The XIST gene is known for its essential roles in turning off one X chromosome in female cells and was long thought to be expressed only in female tissues under healthy conditions.

In a study published online on December 12 in Genome Research, Deyou Zheng, Ph.D., and his MSTP student, Kevin O’Leary, and colleagues challenge that long-held belief. After analyzing large single-cell and bulk gene-expression datasets across human bodies, they discovered that a shorter form of XIST is also active in male Schwann cells, which support peripheral nerves and help them function and regenerate. The researchers discovered that the XIST gene in both male and female Schwann cells is turned on in an unusual way, using a different starting point in the DNA to make a shorter XIST RNA molecule called sXIST. They found no evidence that sXIST turns off X-linked genes in male Schwann cells. Instead, their work suggests that sXIST may influence peripheral nerve function by acting as a “sponge” for microRNAs—small molecules that normally act to suppress other genes. Schwann cells’ sXIST activity was closely associated with genes linked to nerve signaling, cilia function, and axon organization. Its abundance was also found to change in diseases such as cardiomyopathy and peripheral neuropathy, suggesting that sXIST may play a role in nerve-related disease processes beyond X-chromosome inactivation.

Dr. Zheng is professor of bioinformatics, of genetics, in the Saul R. Korey Department of Neurology, and in the Dominick P. Purpura Department of Neuroscience at Einstein. He is also a member of the Data Science Institute at Einstein and the Marilyn and Stanley M. Katz Institute for Immunotherapy for Cancer and Inflammatory Disorders at the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center.