X-linked genes exhibit miR6891-5p-regulated skewing in Sjögren's syndrome.

Autor: Shaw TM; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI, 53706, USA., Zhang W; Department of Medicine, University of California, San Diego, CA, USA.; Present address: Bristol Myers Squibb, New York, NY, USA., McCoy SS; Division of Rheumatology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA., Pagenkopf A; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI, 53706, USA., Carp DM; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI, 53706, USA., Garg S; Division of Rheumatology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA., Parker MH; Division of Rheumatology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA., Qiu X; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI, 53706, USA., Scofield RH; Department of Pathology and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Galipeau J; Department of Medicine, Carbone Comprehensive Cancer Center, University of Wisconsin, WI, Madison, USA., Liang Y; Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI, 53706, USA. liang95@wisc.edu.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2022 Sep; Vol. 100 (9), pp. 1253-1265. Date of Electronic Publication: 2022 May 10.
DOI: 10.1007/s00109-022-02205-3
Abstrakt: Many autoimmune diseases exhibit a strikingly increased prevalence in females, with primary Sjögren'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) from 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 exhibited preferential expression from one of the two X chromosomes. Concomitantly, pSS MSCs showed decrease in XIST levels and reorganization of H3K27me3 + foci in the nucleus. Moreover, the HLA-locus-expressed miRNA miR6891-5p was decreased in pSS MSCs. miR6891-5p inhibition in control MSCs caused XIST dysregulation, ectopic silencing, and allelic skewing. Allelic skewing was accompanied by the mislocation of protein products encoded by the skewed genes, which was recapitulated by XIST and miR6891-5p 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 MESSAGES: X-linked genes exhibit skewing in primary Sjögren's syndrome (pSS). X skewing in pSS associates with alterations in H3K27me3 deposition. pSS MSCs show decreased levels of miR6891-5p, a HLA-expressed miRNA. miR6891-5p inhibition causes H3K27me3 dysregulation and allelic skewing.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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