Epigenetics of Sex Differences in Scleroderma

Howard W. Chang, MD, PhD
Stanford University

Project Summary:

The majority of patients with scleroderma are female, with women having an incidence four times that of men. Scleroderma in men, although rarer, can be a more aggressive form of the disease. Despite compelling epidemiological evidence of sex-related differences in the pathogenesis of the disease, there is very little consensus as to what is happening at the molecular level. We are investigating “X chromosome inactivation,” a female-specific cellular mechanism that silences one of the cell’s two X chromosomes. The body’s inefficient or incomplete silencing of the activity of one X chromosome in female cells (known as X chromosome inactivation escape), has been theorized to be involved in scleroderma and other autoimmune diseases. This project aims to build upon our finding of strong sex-related differences in gene regulation in T cells from scleroderma skin.

Research Update:

Using a technique we developed called ATAC-seq, we have demonstrated marked differences in gene regulation in immune cells from males and females. We have discovered that the inactive X chromosome has many proteins associated with it that are autoantigens in systemic autoimmune diseases and we are investigating this connection to scleroderma and other autoimmune disorders.

Dr. Chang on the SRF and Collaboration:

Scleroderma is a complex and uncommon disease, so it is especially important that we collaborate as teams with investigators across the country. The SRF plays a major role in organizing the entire community, supporting large-scale programs and genetic studies. The SRF has really catalyzed how all of these investigators can work together in the U.S. and across the world. With the SRF, there is a sense of collaboration and community. All of the investigators learn from and help each other to make the research go faster and bring solutions more quickly to patients.

Dr. Chang on the Rewards of Research:

The research we are doing is very rewarding– we can show a direct connection and potentially help patients. A few years ago, our team discovered a class of drugs that was not previously used to treat scleroderma. Because of our molecular studies, these were nominated and used in this disease. In some patients, it had a dramatic effect. This is one of those cases where we were really happy that our research provided some useful information.

Dr. Chang on the Future of Scleroderma Research:

I’m really optimistic about the prospects for scleroderma, because in the last five to 10 years there’s really been an increasing pace of understanding about the disease, its subtypes, and also some potential causes. I’m hopeful that maybe in a five-year time frame, many of these ideas will start moving into actual therapies.

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