Altered gene regulation underlies many facets of autoimmunity and its treatments. Pathogenic autoantibodies and immune complexes ultimately exert their effects through cellular signal transduction to impact gene expression. The central roles of specific transcription factors in driving immune cell fates, and anti-inflammatory and immunosuppressive drugs that control gene expression - such as steroids, cyclosporine A (CsA), and inhibitors of JAKs, lnterieukin-1 (IL-1), Tumor Necrosis Factor (TNF), and B Cell Activating Factor (BAFF) - suggest the importance of understanding gene regulation in autoimmunity. Rather than simply observing changes in gene expression, recent epigenomic tools have made it possible to determine the causality of gene expression, revealing the specific transcription factors and regulatory elements driving different gene expression programs. However, existing experimental methods require 10 million cells or more per assay, and are complex and laborious to perform. These limitations have largely kept epigenomic analyses out of the reach of the clinical studies of human diseases, including autoimmunity. Here we propose to develop and apply a revolutionary new method called ATAC-Seq to map open chromatin sites genome-wide, to enable facile and rapid epigenomic studies of patients with autoimmune diseases and their response to treatments in real time. We will also explore the role of epigenetics in known genotypes of SLE patients with single nucleotide polymorphisms in genes such as Tyk2, STAT4, and IRF5. The end result will be a set of robust biomarkers and important biological insights into autoimmune and inflammatory diseases. The long term goal of our studies is to include ATAC-Seq in the ACE Shared Research Agenda, where it can be used by ACE investigators as part of their basic science projects, and as a mechanistic assay in ACE clinical trials.

Public Health Relevance

Autoimmune diseases are associated with altered activities of cells of the immune system, which are driven by changes in the sets of genes that become active in immune cells. Understanding which genes are active and why will allow much more precise tracking and treatment of autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-PA-I (J1))
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Stanford University
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Tan, Yann-Chong; Kongpachith, Sarah; Blum, Lisa K et al. (2014) Barcode-enabled sequencing of plasmablast antibody repertoires in rheumatoid arthritis. Arthritis Rheumatol 66:2706-15