Background
Genetic, epigenetic and environmental factors
DNA methylation
Contribution of DNA methylation in patients with MS
References | Comparison | Sample target | Method | Differentially methylated genes |
---|---|---|---|---|
[39] | MS vs CTR | CD8+ T cells | Illumina 450K array | ERG, FTL, DCAF4, NCAPH2, CDKN1C, ZNF462, CBX7, MIR492, HPS1, SASH1, MYL3, KCNG1, DYDC2, MEGF10, SP5, LMO3, SLC12A7, MORN1, IGF2BP1, PLCB3, ABCC4, CREG2, CDC42BPB, UGT1A10, TMEM125, ARHGAP22, DACH1, OR8B12, TMEM8C, BAI1, EIF2S1, CRTAC1, DHX36, C19orf41, DLGAP2, TNXB, PRDM8, HEATR2, WHSC2, CAMTA1, ALK, KCNQ2, SCTR, RHEB, LOC202181, RRP9, KRT75, DGKE, PLD5, ZC3H14. |
[40] | RRMS vs CTR | CD4+ T cells | Illumina 450K array | MICA, MICB, HLA-DRB, MORN1, LCLAT1, PDCD1, MUC4, AHRR, ARSB, PCBD2, TGFBI, PCDHB13, PCDHB15, KIF25, CSGALNACT1, ADARB2, LDHAL6A, CORO1B, USP35, FUT4, ERC1, TCRA, PACS2, IL32, KCTD11, C17orf108, ARHGAP27, NPLOC4, SBNO2, GNG7, C21orf56, RIBC2. |
[41] | Myelinated vs demyelinated MS brains | Hippocampus | Illumina 450K array | MLLT4, PPIF, SCRT2, SNRNP40, ISLR2, MEF2A, PMEPA1, ABCA4, ADAMTS12, AHRR, BEST3, CASP7, CCL4L2, CPXM2, FBXW8, HLA-B, LOC145845, MEIS1, MGMT, MYO7A, NXN, PKP2, PQLC1, PSD3, SCN4B, SDK2, SMYD3, TGFBI, TMEM165, PON1, HDLBP, MKKS, TRIM26, TRPS1, KRTAP27-1, MGP, AJAP1, C1orf106, C2orf62, DSE, EIF2C2, GATA5, HLA-B, IGSF9B, INSC, KIAA1026, KIF25, LOC100292680, NFASC, RASA3, SDK1, SHISA2, SOLH, SORBS2, TAGLN3, TBX5, TM9SF1, TOP1MT, ZSCAN1, AKNA, EBPL, FLJ42709, HERC6, OR52M1, SFRP1, C22orf43, LOC285830, NAPEPLD, NHLH2, PLCH1, SERPINA9, SLFN13, TMEM132B, TTLL3, WDR81. |
[42] | SPMS vs CTR | PMBCs | Microarray dataset and RT-PCR | DNMT3A, GADD45A, GADD45B, MBD4, APOBEC3D, APOBEC4, GADD45G, TET1, TDG, APOBEC3C, APOBEC2, MBD2, MBD3, APOBEC3A, DNMT3B, APOBEC1, TET2, TET3. |
[43] | RRMS vs PPMS vs CTR | PMBCs | Illumina 450K array | RRMS vs CTR: ASB2, ATP11A, CACNA2D3, CERS5, ESRRG, FRMD4A, GNAS, HOXC4-HOXC6, IFITM5, ILDR1, KCNK15, KLHL35, LEFTY2, PLEKHA2, RPH3AL, WRAP73, ZFYVE28.PPMS vs CTR: ATG16L2, CES1, CSGALNACT2, CYB5D1, LSMD1, FAM110A, GDF7, HKR1, HLA-F, HOXB13, IGSF9B, ILDR1, LDB2, MTPN, LUZP6, NTN1, OPCML, OR2L13, RBM46, TBX1, TCP10L, TMEM44, VIPR2, WRAP73. RRMS vs SPMS: ABCC5, AKAP12, CARS, CBFA2T3, CCDC67, FAM110A, FRMD4A, GIMAP5, HIVEP3, ICAM5, KCNQ1, KLF4, LEFTY2, OLFM3, PTH1R, RASA3, RNF39, RPH3AL, TRAF3, USP35, XKR5. |
[44] | Smoker vs non-smoker MS | PMBCs | Bisulphite Illumina Methylation 450k Beadchip | SRM, GNG12, GFI1, ANXA4, NFE2L2, ABLIM2, AHRR, SMIM3, CDKN1A, TPST1, CNTNAP2, SNTG1, MTSS1, PTK2, ZC3H3, ZMIZ1, PTGDR2, PRSS23, GRIK4, ETV6, RARG, LOC348021, CCDC88C, ITPK1, ANPEP, RARA, SMIM6, RECQL5, F2RL3, LINC00111, ACOT9. |
[45] | MS vs CTR | NAWM | Direct BS-sequencing | PAD2 |
[46] | RRMS vs CTR | cfDNA (whole blood) | BS-PCR sequencing assay | MBP3, WM1. |
[47] | MS vs CTR | NAWM | Bisulphite Illumina Methylation 450k Beadchip | ALDOA, ATP1A2, BCAR1, BRK1, CDK5, CORO1A, CSF3, DLC1, DTNBP1, FGD2, FMNL1, MLST8, MYBPC3, MYH6, MYH7, MYO1F, OBSCN, PDGFA, PRKCZ, SHC1, SIPA1L1, SSH3, TPM3, ADA, AGAP1, ALDOA, ARHGEF16, ATP1A1, ATP1A2, ATP1A4, ATP5H, BIN1, DAB2IP, DLC1, FGD2, LDHC, MACROD1, MLST8, MYBPC3, MYH6, MYH7, NME4, NT5C, PLXNB1, PTPRN2, RASA3, SEPT9, SIPA1L1, TBCD, TK1, ACSBG1, ACSL1, ACTR8, ADA, AGAP1, AGPAT1, AGRP, AKAP8, ALDH3A1, ALDOA, AMH, ANGPT2, APBB1IP, APEX, ARHGEF16, ATF6B, ATP11A, ATP1A1, ATP1A2, ATP1A4, ATP6V0E1, ATRIP, BBS2, BCAR1, BCL2L2, BIN1, BIRC5, BPI, BRD4, BRK1, C4B, CACNA1D, CASKIN1, CBX4, CCL17, CCL22, CD37, CD59, CDH1, CDK5, CHST3, CHURC1, CLASP1, CLIC5, CORO1A, CREB5, CRY2, CSF3, CSNK1E, CX3CL1, CXXC5, CYP21A2, DAB2IP, DAND5, DCPS, DHRS3, DLC1, DLL1, DOK4, DOT1L, DSCAML1, DTNBP1, DYRK1B, E2F6, E4F1, EDN2, EFS, ENTPD2, ERCC3, F7, FAM109A, FGD2, FGFR3, FMNL1, GBX1, GDF10, GPR114, GPR56, GTF2H1, GYLTL1B, HDAC11, HEG1, HEXIM1, HEXIM2, HIGD1A, HIST3H3, HLA-DMA, IL17RB, IL25, IL34, INO80E, INPP5J, INTS1, IRAK2, ITPKB, JARID2, LIMD1, LMF1, LPCAT1, MAB21L2, MADD, MAML3, MAP3K14, MAPK3, MBP, MCF2L, MED24, MEIS2, MLLT10, MLST8, MT1A, MT1E, MT1F, MT1G, MT1M, MT2A, MT4, MTCH1, MTSS1L, MUSK, MYBPC3, MYH6, MYH7, MYO1F, NARFL, NCOR2, NDRG1, NLRP3, NOTCH4, NR1H3, NUP210, OBSCN, OTX2, PABPN1, PAG1, PBX2, PCSK6, PDGFA, PEG10, PHF21A, PIK3R1, PLEKHG3, PLLP, PLXNB1, POLD4, POLR2C, POU2F1, PPARA, PPIL2, PPP1R13B, PPP4C, PRAM1, PRDM16, PRKCH, PRKCZ, PTGDS, PTPRN2, RAD9A, RAI1, RASA3, RBP1, RFX5, RIN2, RNF187, RPA1, RRM2, RXRA, SACS, SEMA4C, SETD1A, SHC1, SHISA5, SIPA1L1, SLC17A7, SLC22A17, SLC39A13, SLC7A8, SMAD6, SOX1, SOX8, SPI1, SPOCK2, SREBF1, SSH3, SSTR5, SUN1, TACC3, TBCD, TBX6, TEAD2, TEF, TEP1, THRA, TLN2, TNRC6C, TPM3, TRAF2, TSNARE1, UBE2L3, USP19, VAC14, WHSC1, WISP1, WISP2, WNK2, ZBTB47, ZFP1, ZIC1, ZNF135, ZNF256, ZNF329, ZNF362, ZNF414, ZNF418, ZNF488, ZNF606, ZNF664, ZNF687, ADAMDEC1, AIF1, AIRE, B2M, BPI, C1QA, C1QB, C1QC, C4BPA, C4BPB, CCR6, CD19, CD37, CD4, CD7, CD81, CFD, DLG1, FCER2, HAMP, HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DQA2, HLA-DQB2, HLA-F, IRF6, IRF8, IRF9, JAK1, JAK3, KYNU, LAG3, LAT, LBP, LCP2, LGMN, LST1, LTA, LTB, MBL2, MICB, NCR3, OSM, PSMB8, PTPN22, RARA, RNF31, SECTM1, SLAMF7, STXBP2, TAP1, TAP2, TAPBP, TNF, TNIP2, B2M, C1QA, C1QB, C1QC, C4BPA, C4BPB, DLG1, FCER2, HLA-DMA, LAG3, LTA, MBL2, NCR3, SLAMF7, TAP1, TAP2, TNF, B2M, C1QA, C1QB, C1QC, C4BPA, C4BPB, DLG1, FCER2, HLA-DMA, LAG3, LAT, LTA, MBL2, NCR3, SLAMF7, STXBP2, TAP1, TAP2, TNF, B2M, FCER2, HAMP, LAG3, MBL2, NCR3, SLAMF7, STXBP2, TAP1, TAP2, BHLHE23, CTSZ, DLG1, DLL1, DLX1, DLX2, EDARADD, EPHB4, FOXL2, GLI1, GNAS, HOXC11, HOXC13, HOXC4, HOXC8, HOXC9, HOXD10, HOXD11, HOXD13, HOXD3, HOXD4, HOXD8, HOXD9, MSX1, PHLDA2, PPP1R13L, PTCD2, RARA, RUNX3, SOX1, SOX8, TBX3, TEAD2, TGM1, TH, TNF, TWIST1, WNT2, ZIC1. |
[48] | RRMS and CTR | CD4+ T cells CD8+ T cells Whole blood | Illumina 450K array | CD4+T cells: DCX, RDH13, DNHD1, TEKT5, TXNL1, MAGI2, TTC30B, APC2, TMEM48, ANGPTL2, RALGPS1, USP29, C20orf151, DLL1 6, DACH2, INPP5A, LOC727677, SEMA5B, SUGT1L1, HOXB2, OR10J5, RBMS1, C20orf151, AEN. CD8+T cells: APC2, HOXA2, HRNBP3, HEXDC, NTRK3, DCX, TRIL, ARHGEF17, ESPNP, LHX5, TEKT5, LRRC43, CYP27C1, TMEM48, HHATL, AMMECR1, C19orf45, SRRM3, PSD3, PTPRN2, LOC654342, ARHGEF17, DNHD1, KIF1C, INCA1, VSIG1. Whole blood: DACH2, LAMA2, TTLL8, GALNT9, POU3F4, NLRP12, PLS3, ANKRD1, CLSTN2, MAGEB4, APC2, PCDHA7, TMEM27, DNHD1, LGI1, PTCHD2, MMD2, HHATL, TMEM48, NXPH1, TDRD9, CDX1, YTHDC2, RGPD1, PLGLB2. |
[49] | RRMS vs PPMS vs SPMS vs CTR | Buffy coat | BS-sequencing | SHP-1 |
[50] | MS vs CTR | Whole blood PBMCs NAWM | Illumina 450K array | IL2RA |
[51] | MS treatment-naïve vs 1 year IFN-b vs CTR | PMBCs | BS-PCR sequencing assay | LINE-1 |
[52] | Discordant twins (RRMS vs CTR) | CD4+ T cells | RRBS | TMEM1, PEX14. |
[53] | RRMS(e)vs RRMS(r) vs CTR | Serum | BS-PCR sequencing assay | MOG |
[54] | RRMS vs CTR | cfDNA (serum) | BS-PCR sequencing assay | LINE-1 |
[55] | RRMS vs CTR | CD3+ T cells | BS-PCR sequencing assay | VDR |
[56] | RRMS(e) vs RRMS(r) vs CTR | cfDNA (plasma) | MethDet-56 microarray based assay | RRMS(r) vs CTR: CDH1, CDKN2A, CDKN2B, FAS, ICAM1, MCJ, MDGI, MUC2, MYF3, PAX5, PGK1, RB1, SOCS1, SYK, TP73. RRMS(e) vs CTR:BRCA1, CCND2, DAPK, FAS, FHIT, MCT1, MDGI, MCJ, CDKN2A, TP73, PGK1, PR-PROX.RRMS(r) vs RRMS(e): CDH1, CDKN2B, HIC1, PR-PROX, SYK. |
[57] | RRMS(e) vs RRMS(r) vs CTR | Whole Blood | Methylation-Specific Multiple Ligation Probe Amplification PCR | CDKN2A, SOCS1, RUNX3, NEUROG1. |
[58] | Discordant twins (MS vs CTR) | PMBCs CD4+ T cells | Bisulphite Illumina Methylation 450k Beadchip | TMEM232, SEMA3C, YWHAGI, ZBTB16, MRI1. |
[59] | RRMS and SPMS vs CTR | PMBCs | BS-PCR sequencing assay | PAD2 |
[60] | RRMS and SPMS vs CTR | PMBCs | EpiTyper assay | DNMT1, TET2 |
[61] | RRMS vs SPMS vs CTR | CD4+ T cells | Illumina 450K array | VMP1, MIR21 |
BBB breakdown
Inflammation
Demyelination
Remyelination failure
Neurodegeneration
Environmental and lifestyle risk factors
Smoking
Epstein Barr virus
Vitamin D
Organic solvents and pesticides
Diet
Gut microbiota
Metabolite | Effect on DNA methylation |
---|---|
p-Cresol | |
Hydrogen sulphide (H2S) | Involved in the neutralisation of ROS. It increases DNA methylation [154]. |
Riboflavin (vitamin B2) Pyridoxine (vitamin B6) Cobalamin (vitamin B12) | |
Folate (vitamin B9) | |
It reduces the activity of DNA methyltransferase [157]. | |
Choline | It acts as a methyl donor that can be recruited by human gut microbiota, reducing its availability [158]. |
Involved in DNA methylation and gene expression in murine colitis model, an inflammatory disease [159]. | |
Betaine | |
Associated with changes in DNA methyltransferases and coupled with changes in DNA methylation [161]. | |
Ammonium (NH4) | Inverse correlation between faecal NH3 and LINE-1 gene methylation [162]. |
α-ketoglutarate | |
L-ascorbic acid (vitamin C) | It exerts a strong influence on active DNA demethylation. It enhances TET-mediated generation of 5-hydroxymethylation [165]. |