The mechanisms underlying the female-bias in autoimmunity are poorly understood. The contribution of genetic and epigenetic factors from the inactive X chromosome (Xi) are beginning to emerge as critical mediators of autoimmunity in females. Here, we ask how epigenetic features of the Xi change during disease development in B cells from the NZB/W F1 spontaneous mouse model of lupus, which is female-biased. We find that Xist RNA becomes increasingly mislocalized from the Xi with disease onset. While NZB/W F1 naïve B cells have H3K27me3 foci on the Xi, which are missing from healthy C57BL/6 and BALB/c mice, these foci are progressively lost in stimulated B cells during disease. Using single-molecule RNA FISH, we show that the X-linked gene Tlr7 is biallelically expressed in ~20% of NZB/W F1 B cells, and that the amount of biallelic expression does not change with disease. We also present sex-specific gene expression profiles for diseased NZB/W F1 B cells, and find female-specific upregulation of 20 genes, including the autoimmunity-related genes Cxcl13, Msr1, Igj, and Prdm1. Together, these studies provide important insight into the loss of epigenetic modifications from the Xi and changes with gene expression in a mouse model of female-biased SLE.

中文翻译：

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患有狼疮样疾病的NZB / W F1小鼠的B细胞中无活性X染色体上表观遗传修饰的缺失和性别偏向的基因表达谱。

对自身免疫中女性偏见的潜在机制了解甚少。来自非活动X染色体（Xi）的遗传和表观遗传因素的贡献开始成为女性自身免疫的重要介质。在这里，我们从女性偏见的NZB / W F1狼疮自发小鼠模型中，询问Xi的表观遗传特征在疾病发展过程中如何在B细胞中发生变化。我们发现Xist RNA从疾病发作的Xi中越来越多地错位。尽管NZB / W F1幼稚B细胞在Xi上具有H3K27me3病灶，但从健康的C57BL / 6和BALB / c小鼠中缺失了这些病灶，但这些病灶在疾病过程中逐渐在受激B细胞中丢失。使用单分子RNA FISH，我们显示X连锁基因Tlr7在〜20％的NZB / W F1 B细胞中双等位表达，并且双等位基因表达的量不会随疾病而改变。我们还提出了患病的NZB / W F1 B细胞的性别特异性基因表达谱，并发现了20种基因的女性特异性上调，包括自身免疫相关基因Cxcl13，Msr1，Igj和Prdm1。在一起，这些研究提供了从习性丧失的表皮遗传修饰的损失以及在女性偏向性SLE小鼠模型中基因表达变化的重要见解。