Systemic lupus erythematosus (SLE) is an autoimmune disease with known genetic, epigenetic, and environmental risk factors. To assess the role of DNA methylation in SLE, we collected CD4+ T-cells, CD19+ B-cells, and CD14+ monocytes from 49 SLE patients and 58 controls, and performed genome-wide DNA methylation analysis with Illumina Methylation450 microarrays. We identified 166 CpGs in B-cells, 97 CpGs in monocytes, and 1,033 CpGs in T-cells with highly significant changes in DNA methylation levels (p<1×10−8) among SLE patients. Common to all three cell-types were widespread and severe hypomethylation events near genes involved in interferon signaling (type I). These interferon-related changes were apparent in patients collected during active and quiescent stages of the disease, suggesting that epigenetically-mediated hypersensitivity to interferon persists beyond acute stages of the disease and is independent of circulating interferon levels. This interferon hypersensitivity was apparent in memory, naïve and regulatory T-cells, suggesting that this epigenetic state in lupus patients is established in progenitor cell populations. We also identified a widespread, but lower amplitude shift in methylation in CD4+ T-cells (>16,000 CpGs at FDR<1%) near genes involved in cell division and MAPK signaling. These cell type-specific effects are consistent with disease-specific changes in the composition of the CD4+ population and suggest that shifts in the proportion of CD4+ subtypes can be monitored at CpGs with subtype-specific DNA methylation patterns.
Vyšlo v časopise: Genome-Wide DNA Methylation Analysis of Systemic Lupus Erythematosus Reveals Persistent Hypomethylation of Interferon Genes and Compositional Changes to CD4+ T-cell Populations. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003678 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003678
1. HirakiLT, FeldmanCH, LiuJ, AlarcónGS, FischerMA, et al. (2012) Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US medicaid beneficiary population. Arthritis Rheum 64 : 2669–2676 doi:10.1002/art.34472
2. Alarcón-SegoviaD, Alarcón-RiquelmeME, CardielMH, CaeiroF, MassardoL, et al. (2005) Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 52 : 1138–1147 doi:10.1002/art.20999
3. DeapenD, EscalanteA, WeinribL, HorwitzD, BachmanB, et al. (1992) A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 35 : 311–318.
4. LawrenceJS, MartinsCL, DrakeGL (1987) A family survey of lupus erythematosus. 1. Heritability. J Rheumatol 14 : 913–921.
5. GatevaV, SandlingJK, HomG, TaylorKE, ChungSA, et al. (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41 : 1228–1233 doi:10.1038/ng.468
6. GrahamRR, HomG, OrtmannW, BehrensTW (2009) Review of recent genome-wide association scans in lupus. Journal of Internal Medicine 265 : 680–688 doi:10.1111/j.1365-2796.2009.02096.x
7. HanJW, ZhengHF, CuiY, SunLD, YeDQ, et al. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nature Genetics 41 : 1234–1237.
8. SawalhaAH, WebbR, HanS, KellyJA, KaufmanKM, et al. (2008) Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 3: e1727 doi:10.1371/journal.pone.0001727
9. YangW, ShenN, YeD-Q, LiuQ, ZhangY, et al. (2010) Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 6: e1000841 doi:10.1371/journal.pgen.1000841
10. ZhouX-JX, LuX-LX, NathSKS, LvJ-CJ, ZhuS-NS, et al. (2012) Gene-gene interaction of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in systemic lupus erythematosus. Arthritis Rheum 64 : 222–231 doi:10.1002/art.33318
11. RichardsonBB, ScheinbartLL, StrahlerJJ, GrossLL, HanashSS, et al. (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33 : 1665–1673 doi:10.1002/art.1780331109
12. QuddusJ, JohnsonKJ, GavalchinJ (1993) Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. Journal of Clinical Investigation 92 : 38–53.
13. CornacchiaE, GolbusJ, MaybaumJ, StrahlerJ, HanashS, et al. (1988) Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol 140 : 2197–2200.
14. JavierreBM, FernandezAF, RichterJ, Al-ShahrourF, Martin-SuberoJI, et al. (2010) Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res 20 : 170–179 doi:10.1101/gr.100289.109
15. JeffriesMA, DozmorovM, TangY, MerrillJT, WrenJD, et al. (2011) Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics 6 : 593–601.
16. LinS-Y, HsiehS-C, LinY-C, LeeC-N, TsaiM-H, et al. (2012) A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity. Genes Immun 13 : 214–220 doi:10.1038/gene.2011.74
17. BaechlerEC, BatliwallaFM, KarypisG, GaffneyPM, OrtmannWA, et al. (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA 100 : 2610–2615 doi:10.1073/pnas.0337679100
18. KirouKA, LeeC, GeorgeS, LoucaK, PapagiannisIG, et al. (2004) Coordinate overexpression of interferon-?-induced genes in systemic lupus erythematosus. Arthritis Rheum 50 : 3958–3967 doi:10.1002/art.20798
19. KirouKA, LeeC, GeorgeS, LoucaK, PetersonMGE, et al. (2005) Activation of the interferon-α pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 52 : 1491–1503 doi:10.1002/art.21031
20. DengCC, KaplanMJM, YangJJ, RayDD, ZhangZZ, et al. (2001) Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum 44 : 397–407 doi:;10.1002/1529-0131(200102)44 : 2<397::AID-ANR59>3.0.CO;2-N
21. Becker-MerokA, Ostli-EilerstenG, LesterS, NossentJ (2012) Circulating interferon-α2 levels are increased in the majority of patients with systemic lupus erythematosus and are associated with disease activity and multiple cytokine activation. Lupus 22 : 155–63 doi:10.1177/0961203312468964
22. NiewoldTB, HuaJ, LehmanTJA, HarleyJB, CrowMK (2007) High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun 8 : 492–502 doi:10.1038/sj.gene.6364408
23. HochbergMC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40 : 1725–1725 doi:;10.1002/1529-0131(199709)40 : 9<1725::AID-ART29>3.0.CO;2-Y
24. PetriMM, OrbaiA-MA, AlarcónGSG, GordonCC, MerrillJTJ, et al. (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64 : 2677–2686 doi:10.1002/art.34473
25. TanEME, CohenASA, FriesJFJ, MasiATA, McShaneDJD, et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25 : 1271–1277 doi:10.1002/art.1780251101
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
