Constance J Ulff-Møller1, Fazila Asmar2, Yi Liu3, Anders J Svendsen4, Florence Busato3, Kirsten Grønbaek5, Jörg Tost3, Søren Jacobsen5. 1. Rigshospitalet and University of Copenhagen, Copenhagen, Denmark, and Commissariat à l'énergie atomique et aux énergies alternatives, Institut de Biologie Francois Jacob, Evry, France. 2. Rigshospitalet, Copenhagen, Denmark. 3. Commissariat à l'énergie atomique et aux énergies alternatives, Institut de Biologie Francois Jacob, Evry, France. 4. University of Southern Denmark, Odense, Denmark. 5. Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
Abstract
OBJECTIVE: Systemic lupus erythematosus (SLE) has limited monozygotic twin concordance, implying a role for pathogenic factors other than genetic variation, such as epigenetic changes. Using the disease-discordant twin model, we investigated genome-wide DNA methylation changes in sorted CD4+ T cells, monocytes, granulocytes, and B cells in twin pairs with at least 1 SLE-affected twin. METHODS: Peripheral blood obtained from 15 SLE-affected twin pairs (6 monozygotic and 9 dizygotic) was processed using density-gradient centrifugation for the granulocyte fraction. CD4+ T cells, monocytes, and B cells were further isolated using magnetic beads. Genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChips. When comparing probes from SLE-affected twins and co-twins, differential DNA methylation was considered statistically significant when the P value was less than 0.01 and biologically relevant when the median DNA methylation difference was >7%. Findings were validated by pyrosequencing and replicated in an independent case-control sample. RESULTS: In paired analyses of twins discordant for SLE restricted to the gene promoter and start region, we identified 55, 327, 247, and 1,628 genes with differentially methylated CpGs in CD4+ T cells, monocytes, granulocytes, and B cells, respectively. All cell types displayed marked hypomethylation in interferon-regulated genes, such as IFI44L, PARP9, and IFITM1, which was more pronounced in twins who experienced a disease flare within the past 2 years. In contrast to what was observed in the other cell types, differentially methylated CpGs in B cells were predominantly hypermethylated, and the most important upstream regulators included TNF and EP300. CONCLUSION: Hypomethylation of interferon-regulated genes occurs in all major cellular compartments in SLE-affected twins. The observed B cell promoter hypermethylation is a novel finding with potential significance in SLE pathogenesis.
OBJECTIVE: Systemic lupus erythematosus (SLE) has limited monozygotic twin concordance, implying a role for pathogenic factors other than genetic variation, such as epigenetic changes. Using the disease-discordant twin model, we investigated genome-wide DNA methylation changes in sorted CD4+ T cells, monocytes, granulocytes, and B cells in twin pairs with at least 1 SLE-affected twin. METHODS: Peripheral blood obtained from 15 SLE-affected twin pairs (6 monozygotic and 9 dizygotic) was processed using density-gradient centrifugation for the granulocyte fraction. CD4+ T cells, monocytes, and B cells were further isolated using magnetic beads. Genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChips. When comparing probes from SLE-affected twins and co-twins, differential DNA methylation was considered statistically significant when the P value was less than 0.01 and biologically relevant when the median DNA methylation difference was >7%. Findings were validated by pyrosequencing and replicated in an independent case-control sample. RESULTS: In paired analyses of twins discordant for SLE restricted to the gene promoter and start region, we identified 55, 327, 247, and 1,628 genes with differentially methylated CpGs in CD4+ T cells, monocytes, granulocytes, and B cells, respectively. All cell types displayed marked hypomethylation in interferon-regulated genes, such as IFI44L, PARP9, and IFITM1, which was more pronounced in twins who experienced a disease flare within the past 2 years. In contrast to what was observed in the other cell types, differentially methylated CpGs in B cells were predominantly hypermethylated, and the most important upstream regulators included TNF and EP300. CONCLUSION: Hypomethylation of interferon-regulated genes occurs in all major cellular compartments in SLE-affected twins. The observed B cell promoter hypermethylation is a novel finding with potential significance in SLE pathogenesis.
Authors: Kit San Yeung; Tsz Leung Lee; Mo Yin Mok; Christopher Chun Yu Mak; Wanling Yang; Patrick Chun Yin Chong; Pamela Pui Wah Lee; Marco Hok Kung Ho; Sanaa Choufani; Chak Sing Lau; Yu Lung Lau; Rosanna Weksberg; Brian Hon Yin Chung Journal: Epigenetics Date: 2019-03-16 Impact factor: 4.528
Authors: Shaylynn Miller; Pei-Suen Tsou; Patrick Coit; Elizabeth Gensterblum-Miller; Paul Renauer; Dallas M Rohraff; Nathan C Kilian; Mark Schonfeld; Amr H Sawalha Journal: Ann Rheum Dis Date: 2019-01-23 Impact factor: 19.103
Authors: Kevin S Cashman; Scott A Jenks; Matthew C Woodruff; Deepak Tomar; Christopher M Tipton; Christopher D Scharer; F Eun-Hyung Lee; Jeremy M Boss; Iñaki Sanz Journal: Immunol Rev Date: 2019-11-22 Impact factor: 12.988