Epigenetics of Sex Differences in Scleroderma


Howard Chang, MD, PhD

Stanford University School of Medicine
Howard Hughes Medical Institute

Project Overview

Dr. Chang: 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. We are testing whether a male animal engineered to have a chromosome resembling the inactive X will experience female-level risk of autoimmunity.

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