Joint damage and synovial inflammation in rheumatoid arthritis (RA) are influenced by genetic and environmental factors. Epigenetics offers new ways to think about how environmental exposure and stress in inflamed tissues can alter gene expression and cellular function. One of the best-studied mechanisms is DNA methylation, which can profoundly alter cellular function by repressing gene expression. Methylation typically occurs on CpG loci and is mediated by DNA methyltransferases (DNMTs). Methylation status is influenced by the environment or through pre-programmed events during embryonic development. DNMT expression can maintain methylation during cell division, thus preserving the cellular imprinting from the environment in daughter cells. Abnormalities in methylation patterns have been described in a variety of diseases, most notably cancer where hyper- and hypo-methylated CpG loci can de-repress critical oncogenes. Autoimmunity has also been associated with altered methylation, such as lupus-like diseases in mice, RA synovium, and possibly RA synoviocytes. We recently showed that RA synoviocytes exhibit a distinct DNA methylation pattern that can regulate expression of key genes. In this proposal, we will expand the DNA methylation signature of RA and integrate this information with genomic and transcriptomic data to identify key genes that participate in the disease. Additional studies will be performed to determine how transcription factor motifs can shape disease specific methylation pattern even though there are a limited number of DNMT enzymes. This hypothesis will be explored by 1) refining the DNA methylation to create a high resolution map in RA fibroblast- like synoviocytes (FLS);2) integrating genomic, epigenomic, and transcriptomic data to create a unified approach to understanding RA FLS function;and 3) determine how transcription factor motifs contribute to the unique RA methylome signature.

Public Health Relevance

Epigenetics offers new ways to think about how environmental exposure and stress can alter gene expression and cellular function in rheumatoid arthritis (RA). Our preliminary data show that RA synoviocytes exhibit a distinct DNA methylation pattern that can regulate key genes. The studies are highly relevant to the goals of the NIH because they focus on understanding the pathogenesis of RA and identifying critical pathways that can be targeted with novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR065466-01A1
Application #
8760169
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mao, Su-Yau
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Firestein, Gary S (2018) PATHOGENESIS OF RHEUMATOID ARTHRITIS: THE INTERSECTION OF GENETICS AND EPIGENETICS. Trans Am Clin Climatol Assoc 129:171-182
Ai, Rizi; Laragione, Teresina; Hammaker, Deepa et al. (2018) Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nat Commun 9:1921
Hammaker, Deepa; Firestein, Gary S (2018) Epigenetics of inflammatory arthritis. Curr Opin Rheumatol 30:188-196
Doody, Karen M; Bottini, Nunzio; Firestein, Gary S (2017) Epigenetic alterations in rheumatoid arthritis fibroblast-like synoviocytes. Epigenomics 9:479-492
Rhead, Brooke; Holingue, Calliope; Cole, Michael et al. (2017) Rheumatoid Arthritis Naive T Cells Share Hypermethylation Sites With Synoviocytes. Arthritis Rheumatol 69:550-559
Matsuda, Shinji; Hammaker, Deepa; Topolewski, Katharyn et al. (2017) Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor LBH Gene. J Immunol 199:2316-2322
Firestein, Gary S; McInnes, Iain B (2017) Immunopathogenesis of Rheumatoid Arthritis. Immunity 46:183-196
Maeshima, Keisuke; Stanford, Stephanie M; Hammaker, Deepa et al. (2016) Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight 1:
Hammaker, Deepa; Whitaker, John W; Maeshima, Keisuke et al. (2016) LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis. Arthritis Rheumatol 68:2637-2645
Fan, Shicai; Li, Chengzhe; Ai, Rizi et al. (2016) Computationally expanding infinium HumanMethylation450 BeadChip array data to reveal distinct DNA methylation patterns of rheumatoid arthritis. Bioinformatics 32:1773-8

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