NDC80;DKC1;NUSAP1;SASS6;PLD2;N EK3;CHAF1A;NOS3;NPM1;NFE2;TCF7L1;RACGAP1;TEP1 microtubule-based process (GO:0007017)5/740.0105981610.484995848-1.9247537751.392780604NUSAP1;ESPL1;UNC84B;SPAG5;NDC80 positive regulation of transcription factor activity (GO:0051091)3/370.0295523740.484995848-1.8976626041.373177029AGT;NPM1;CARD11 regulation of mitotic cell cycle (GO:0007346)5/990.0310578260.484995848-1.8934742611.37014628ESPL1;AFAP1L2;GAS1;CDC6;NUSAP1 defense response to bacterium (GO:0042742)3/290.0163500690.484995848-1.8771820561.358356997TLR6;PGLYRP2;SELP positive regulation of cytokine production (GO:0001819)3/350.0258520920.484995848-1.8755958571.357209201AFAP1L2;AGT;CARD11 regulation of cytokine production (GO:0001817)5/1010.0333357490.484995848-1.873769521.355887635TLR6;AFAP1L2;NLRP3;CARD11;AGT cell cycle (GO:0007049)3/330.0224181140.484995848-1.8605639541.34633189CDC20;NDC80;SPAG5 cell division (GO:0051301)3/350.0258520920.484995848-1.8285737051.323183268NUSAP1;ESPL1;RACGAP1 signal transduction (GO:0007165)39/17220.0358531590.484995848-1.8222744551.318625037 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:0043388)3/400.0355987130.484995848-1.766239231.27807711AGT;NPM1;CARD11

7. 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 DEGRADATION4/300.0134291770.249585001-1.9965538852.77112842ARSB;HPSE2;HYAL1;NEU1 HSA00071 FATTY ACID METABOLISM5/470.0135105250.249585001-1.9732623922.738800858EHHADH;ACOX3;CPT1A;ALDH2;ALDH9A1 HSA04520 ADHERENS JUNCTION7/750.0069566360.249585001-1.9480179152.703762642EGFR;CTNNA3;CTNNA2;PARD3;SORBS1;PVRL3;MET HSA00310 LYSINE DEGRADATION5/470.0135105250.249585001-1.8946722162.629721172EHHADH;PIPOX;SHMT2;ALDH2;ALDH9A1 HSA03320 PPAR SIGNALING PATHWAY6/700.0175561430.249585001-1.5092795492.09481321EHHADH;ACOX3;PDPK1;SLC27A2;SORBS1;CPT1A HSA04530 TIGHT JUNCTION9/1360.0177091720.249585001-1.4560850612.020981614 MYH15;INADL;MPDZ;CTNNA3;CTNNA2;PPP2R1B;MPP5; PARD3;EXOC4 HSA05213 ENDOMETRIAL CANCER5/520.0195310750.249585001-1.3718752691.904102151PDPK1;EGFR;PIK3CB;CTNNA3;CTNNA2 HSA04070 PHOSPHATIDYLINOSITOL SIGNALING SYSTEM6/780.0273592590.304826853-1.3733271411.631528241PLCB1;PIK3CB;PI4KA;DGKG;INPP5B;DGKQ HSA00531 GLYCOSAMINOGLYCAN DEGRADATION3/170.0165224760.249585001-1.0769530441.494763157ARSB;HYAL1;HPSE2 HSA00640 PROPANOATE METABOLISM4/340.0196523620.249585001-1.0731560921.489493155EHHADH;ACSS2;ALDH2;ALDH9A1 HSA00770 PANTOTHENATE AND COA BIOSYNTHESIS3/160.0143271470.249585001-0.9198995941.276779919COASY;ENPP3;PANK3 HSA00380 TRYPTOPHAN METABOLISM5/600.0324203190.310079534-1.0688214961.251511365EHHADH;AFMID;CAT;ALDH9A1;ALDH2 HSA00561 GLYCEROLIPID METABOLISM5/580.0288025370.304826853-1.0510484931.248657547GPAM;ALDH9A1;DGKG;DGKQ;ALDH2 HSA00650 BUTANOATE METABOLISM4/450.044845460.316409636-0.4746414930.546178315EHHADH;BDH2;ALDH2;ALDH9A1 HSA04012 ERBB SIGNALING PATHWAY5/870.1086012460.529869488-0.5505347050.349658108GAB1;EGFR;PIK3CB;ERBB3;ABL2 HSA05215 PROSTATE CANCER5/870.1086012460.529869488-0.5304104490.336876699PDPK1;CREB3L2;EGFR;AR;PIK3CB HSA00562 INOSITOL PHOSPHATE METABOLISM4/510.0637630840.385614843-0.280770380.26755065PLCB1;PIK3CB;PI4KA;INPP5B HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 16/1170.1223249030.533521654-0.366922020.230520821MGAT3;XYLT1;FUT8;STT3B;HS6ST1;C1GALT1 HSA00230 PURINE METABOLISM6/1450.2361201040.6971403690.14191469-0.05119835PDE4D;ENPP3;PDE8A;ADK;PDE9A;ADCY9 HSA04650 NATURAL KILLER CELL MEDIATED CYTOTOXICITY1/1320.977110231 5.177667218-0.119893064PIK3CB

8. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes retinoid metabolic process (GO:0001523)3/140.0060526470.398565547-2.6524197462.439916656ALDH8A1;CYP26B1;BCO2 vitamin A metabolic process (GO:0006776)3/140.0060526470.398565547-2.5791326122.372501044ALDH8A1;CYP26B1;BCO2 vitamin metabolic process (GO:0006766)5/440.0046846790.398565547-2.5052929022.304577127ALDH8A1;AFMID;CYP26B1;BCO2;NMNAT1 positive regulation of transferase activity (GO:0051347)9/1230.0028729880.398565547-2.3453331642.157432834 ALS2;EGFR;PIK3CB;SERINC1;PDPK1;ERN1;MAP3K13;PRK D3;PARD3 positive regulation of kinase activity (GO:0033674)8/1160.006770290.398565547-2.2465075152.066524769 ALS2;EGFR;PIK3CB;PDPK1;ERN1;MAP3K13;PRKD3;PARD 3 positive regulation of protein kinase activity (GO:0045860)8/1160.006770290.398565547-2.2454563412.065557812 ALS2;EGFR;PIK3CB;PDPK1;ERN1;MAP3K13;PRKD3;PARD 3 induction of apoptosis by intracellular signals (GO:0008629)4/290.0061109460.398565547-2.2437886822.06402376CUL3;DYRK2;CIDEB;HIPK2 cellular aldehyde metabolic process (GO:0006081)3/120.0041860520.398565547-2.2240157792.045834997ALDH8A1;ALDH9A1;BCO2 protein amino acid N-linked glycosylation (GO:0006487)4/310.0075517680.398565547-2.0225266591.860488517FUT8;STT3A;ALK;MAGT1 exocytosis (GO:0006887)3/170.0096575280.404482497-1.9724463541.785353534SNAP29;LIN7A;MIA3 nucleotide metabolic process (GO:0009117)6/760.0102185050.404482497-1.9082802551.727273793AFMID;PDE8A;ADK;NMNAT1;COASY;ENPP3 DNA damage response, signal transduction (GO:0042770)5/520.0089072320.404482497-1.825849941.652662256FOXN3;HIPK2;HUS1;DYRK2;CIDEB regulation of protein kinase activity (GO:0045859)10/2000.0200876390.470002284-2.1252526981.604603457 ALS2;PIK3CB;DUSP16;PDPK1;MAP3K13;PARD3;EGFR;CD K5RAP1;ERN1;PRKD3 metabolic process (GO:0008152)81/28810.0159796920.442023628-1.9372650941.581567612 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:0007173)3/190.0126242420.442023628-1.8753227521.530998383EGFR;REPS2;GAB1 lipid metabolic process (GO:0006629)16/3930.0217685270.470002284-2.0029057381.512229332 ALDH8A1;PDSS1;ASAH2;PI4KA;CPT1A;PNPLA8;ACOX3;G PAM;SERINC1;BCO2;ALOX12B;SLC27A2;ACSS2;AOAH;CY P26B1;BDH2 brain development (GO:0007420)4/400.0167503690.442023628-1.8015918161.470805042SHROOM4;UBE3A;CDK5RAP1;ALK cofactor metabolic process (GO:0051186)6/850.0164979680.442023628-1.7959314981.466184004AFMID;CPOX;FECH;NMNAT1;COASY;PDSS1 carboxylic acid transport (GO:0046942)4/380.014297030.442023628-1.7465335771.425855939SERINC1;SLC22A6;SLC3A1;SLC16A2 secretion by cell (GO:0032940)5/590.0143074230.442023628-1.7010372071.388713069HNF1A;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.

9. 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 DISEASE1/140.0495998740.204640389-1.7313995292.746867153HSPD1 HSA00100 BIOSYNTHESIS OF STEROIDS1/240.081386660.204640389-1.7189397412.727099688NQO1 HSA05010 ALZHEIMERS DISEASE1/280.0938226830.204640389-1.6001366962.538618532MAPT HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS1/300.0999818990.204640389-1.5946852492.529969807NAGS HSA00512 O GLYCAN BIOSYNTHESIS1/310.1030469080.204640389-1.4885908552.361650941GALNT14 HSA00252 ALANINE AND ASPARTATE METABOLISM1/330.1091478710.204640389-1.4332672072.273879915ASPA HSA01510 NEURODEGENERATIVE DISEASES1/380.1242321030.204640389-1.3466734632.136498851MAPT HSA00600 SPHINGOLIPID METABOLISM1/390.1272203430.204640389-1.1914842871.890291061SPTLC1 HSA00340 HISTIDINE METABOLISM1/410.1331684410.204640389-1.1896485051.887378591ASPA HSA00510 N GLYCAN BIOSYNTHESIS1/420.1361283540.204640389-1.182014281.875266885DHDDS HSA00280 VALINE LEUCINE AND ISOLEUCINE DEGRADATION1/440.1420200440.204640389-1.0608158671.682985477IVD HSA00650 BUTANOATE METABOLISM1/450.1449518770.204640389-1.034768531.641661349AACS HSA00310 LYSINE DEGRADATION1/470.1507876550.204640389-0.9120306371.446937554TMLHE HSA04940 TYPE I DIABETES MELLITUS1/450.1449518770.204640389-0.8751006211.388348045HSPD1 HSA00564 GLYCEROPHOSPHOLIPID METABOLISM1/680.2098702360.265835632-0.9463469691.253793413LYPLA1 HSA04640 HEMATOPOIETIC CELL LINEAGE1/880.2625694160.311801181-0.976500591.138003567TFRC HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 11/1170.3332087810.372409815-1.0000194210.987779562GALNT14 HSA04080 NEUROACTIVE LIGAND RECEPTOR INTERACTION1/2540.5897629460.594180846-1.1432205720.595128107GRIK2 HSA04010 MAPK SIGNALING PATHWAY1/2570.594180846 -1.1203684170.583231925MAPT

10. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes protein folding (GO:0006457)2/740.0162756640.320295499-1.8741398392.133729335CCT6B;HSPD1 regulation of protein complex assembly (GO:0043254)1/260.0679061470.354540838-1.9525628112.024674357MAPT positive regulation of T cell mediated immunity (GO:0002711)1/90.0256807710.320295499-1.7741405682.019879038HSPD1 B cell activation (GO:0042113)1/220.058130090.344130134-1.885683072.011524879HSPD1 anatomical structure development (GO:0048856)4/6390.0797833110.354540838-1.9196739881.990570892SH3GL2;FHL1;KLK7;AQP4 adaptive immune response (GO:0002250)1/160.0432831760.320295499-1.7341696961.97437175HSPD1 regulation of macrophage activation (GO:0043030)1/90.0256807710.320295499-1.6925610281.926999812HSPD1 regulation of interleukin-6 production (GO:0032675)1/150.0407871760.320295499-1.6233576061.848210936HSPD1 positive regulation of programmed cell death (GO:0043068)2/2260.1170414320.354540838-1.7197566611.78327027GRIK2;HSPD1 Wnt receptor signaling pathway through beta-catenin (GO:0060070)1/90.0256807710.320295499-1.5643818831.78106641PTPRU positive regulation of cytoskeleton organization (GO:0051495)1/170.0457730050.3225907-1.5679358931.773917111MAPT sphingolipid biosynthetic process (GO:0030148)1/200.053205610.342366537-1.6305862111.747781939SPTLC1 positive regulation of innate immune response (GO:0045089)1/200.053205610.342366537-1.5933852321.7079072HSPD1 protein complex assembly (GO:0006461)2/2330.1230393610.354540838-1.6313397171.691587934CCT6B;HSPD1 positive regulation of T cell activation (GO:0050870)1/320.0823896770.354540838-1.6273186751.687418388HSPD1 xenobiotic metabolic process (GO:0006805)1/130.0357766040.320295499-1.4818621071.687116715NQO1 positive regulation of protein polymerization (GO:0032273)1/90.0256807710.320295499-1.4598746321.662083727MAPT mononuclear cell proliferation (GO:0032943)1/100.0282141020.320295499-1.4588529221.660920498HSPD1 response to toxin (GO:0009636)1/160.0432831760.320295499-1.4402091151.639694314NQO1 mitochondrial membrane organization (GO:0007006)1/120.0332620040.320295499-1.4160629761.612203663LETM1 negative regulation of transcription (GO:0016481)2/2300.1204589790.354540838-1.5485071241.605696189PTPRU;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.

11. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA00564 GLYCEROPHOSPHOLIPID METABOLISM3/680.0051206520.148498896-1.9553286973.729159401LYPLA1;CHPT1;DGKB HSA00150 ANDROGEN AND ESTROGEN METABOLISM2/540.031889530.343031589-2.0851304172.230949302SRD5A2;HSD3B2 HSA04080 NEUROACTIVE LIGAND RECEPTOR INTERACTION3/2540.1372860270.363465962-1.6461877011.666056572MCHR1;GHR;P2RY1 HSA00410 BETA ALANINE METABOLISM1/250.1239501460.363465962-1.0257181061.03809814CNDP1 HSA00565 ETHER LIPID METABOLISM1/310.1503997080.363465962-0.8344566040.844528183CHPT1 HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS1/300.1460449110.363465962-0.8095237650.819294414NAGS HSA00120 BILE ACID BIOSYNTHESIS1/380.1802963850.371783766-0.7144940640.706951057SRD5A2 HSA00601 GLYCOSPHINGOLIPID BIOSYNTHESIS LACTOSERIES1/100.0543521170.343031589-0.6456639980.690817051B3GALT2 HSA00340 HISTIDINE METABOLISM1/410.1928001220.371783766-0.6923111720.685002353CNDP1 HSA00440 AMINOPHOSPHONATE METABOLISM1/160.0828007280.343031589-0.5883264830.629469766CHPT1 HSA00512 O GLYCAN BIOSYNTHESIS1/310.1503997080.363465962-0.6023421760.609612221GALNT11 HSA00380 TRYPTOPHAN METABOLISM1/600.2678713510.42030893-0.7025252250.608924481AFMID HSA00561 GLYCEROLIPID METABOLISM1/580.2602939240.42030893-0.6813270070.590550601DGKB HSA04012 ERBB SIGNALING PATHWAY1/870.3632004850.446805686-0.7284482080.586860813NRG4 HSA00140 C21 STEROID HORMONE METABOLISM1/110.05915120.343031589-0.5469966350.585249609HSD3B2 HSA04070 PHOSPHATIDYLINOSITOL SIGNALING SYSTEM1/780.3328210010.446805686-0.7258689530.584782884DGKB HSA00620 PYRUVATE METABOLISM1/420.1969275140.371783766-0.5898593110.583632089ACOT12 HSA05215 PROSTATE CANCER1/870.3632004850.446805686-0.7125943320.574088431SRD5A2 HSA00280 VALINE LEUCINE AND ISOLEUCINE DEGRADATION1/440.2051220780.371783766-0.5635584290.557608869DBT HSA04610 COMPLEMENT AND COAGULATION CASCADES1/690.3010643480.436543305-0.6523911250.540745931C4A HSA00630 GLYOXYLATE AND DICARBOXYLATE METABOLISM1/140.0734096710.343031589-0.4527330310.484393893AFMID HSA00240 PYRIMIDINE METABOLISM1/890.3697702230.446805686-0.5425549570.437099356UPP2 HSA01031 GLYCAN STRUCTURES BIOSYNTHESIS 21/620.2753748160.42030893-0.4768011030.413274646B3GALT2 HSA00232 CAFFEINE METABOLISM1/70.0398145910.343031589-0.3351433950.358580891NAT2 HSA01030 GLYCAN STRUCTURES BIOSYNTHESIS 11/1170.4552327390.528069978-0.5395849470.344539272GALNT11 HSA00230 PURINE METABOLISM1/1450.5295853560.568592542-0.5147284160.290611132AMPD1 HSA04530 TIGHT JUNCTION1/1360.5068101430.565288236-0.4742144490.270501181RAB3B HSA04630 JAK STAT SIGNALING PATHWAY1/1530.5489859020.568592542-0.4503818070.254281603GHR HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION1/2570.741172032 -0.540907780.16201406GHR Table S11: 84 genes which were down-regulated between 4-8 weeks but no changes between 8-12 weeks further analyzed for Enrichr KEGG.

12. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes excretion (GO:0007588)3/414.12E-040.062747822-2.094305855.798360969AQP4;AQP1;KCNK5 secretion (GO:0046903)4/1186.82E-040.062747822-1.9876908135.503183228AQP4;AQP1;KCNK5;SYN3 lipid metabolic process (GO:0006629)5/3930.0095758570.315479274-2.2602328942.607545458GHR;NR1H4;CHPT1;ACOT12;SRD5A2 cation transport (GO:0006812)3/1990.0295964290.315479274-2.118454122.443980633AQP1;KCNK5;KCNC1 fatty acid metabolic process (GO:0006631)2/830.0329117880.315479274-2.0868231662.407489194ACOT12;GHR cellular amino acid and derivative metabolic process (GO:0006519)3/1490.0140202710.315479274-2.0377876212.350918735BPHL;CHPT1;GHR cellular amino acid derivative metabolic process (GO:0006575)2/650.0211502820.315479274-1.9908801052.296803303GHR;CHPT1 potassium ion transport (GO:0006813)2/620.0194042570.315479274-1.9091488452.202513031KCNC1;KCNK5 cofactor metabolic process (GO:0051186)2/850.0343472140.315479274-1.8885453352.178743538AFMID;ACOT12 steroid metabolic process (GO:0008202)2/890.037290720.315479274-1.8857947322.17557027SRD5A2;NR1H4 ion transport (GO:0006811)3/2520.0531224770.315479274-1.7760346782.048944236AQP1;KCNK5;KCNC1 regulation of growth (GO:0040008)2/1190.0621857460.315479274-1.7334445361.999809594CHPT1;GHR metabolic process (GO:0008152)14/28810.0667375570.315479274-1.6411151141.893292622 C4A;GHR;MMP10;NR2E3;NR1H4;CHPT1;AC OT12;B3GALT2;BPHL;UPP2;SRD5A2;GLYCTK ;AFMID;MCHR1 second-messenger-mediated signaling (GO:0019932)2/1410.0831656620.32793897-1.5987798531.782524031P2RY1;MCHR1 transport (GO:0006810)6/9800.1055162140.354569998-1.5222399861.578333763GHR;KCNK5;KCNC1;AQP4;AQP1;SYN3 response to chemical stimulus (GO:0042221)4/5660.1214863050.355772739-1.5096933411.560212397GHR;BPHL;HSPB7;ANGPTL7 regulation of multicellular organism growth (GO:0040014)1/90.0332428780.315479274-1.2973507221.496704606GHR cellular amine metabolic process (GO:0009308)2/1730.1169049240.355772739-1.3916204581.438188427CHPT1;GHR positive regulation of growth (GO:0045927)1/250.0842321250.32793897-1.125613961.254978244GHR male gonad development (GO:0008584)1/140.0494632670.315479274-1.0639498291.227438797SRD5A2 positive regulation of JAK-STAT cascade (GO:0046427)1/190.0654218070.315479274-1.0603528691.22328912GHR positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531)1/170.0590695520.315479274-1.0574727521.219966438GHR gonad development (GO:0008406)1/170.0590695520.315479274-1.0471481761.208055363SRD5A2 organic cation transport (GO:0015695)1/160.0558778760.315479274-1.0121486051.167677678AQP1 phosphatidylcholine metabolic process (GO:0046470)1/120.0430067630.315479274-1.0058067351.160361302CHPT1 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.

13. 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 INTERACTION18/2578.36E-062.97E-04-2.05842791916.71987221 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-062.97E-04-1.86361743815.1374965 CD8A;CD3G;CD3D;CD3E;CD37;ITGB3;CD2;CD2 2;CD4;IL2RA;CD14 HSA04660 T CELL RECEPTOR SIGNALING PATHWAY10/934.09E-059.67E-04-1.78639154812.39975168 CD8A;CD3G;CD3D;CD3E;CD247;ICOS;CD4;CD2 8;CTLA4;LAT HSA04514 CELL ADHESION MOLECULES11/1341.62E-040.002867264-1.6437736259.623303247 PDCD1LG2;ICOS;CD8A;VCAM1;CD2;CD22;CD4; CD6;SELPLG;CD28;CTLA4 HSA04610 COMPLEMENT AND COAGULATION CASCADES6/690.0041870650.059456325-1.6917176764.774895598F10;F7;C1QA;C1QB;C3AR1;C6 HSA04670 LEUKOCYTE TRANSENDOTHELIAL MIGRATION7/1150.0123213970.109352396-1.5767102983.4895431MMP9;MMP2;NCF2;NCF1;THY1;RAC2;VCAM1 HSA04512 ECM RECEPTOR INTERACTION6/870.0118046280.109352396-1.5565378763.444897906 COL1A2;COL1A1;COL3A1;ITGB3;COL6A2;COL6 A1 HSA04110 CELL CYCLE7/1150.0123213970.109352396-1.4702145053.253848782 CCNA2;ESPL1;CDC20;MCM5;MCM6;SFN;CCNB 2 HSA04510 FOCAL ADHESION8/2000.0635394660.451130209-1.6292033721.296844692 RAC2;PARVG;COL3A1;COL6A2;COL6A1;COL1A 2;COL1A1;ITGB3 HSA01430 CELL COMMUNICATION6/1380.0755579320.487692108-1.3316585510.956225385 KRT19;COL1A2;COL1A1;COL3A1;COL6A2;COL6 A1 HSA04612 ANTIGEN PROCESSING AND PRESENTATION4/830.1039485340.615028826-1.2171041050.591617437CD8A;CTSS;CD74;CD4 HSA04650 NATURAL KILLER CELL MEDIATED CYTOTOXICITY5/1320.1515883160.666506721-1.0781751910.437421125CD48;RAC2;TYROBP;LAT;CD247 HSA04662 B CELL RECEPTOR SIGNALING PATHWAY3/640.1595861160.666506721-0.8725563420.354000519LILRB3;RAC2;CD22 HSA05210 COLORECTAL CANCER3/850.2726422580.797805687-0.6388703290.144314553RAC2;TCF7;BIRC5 HSA00220 UREA CYCLE AND METABOLISM OF AMINO GROUPS2/300.1404907220.666506721-0.2860827750.116065228ARG1;ALDH1B1

14. Table S14: 240 genes which were up-regulated between 4-8 weeks but no changes between 8- 12 weeks further analyzed by GO Biological Process TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes immune system process (GO:0002376)37/5526.53E-131.30E-10-3.19640113672.75370018 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:0006952)29/3091.55E-136.19E-11-2.43708293657.28395868 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:0006955)29/4211.94E-102.57E-08-3.20157887155.94855313 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:0006950)34/7672.09E-072.08E-05-2.26235669624.38593252 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:0009605)21/3528.52E-074.29E-05-2.28844244923.01212127 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:0006954)14/1484.64E-073.71E-05-2.21025900122.55153164 AIF1;CCR7;CCR4;CCR2;C3AR1;CCL3;CCL5;NFAM1;KLRG1;PLA2 G7;CCR1;GPR68;CCL24;CCL22 response to wounding (GO:0009611)15/1839.68E-074.29E-05-2.21777439222.30149737 AIF1;CCR7;CCR4;CCR2;C3AR1;CCL3;CCL5;NFAM1;KLRG1;PLA2 G7;CCR1;COL3A1;GPR68;CCL24;CCL22 chemotaxis (GO:0006935)12/1108.06E-074.29E-05-2.16895023221.81053134 CCR7;CCR4;CCR2;CCL3;CCL2;CCL5;CORO1A;CXCL5;CCR1;CCL24 ;CCL22;CCL17 T cell activation (GO:0042110)8/399.15E-074.29E-05-2.05920613320.70696656CD8A;TNFRSF4;CD2;CD28;CD3G;CD3E;FOXP3;CLEC7A locomotory behavior (GO:0007626)12/1201.88E-066.82E-05-2.08542193920.00561434 CCR7;CCR4;CCR2;CCL3;CCL2;CCL5;CORO1A;CXCL5;CCR1;CCL24 ;CCL22;CCL17

15. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION4/2570.0153174930.322704516-2.1146323682.391687667IL7R;CCL8;CXCR4;PF4 HSA05214 GLIOMA2/640.0259665920.322704516-2.077574992.349775098E2F1;IGF1 HSA05218 MELANOMA2/710.0313188860.322704516-1.7973778132.032866995E2F1;IGF1 HSA04730 LONG TERM DEPRESSION2/760.0353897880.322704516-1.7475130221.976469009PLA2G2D;IGF1 HSA05215 PROSTATE CANCER2/870.0450285370.322704516-1.744969671.973592432E2F1;IGF1 HSA04080 NEUROACTIVE LIGAND RECEPTOR INTERACTION3/2540.0724806520.3567292-1.7020729381.754459899C5AR1;P2RY10;PTGER4 HSA04630 JAK STAT SIGNALING PATHWAY2/1530.1185050710.3567292-1.3942535161.437166309SOCS3;IL7R HSA00591 LINOLEIC ACID METABOLISM1/310.116847640.3567292-0.9947372741.025353625PLA2G2D HSA00565 ETHER LIPID METABOLISM1/310.116847640.3567292-0.9589200060.988433962PLA2G2D HSA05219 BLADDER CANCER1/420.153965320.3567292-0.9323959110.961093499E2F1 HSA00860 PORPHYRIN AND CHLOROPHYLL METABOLISM1/410.1506524080.3567292-0.8799576570.907041283ALAS2 HSA04930 TYPE II DIABETES MELLITUS1/440.1605548310.3567292-0.7910417580.815388702SOCS3 HSA04150 MTOR SIGNALING PATHWAY1/480.1735897640.3567292-0.780551550.804575623IGF1 HSA00260 GLYCINE SERINE AND THREONINE METABOLISM1/450.1638315140.3567292-0.7562035010.779478181ALAS2 HSA05131 PATHOGENIC ESCHERICHIA COLI INFECTION EPEC1/530.1896166290.3567292-0.6551662740.675331197TUBB2B HSA00562 INOSITOL PHOSPHATE METABOLISM1/510.1832411720.3567292-0.6222997260.641453072PIP4K2A HSA05223 NON SMALL CELL LUNG CANCER1/540.1927868320.3567292-0.6010530690.619552479E2F1 HSA05130 PATHOGENIC ESCHERICHIA COLI INFECTION EHEC1/530.1896166290.3567292-0.4735755950.488151461TUBB2B HSA00590 ARACHIDONIC ACID METABOLISM1/540.1927868320.3567292-0.4458240540.459545773PLA2G2D HSA00592 ALPHA LINOLENIC ACID METABOLISM1/150.0601247710.3567292-0.4425335990.456154044PLA2G2D HSA04662 B CELL RECEPTOR SIGNALING PATHWAY1/640.2238557780.3567292-0.4366932790.450133968CD79B HSA00601 GLYCOSPHINGOLIPID BIOSYNTHESIS LACTOSERIES1/100.0417099440.322704516-0.3032664230.34299984B3GALT1 HSA04370 VEGF SIGNALING PATHWAY1/700.2419552650.3567292-0.2711177650.279462317PLA2G2D HSA01031 GLYCAN STRUCTURES BIOSYNTHESIS 21/620.2177331310.3567292-0.261996510.270060325B3GALT1 HSA04115 P53 SIGNALING PATHWAY1/680.2359665380.3567292-0.245446570.253001005IGF1 HSA04610 COMPLEMENT AND COAGULATION CASCADES1/690.2389664240.3567292-0.2366605050.24394452C5AR1 HSA00564 GLYCEROPHOSPHOLIPID METABOLISM1/680.2359665380.3567292-0.2256457350.232590733PLA2G2D HSA05212 PANCREATIC CANCER1/730.2508558950.3567292-0.2058448630.212180424E2F1 HSA04664 FC EPSILON RI SIGNALING PATHWAY1/750.2567351150.3567292-0.152256110.156942298PLA2G2D HSA04920 ADIPOCYTOKINE SIGNALING PATHWAY1/720.2478999620.3567292-0.1136097460.117106464SOCS3 Table S15: 66 genes which were up-regulated between 4-8 weeks and between 8-12 weeks further analyzed for Enrichr KEGG.

16. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes immune response (GO:0006955)7/4210.001868350.074973786-3.1854639268.252316191IL7R;POU2AF1;PTGER4;C5AR1;LAX1;CD79B;CXCR4 immune system process (GO:0002376)7/5520.0082266860.118346319-2.9690019966.336266049IL7R;POU2AF1;PTGER4;C5AR1;LAX1;CD79B;CXCR4 defense response (GO:0006952)6/3090.0019229410.074973786-2.3797347676.16498074S100A8;S100A9;C5AR1;PLA2G2D;TPSAB1;CXCR4 response to chemical stimulus (GO:0042221)8/5660.0023448340.074973786-2.292166095.938123858GNG2;RTP4;FHL2;CYGB;CCL8;ALAS2;C5AR1;CXCR4 cell communication (GO:0007154)17/18968.38E-040.074973786-2.2313648955.780611262 IL7R;IGF1;CCL8;CD53;C5AR1;STK17B;IL1RL1;GPR176;PLEK;CX CR4;GNG2;FHL2;S100A9;LAX1;SOCS3;PTGER4;LPAR1 intracellular signaling cascade (GO:0007242)8/5860.0029084660.074973786-2.22012555.751494297GNG2;FHL2;IGF1;PTGER4;STK17B;LAX1;PLEK;SOCS3 signal transduction (GO:0007165)16/17229.05E-040.074973786-2.2068857245.717195113 IL7R;IGF1;CCL8;CD53;C5AR1;STK17B;IL1RL1;GPR176;PLEK;CX CR4;GNG2;FHL2;LAX1;SOCS3;PTGER4;LPAR1 response to external stimulus (GO:0009605)6/3520.0036558920.080129244-2.246514825.670460399S100A8;S100A9;C5AR1;PLA2G2D;CCL8;CXCR4 inflammatory response (GO:0006954)4/1480.0037992310.080129244-2.1242451035.361837646S100A8;S100A9;PLA2G2D;CXCR4 response to virus (GO:0009615)3/530.0016939220.074973786-2.0490169195.308217543ISG20;CXCR4;CCL8 cytosolic calcium ion homeostasis (GO:0051480)3/640.0028353190.074973786-1.9728555635.110912659LPAR1;CXCR4;C5AR1 elevation of cytosolic calcium ion concentration (GO:0007204)3/610.0024875150.074973786-1.9513402035.055174607LPAR1;CXCR4;C5AR1 regulation of MAP kinase activity (GO:0043405)3/810.0053681330.1037839-2.0537808284.652726325CXCR4;C5AR1;LAX1 response to wounding (GO:0009611)4/1830.007895110.118346319-2.1466970794.581352197S100A8;S100A9;PLA2G2D;CXCR4 homeostatic process (GO:0042592)5/3010.0090455530.118346319-2.1326889954.551456985LPAR1;C5AR1;IGF1;ALAS2;CXCR4 calcium ion homeostasis (GO:0055074)3/940.0079995770.118346319-2.069759734.41715712LPAR1;CXCR4;C5AR1 cellular calcium ion homeostasis (GO:0006874)3/930.0077746370.118346319-2.0661918894.409542849LPAR1;CXCR4;C5AR1 cellular metal ion homeostasis (GO:0006875)3/990.0091820420.118346319-2.0244685794.320499462LPAR1;C5AR1;CXCR4 metal ion homeostasis (GO:0055065)3/1020.0099382440.121351192-2.0187637534.25770705LPAR1;C5AR1;CXCR4 G-protein coupled receptor protein signaling pathway (GO:0007186)5/3330.013536560.143119882-2.0953177324.07344993LPAR1;GPR176;PLEK;CXCR4;PTGER4 response to stress (GO:0006950)8/7670.0142678870.143119882-2.0121262923.911719726CYGB;TPSAB1;ALAS2;S100A8;S100A9;C5AR1;PLA2G2D;CXCR4 cell proliferation (GO:0008283)4/2370.0186649830.143119882-1.9836482453.856356333ISG20;IGF1;TGFBI;E2F1 chemotaxis (GO:0006935)3/1100.0121290770.140697298-1.9642422843.852162986C5AR1;CCL8;CXCR4 locomotory behavior (GO:0007626)3/1200.0152307020.143119882-1.9134807933.719945707C5AR1;CCL8;CXCR4 cellular cation homeostasis (GO:0030003)3/1270.0176459230.143119882-1.8324418933.562400196LPAR1;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

17. 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 PATHWAY2/900.0195927080.181488373-1.7741985823.027782876TGFB3;DCN HSA04060 CYTOKINE CYTOKINE RECEPTOR INTERACTION2/2570.1260257430.264919173-1.889814572.510298345CCL28;TGFB3 HSA04710 CIRCADIAN RHYTHM1/130.0333580350.181488373-1.250114152.133399415PER1 HSA05217 BASAL CELL CARCINOMA1/560.1296478280.264919173-1.5640643562.077594398PTCH2 HSA00272 CYSTEINE METABOLISM1/170.0427031470.181488373-1.214635082.072852122CDO1 HSA04610 COMPLEMENT AND COAGULATION CASCADES1/690.1570085210.264919173-1.4838523661.971046365KNG1 HSA00430 TAURINE AND HYPOTAURINE METABOLISM1/80.0215612250.181488373-1.1239426681.918079746CDO1 HSA05212 PANCREATIC CANCER1/730.1652700440.264919173-1.4339092641.904705419TGFB3 HSA04340 HEDGEHOG SIGNALING PATHWAY1/570.1317805210.264919173-1.4110843821.874386433PTCH2 HSA05211 RENAL CELL CARCINOMA1/690.1570085210.264919173-1.3776805831.830015147TGFB3 HSA05210 COLORECTAL CANCER1/850.1896192620.268627288-1.3271378491.744430342TGFB3 HSA05220 CHRONIC MYELOID LEUKEMIA1/760.1714182880.264919173-1.304801541.733207691TGFB3 HSA04620 TOLL LIKE RECEPTOR SIGNALING PATHWAY1/1020.2230201050.291641676-1.2893856021.588818804TLR7 HSA04110 CELL CYCLE1/1150.2477202470.300803157-1.1352534311.363779028TGFB3 HSA00190 OXIDATIVE PHOSPHORYLATION1/1280.2717114340.30780113-1.0892282031.283439102COX7B2 HSA01430 CELL COMMUNICATION1/1380.2896951810.30780113-1.051175391.238601419KRT23 HSA04010 MAPK SIGNALING PATHWAY1/2570.475074285 -1.2364180590.920246299TGFB3

18. TermOverlapP-valueAdjusted P-valueZ-scoreCombined ScoreGenes response to external stimulus (GO:0009605)7/3521.77E-040.028868175-2.3722977058.409832107CTGF;TPST1;CCL28;PER1;CDO1;LYVE1;KNG1 response to wounding (GO:0009611)5/1834.27E-040.03477133-2.317282637.783664481CTGF;CDO1;TPST1;LYVE1;KNG1 negative regulation of coagulation (GO:0050819)2/140.0013754060.056047784-2.3097515536.655666113KNG1;TMPRSS6 negative regulation of blood coagulation (GO:0030195)2/130.0012060820.056047784-2.1953568686.326032033KNG1;TMPRSS6 regulation of blood coagulation (GO:0030193)2/220.0031092830.101362625-2.4681543385.649730773KNG1;TMPRSS6 cell-matrix adhesion (GO:0007160)2/320.0061852340.168032186-2.2396913683.994712928LYVE1;FBLN5 cell-substrate adhesion (GO:0031589)2/390.0089056720.207374928-2.1342718313.357693809LYVE1;FBLN5 response to stress (GO:0006950)7/7670.0148054760.226409737-2.192848253.257276368CTGF;TGFB3;CDO1;LYVE1;KNG1;TPST1;TLR7 inflammatory response (GO:0006954)3/1480.0152720820.226409737-2.1385807533.176666942CDO1;TPST1;KNG1 anatomical structure morphogenesis (GO:0009653)4/2750.0152791850.226409737-2.0395144663.029512995TGFB3;LYVE1;GCM1;DCN defense response (GO:0006952)4/3090.0223681360.269898167-2.265038432.966544727TPST1;TLR7;CDO1;KNG1 anatomical structure development (GO:0048856)6/6390.0216835430.269898167-2.1543450082.821568385CTGF;IGF2;TGFB3;PTCH2;GATA6;GREM1 sulfur metabolic process (GO:0006790)2/480.0130494480.226409737-1.7741330282.635313038CDO1;TPST1 regulation of gene-specific transcription (GO:0032583)2/760.0301285770.269898167-1.9805332562.593925299TGFB3;IGF2 epidermis development (GO:0008544)2/720.0273311780.269898167-1.9067234192.497255778CTGF;PTCH2 response to hormone stimulus (GO:0009725)2/1050.0534895160.269898167-1.8165955612.379214371TGFB3;RERG oxidation reduction (GO:0055114)2/890.0399611570.269898167-1.8137542382.37549306LOXL1;CDO1 small GTPase mediated signal transduction (GO:0007264)2/1050.0534895160.269898167-1.7899894132.344368018NGF;RERG organ morphogenesis (GO:0009887)2/1000.0491035330.269898167-1.6794042522.199533466TGFB3;DCN tissue development (GO:0009888)2/1310.0783604010.297040589-1.4838465511.801221276CTGF;PTCH2 cell adhesion (GO:0007155)3/3190.101002290.323647289-1.5848015451.787816161FBLN5;LYVE1;ISLR positive regulation of MAPKKK cascade (GO:0043410)1/200.0711197150.297040589-1.2469377291.513640859IGF2 positive regulation of mitosis (GO:0045840)1/200.0711197150.297040589-1.236198321.500604435IGF2 regulation of bone mineralization (GO:0030500)1/190.0678464480.297040589-1.2280364361.490696835TGFB3 regulation of protein kinase B signaling cascade (GO:0051896)1/130.0479723530.269898167-1.1369987291.48913923IGF2 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