Department of Medical Microbiology & Immunology, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Department of Medicine, University of California, San Diego, CA, USA.
J Mol Med (Berl). 2022 Sep;100(9):1253-1265. doi: 10.1007/s00109-022-02205-3. Epub 2022 May 10.
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.
许多自身免疫性疾病在女性中表现出明显更高的患病率，原发性干燥综合征（pSS）是最女性为主的例子。然而，pSS 中女性偏倚的分子基础仍然难以捉摸。为了解决这一知识空白，我们对 pSS 患者和对照者的小唾液腺衍生间充质基质细胞（MSCs）进行了全基因组、等位基因特异性分析，并检测到 X 连锁基因调控的主要差异。在对照女性 MSC 中，X 连锁基因从父系和母系 X 染色体表达，中位数父系比约为 0.5。然而，在 pSS 女性 MSC 中，X 连锁基因表现出从两个 X 染色体中的一个优先表达。同时，pSS MSC 表现出 XIST 水平降低和核内 H3K27me3 焦点的重排。此外，HLA 基因座表达的 miRNA miR6891-5p 在 pSS MSC 中减少。在对照 MSC 中抑制 miR6891-5p 导致 XIST 失调、异位沉默和等位基因倾斜。等位基因倾斜伴随着由倾斜基因编码的蛋白质产物的错位，这在对照 MSC 中通过 XIST 和 miR6891-5p 的破坏得到重现。我们的数据揭示了 X 倾斜作为 pSS 的分子标志，并强调了恢复 X 染色体等位基因平衡对 pSS 治疗的重要性。
X 连锁基因在原发性干燥综合征（pSS）中表现出倾斜。pSS 中的 X 倾斜与 H3K27me3 沉积的改变有关。pSS MSC 显示 HLA 表达的 miRNA miR6891-5p 水平降低。miR6891-5p 抑制导致 H3K27me3 失调和等位基因倾斜。
