Research Report 2019_20

Devin Absher, PhD / Absher Lab

The role of epigenetics in lupus frequency and severity

Because females carry two X chromosomes com- pared to men who carry one, mammals evolved X chro- mosome inactivation to randomly silence genes on one of the X chromosomes in females. This allows for equal expression of X-linked genes across sexes. X chromo- some inactivation is largely mediated by the non-coding RNA molecule XIST, which recruits multiple proteins to the inactivated X chromosome to initiate and maintain gene silencing. By using RNA sequencing technology, the team compared expression patterns of X-linked alleles in immune cells from female lupus patients and healthy subjects. They found that SLE patients had bias in expression of X-linked genes in T and B cells, which may indicate a problem with X-inactivation. Offering a potential mechanism for the biased ex- pression of X-linked genes, they also observed that XIST was upregulated in the immune cells of patients with SLE. While additional studies are still needed to prove aberrant X chromosome inactivation, these findings present promising results that may help explain the female predisposition to autoimmune diseases like SLE.

Autoimmune diseases are a complex and mys- terious set of diseases. They present a particu- lar challenge to researchers seeking to define the cause and explain the progression of the diseases. While the study of the human genome, especially genome-wide association studies, has been essential in contributing to the current understanding of autoim- mune diseases, translating that knowledge into mech- anistic insight and disease treatments still remains a challenge. Epigenetics has emerged as an important additional layer of instructions that control how DNA is interpret- ed. Several studies have implicated epigenetic influenc- es in the development of autoimmunity, although there is still much to be elucidated. HudsonAlpha Faculty Investigator Devin Absher, PhD, is a leader in the field of epigenetics. Absher’s work focuses on how changes in the epigenome influ- ence human disease. His lab has previously studied cardiovascular disease and the dietary and metabolic risk factors for heart disease, cancer epigenetics, and the effects of aging on the epigenome. Currently, Absh- er is focused on understanding the role of epigenetics in autoimmune disease, specifically systemic lupus erythematosus (SLE). SLE is a complex autoimmune disease that is char- acterized by a dysregulated immune system, leading to widespread, chronic inflammation and tissue damage. It commonly affects the joints, skin, brain, lungs, kidneys, and blood vessels. Because the underlying mechanisms driving the disease are poorly understood, there is no cure and treatments focus simply on alleviat- ing symptoms of the disease. Like many other autoimmune diseases, SLE dispro- portionately affects women more than men. Although it affects women nearly 10 times more frequently than men, the molecular basis for the sex disparity is widely unknown. In a recent study published in Human Molecular Genetics , Absher and his team present strong evidence that X chromosome inactivation could be involved in the disparity 1 .

Kevin Roberts, PhD preparing systems that help study SLE


HudsonAlpha Institute for Biotechnology

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