Systemic lupus erythematosus is a chronic relapsing autoimmune disease that involves multiple organ systems. The etiology and pathogenesis of lupus are incompletely understood. There is a strong evidence for genetic contribution to the pathogenesis of lupus, however, despite the enormous progress in mapping lupus susceptibility genes, only a small fraction of lupus heritability is accounted for by the genetic associations discovered. A large body of literature supports the contention that epigenetic dysregulation, particularly T cell DNA methylation defect, contributes to the pathogenesis of lupus. Indeed, demethylated T cells are sufficient to cause lupus in animal models. We believe that epigenetic differences between lupus patients and controls contribute towards the missing heritability of the disease. We propose to determine and functionally characterize differentially methylated genetic loci in specific T cell subsets in lupus patients compared to normal controls, using a genome-wide approach, the feasibility of which has been confirmed in our own preliminary experiments. We will further Identify and validate DNA methylation changes over time in relation to disease activity in lupus patients. We hypothesize that genetic variants associated with lupus will alter DNA methylation in known lupus susceptibility loci in an allele-specific manner. Therefore, we will determine allele specific DNA methylation changes in validated genetic susceptibility loci for lupus. We previously reported the genetic association between SNPs within MECP2 and lupus. MECP2 (methyl-CpG-binding protein 2) is a key transcriptional regulator for methylation sensitive genes, and is also known to recruit the DNA methylation enzyme DNMT1 during DNA synthesis. We will resequence the MECP2/IRAK1 LD block using next generation sequencing to identify the causal variants in this locus.

Public Health Relevance

Lupus is a chronic systemic autoimmune disease that causes significant morbidity and mortality in those affected. Therapies still rely largely on relatively nonspecific approaches that have potentially serious side effects. There is evidence for genetic and epigenetic contribution to the pathogenesis of lupus. Our studies will identify and functionally characterize the DNA methylation differences in specific CD4+ T cell subsets between lupus patients and controls, and will determine DNA methylation changes over time in relation to disease activity in lupus patients. We will also study genetic-epigenetic interaction i lupus through allele-specific methylation studies and through the identification of the causal variant(s) in MECP2, a gene that regulates the expression of methylation sensitive genes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-T (02))
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Johnson, David R
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Gensterblum, Elizabeth; Renauer, Paul; Coit, Patrick et al. (2018) CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients. J Autoimmun 86:19-28
Tsou, Pei-Suen; Coit, Patrick; Kilian, Nathan C et al. (2018) EZH2 Modulates the DNA Methylome and Controls T Cell Adhesion Through Junctional Adhesion Molecule A in Lupus Patients. Arthritis Rheumatol 70:98-108
Weeding, Emma; Coit, Patrick; Yalavarthi, Srilakshmi et al. (2018) Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. Clin Immunol 196:110-116
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Dozmorov, Mikhail G; Coit, Patrick; Maksimowicz-McKinnon, Kathleen et al. (2017) Age-associated DNA methylation changes in naive CD4+ T cells suggest an evolving autoimmune epigenotype in aging T cells. Epigenomics 9:429-445
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Knight, Jason S; Meng, He; Coit, Patrick et al. (2017) Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target. JCI Insight 2:
Tsou, Pei-Suen; Sawalha, Amr H (2017) Unfolding the pathogenesis of scleroderma through genomics and epigenomics. J Autoimmun 83:73-94
Zhao, Ming; Zhou, Yin; Zhu, Bochen et al. (2016) IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus. Ann Rheum Dis 75:1998-2006
Tsou, Pei-Suen; Wren, Jonathan D; Amin, M Asif et al. (2016) Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors. Arthritis Rheumatol 68:2975-2985

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