Elucidating the Role of Dynamic X Inactivation Maintenance in the Pathogenesis of SSc

Nikhil Jiwrajka, MD

University of Pennsylvania

About Dr. Jiwrajka

Like several other autoimmune rheumatic diseases, scleroderma affects more females than males. The basis of this female bias is not entirely clear. Clarifying the origin of this female bias may help identify new factors that promote the initiation and progression of scleroderma.

Biological females (XX) possess two X chromosomes and males (XY) possess one X; researchers therefore hypothesize that a dosage imbalance of the X chromosome may underly this female bias. In order to ensure that the overall dosage-or amount of gene expression- coming from the X chromosome is balanced between XX and XY individuals, cells from females (XX individuals) undergo a random “inactivation” of one of the two X chromosomes.

This inactivation is achieved through the production of an RNA molecule called XIST which, through its associated proteins, covers one of the two X chromosomes and inactivates it. This process of inactivation, once initiated, is thereafter maintained in part by the continuous association of XIST with the inactive X chromosome.

Dr. Anguera’s group has discovered that T cells, a type of immune cell that play an important role in the development of scleroderma, exhibit an unusual dynamic mechanism of maintaining silencing of the inactive X chromosome. In resting T cells, XIST is surprisingly not present at the inactive X chromosome, but it subsequently reappears at the inactive X chromosome once these cells become activated and shuts down most gene expression from that chromosome.

Impairment of this maintenance process could permit gene expression from the inactive X chromosome in females. Because many X-linked genes integral to T-cell function and fibrosis are overexpressed in T cells from SSc tissues, Dr. Jiwrajka is investigating whether dynamic X-inactivation is impaired in T cells from patients with SSc, and whether this contributes to the female bias of disease via an abnormal amount of X-linked gene expression.

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