Epigenetics Alters Genes in Rheumatoid Arthritis
It's not just our DNA that makes us susceptible to disease and influences fetal growth
Scientists are beginning to realize more and more that important changes in genes can be unrelated to changes in the DNA sequence itself a field of study known as epigenetics but are just as influential.
A research team at the University of California, San Diego, found that epigenetic changes due to methylation play a key role in altering genes that could potentially contribute specifically to inflammation and joint damage, but also potentially influence cancer and fetal development.
Their study is currently published in the online edition of the Annals of the Rheumatic Diseases.
The researchers, led by Gary S. Firestein, professor in the Division of Rheumatology, Allergy and Immunology at UC San Diego School of Medicine investigated a mechanism - usually implicated in cancer and in fetal development - called DNA methylation, as contributing to the progression of rheumatoid arthritis (RA).
Firestein: "Genomics has rapidly advanced our understanding of susceptibility and severity of rheumatoid arthritis. While many genetic associations have been described in this disease, we also know that if one identical twin develops RA that the other twin only has a 12 to 15 percent chance of also getting the disease. This suggests that other factors are at play epigenetic influences."
DNA methylation is one example of epigenetic change.
A strand of DNA is modified after it is duplicated
through the addition of a methyl to any cytosine molecule
or (C) one of the 4 main bases of DNA.
This is one of the methods used to regulate gene expression, and is often abnormal in cancers and
plays a role in organ development.
While DNA methylation of individual genes has been explored in autoimmune diseases, this study represents a genome-wide evaluation of the process in fibroblast-like synoviocytes (FLS), cells that interact with the immune cells in rheumatoid arthritis (RA) and damages cartilage, bone, and soft tissues of the joint.
In this study, scientists isolated and evaluated genomic DNA from 28 cell lines. They looked at DNA methylation patterns in RA FLS and compared them with FLS derived from normal individuals or patients with non-inflammatory joint disease.
The data showed that the fibroblast-like synoviocytes (FLS)
cells in rhuematoid arthritis display a DNA methyl
signature distinguishing them from
osteoarthritis and normal FLS cells.
These FLS cells possess methylated genes critical to the extracellular matrix which regulates cell survival, cell proliferation, cell differentiation, and cell migration.
"We found that hypomethylation of individual genes was associated with increased gene expression and occurred in multiple pathways critical to inflammatory response." Gary S. Firestein, Division of Rheumatology, Allergy and Immunology, UC San Diego School of Medicine
This led to the researchers conclusion: Methylated genes can alter FLS genes and contribute to the pathology of rhuematoid arthritis.
Additional contributors include Kazuhisa Nakano and David L. Boyle, UCSD Department of Medicine; and John W. Whitaker and Wei Wang, UCSD Department of Chemistry and Biochemistry.
This project was supported by grant number UL1RR031980 from the National Institutes of Health's National Center for Advancing Translational Science.
NexDx, Inc. licensed the technology from UC San Diego and provided informatics support for this study. Gary S. Firestein and Wei Wang are on the Scientific Advisory Board of NexDx, Inc.
Original article: http://www.eurekalert.org/pub_releases/2012-07/uoc--eag070312.php