X-linked genes exhibit miR6891-5p-regulated skewing in Sj ögren’s syndrome

AbstractMany autoimmune diseases exhibit a strikingly increased prevalence in females, with primary Sj ögren’s syndrome (pSS) being the most female-predominant example. However, the molecular basis underlying the female-bias in pSS remains elusive. To address this knowledge gap, we performed genome-wide, allele-specific profiling of minor salivary gland-derived mesenchymal stromal cells (MSCs) fro m pSS patients and control subjects, and detected major differences in the regulation of X-linked genes. In control female MSCs, X-linked genes were expressed from both paternal and maternal X chromosomes with a median paternal ratio of ~ 0.5. However, in pSS female MSCs, X-linked genes exhibite d preferential expression from one of the two X chromosomes. Concomitantly, pSS MSCs showed decrease inXIST levels and reorganization of H3K27me3+ foci in the nucleus. Moreover, theHLA-locus-expressed miRNAmiR6891-5p was decreased in pSS MSCs.miR6891-5p inhibition in control MSCs causedXIST dysregulation, ectopic silencing, and allelic skewing. Allelic skewing was accompanied by the mislocation of protein products encoded by the skewed genes, which was recapitulated byXIST andmiR6891-5p disruption in control MSCs. Our data reveal X skewing as a molecular hallmark of pSS and highlight the importance of restoring X-chromosomal allelic balance for pSS treatment.Key messagesX-linked genes exhibit skewing in primary Sj ögren’s syndrome (pSS).X skewing in pSS associates with alterations ...
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research