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)
Type
Research Project (R01)
Project #
1R01AR065466-01A1
Application #
8760169
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
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