Howard Chang, MD, PhD
Stanford University School of Medicine
Howard Hughes Medical Institute
Dr. Chang: Scleroderma is a disease characterized by excess fibrosis of skin and other organs, and the immune system is involved in triggering and sustaining this fibrosis. My research is focused on how the genes involved in scleroderma are turned on or off. The control of these genes determines a cell’s behavior, such as how active an immune cell may be or whether a fibroblast becomes activated to produce excess extracellular matrix, leading to fibrosis. The gene control switches are like the command lines that run the cell’s software, and we are working out how gene control is altered in scleroderma in order to detect and treat the disease at the most fundamental level.
We have identified the gene switches that are different in scleroderma skin compared to normal skin. Because skin is a complex tissue composed of several types of cells, we have invested a lot of effort to understand which gene switches are changed in which cell types. We found that two cell types in skin have different gene switch activities in scleroderma patients in both fibrotic skin and even in skin that still appears normal. Other cell types only show changes in gene switch activities in the fibrotic skin. Because we can detect these different gene switch activities in “pre-fibrotic” skin, we believe these results may yield insights into the cell types that initiate scleroderma. Our next steps are to understand how the gene switches that are changed in scleroderma affect their target genes, for example, by making the genes turn on too long or in response to the wrong stimuli.
We recently published our new technique for determining the exact gene(s) that are controlled by a particular switch (Mumbach et al. Nature Genetics 2017). Since many of the variations in DNA that have been associated with autoimmune diseases occur in these gene switches, we believe this new technique will greatly add to our knowledge about these diseases. Additionally, this technique will enhance the value of large-scale genomic projects (such as the GRASP Project) by improving our ability to interpret the data those projects generate.
How this work will impact patients
Insights about the cells and the specific gene switches that cause disease manifestations open new avenues for scleroderma diagnosis and treatment. For example, we are testing whether we can learn about tissue fibrosis in different organs by analyzing gene switches in cells from the blood. If successful, such an approach would help patients monitor disease progression without invasive tissue biopsies. We are also asking whether insights about changes in gene switches in scleroderma can match patients to the therapies that target those genes. We hope this will make treatment strategies more rational and precise.