Atypical Xist RNA Localization to the Inactive X in a Female-biased Murine Model of Systemic Lupus Erythematosus

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Abstract Systemic lupus erythematosus (SLE) is a severe autoimmune disease that affects women nine times more than men. The genetic basis for this bias is the X-chromosome, where the greatest concentration of immunity related genes on any chromosome can be found. Females have two X chromosomes (XX), and through a process, known as X-chromosome inactivation (XCI), silence one of their X-chromosomes randomly to have a similar level of X-linked gene expression as males (XY). In XCI, XIST RNA, a long non-coding RNA, is expressed from the future inactive X (Xi) and is bound to it in cis by the transcription factor YY1. As XIST coats the Xi, it recruits heterochromatin modifiers to condense and silence it. Previous research has shown that human SLE patient B cells exhibit altered localization of XIST RNA, thus indicating that they have partial reactivation of the Xi. To explore this relationship, we worked with NZB/W F1mice, which are a well-characterized murine model of SLE that also displays a female bias. The hypothesis of our study is that due to reduced expression of YY1, NZB/W F1 mice have altered Xist RNA localization leading to increased expression of X-linked genes in splenic B cells. Preliminary results using qPCR indicate that the concentration of YY1 is reduced across all stages of disease in NZB/W F1 when compared to age-matched wild type (WT) mice. Using Xist RNA FISH, we have observed that the activated B cells of late stage disease NZB/W F1 mice have decreased localization of Xist RNA to the Xi when compared to WT. In addition, we observed that the expression of TLR7 and CXCR3, two x-linked genes, are increased in diseased NZB/W F1 when compared to age-matched WT.