Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X
Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X
复制标题
DOI：
10.1073/pnas.1520113113
复制
发表时间：
2016-04-05
影响因子：
11.1
通讯作者：
Anguera, Montserrat C.
中科院分区：
文献类型：
--
作者：
Wang, Jianle;Syrett, Camille M.;Anguera, Montserrat C.
女性比男性具有更大的免疫优势，但她们更容易患自身免疫性疾病。这种性别偏见的基础在于X染色体，其中含有许多与免疫相关的基因。雌性哺乳动物利用 X 染色体失活 (XCI) 生成转录沉默的失活 X 染色体 (Xi)，其中富含异染色质修饰和 XIST/Xist RNA，从而均衡两性之间的基因表达。在这里，我们检查了雌性小鼠和人类淋巴细胞中 XCI 的维持情况。引人注目的是，我们发现成熟的初始 T 和 B 细胞具有分散的 XIST/Xist RNA 模式，并且它们缺乏 Xi 的典型异染色质修饰。淋巴细胞的体外激活会触发 XIST/Xist RNA 转录本和一些染色质标记（H3K27me3、泛素-H2A）返回 Xi。雌性 T 细胞的单细胞 RNA FISH 分析显示，X 连锁免疫基因 CD40LG 和 CXCR3 在某些细胞中双等位表达。使用敲除和敲低方法，我们发现 Xist RNA 结合蛋白 YY1 和 hnRNPU 对于将 XIST/Xist RNA 招募回 Xi 至关重要。此外，我们检查了系统性红斑狼疮（一种具有强烈女性偏好的自身免疫性疾病）患者的 B 细胞，并观察到不同的 XIST RNA 定位模式、免疫相关基因双等位基因表达的证据以及这些基因转录的增加。我们提出，女性淋巴细胞中的 Xi 倾向于部分重新激活并过度表达免疫相关基因，这为我们关于女性免疫力增强及其自身免疫易感性增加的知识提供了第一个机制证据。
Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunity-related genes. Femalemammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naive T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.