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The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients [Genetics]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2024624118
Sarah Pyfrom, Bam Paneru, James J. Knox, Michael P. Cancro, Sylvia Posso, Jane H. Buckner, Montserrat C. Anguera

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA fluorescence in situ hybridization and immunofluorescence to profile epigenetic features of the Xi at the single-cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk-cell RNA sequencing datasets, we found that X-linked immunity genes escape XCI in specific healthy human B cell subsets and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female bias in SLE.



中文翻译:

狼疮患者中健康人 B 细胞中失活 X 染色体的动态表观遗传调控失调 [遗传学]

系统性红斑狼疮 (SLE) 是一种以女性为主的疾病,其特征是自身免疫性 B 细胞和致病性自身抗体的产生。具有两条或更多 X 染色体的个体患 SLE 的风险增加,这表明 X 连锁基因导致了观察到的这种疾病的性别偏见。为了使性别之间的 X 连锁基因表达正常化,女性细胞中的一个 X 被随机选择用于通过 X 染色体失活 (XCI) 进行转录沉默,从而导致表观遗传修饰的等位基因特异性富集,包括组蛋白甲基化和长链非编码 RNA XIST/ Xist 位于不活动的 X (Xi) 上。正如我们之前所表明的,小鼠雌性淋巴细胞中 Xi 的表观遗传调控出乎意料地是动态的,我们使用 RNA 荧光原位杂交和免疫荧光在来自儿童和成人 SLE 患者和健康对照的人类 B 细胞亚群的单细胞水平上分析 Xi 的表观遗传特征。我们的数据显示 B 细胞中异常的 XCI 维持是 SLE 的一个特征。使用单细胞和大细胞 RNA 测序数据集,我们发现 X 连锁免疫基因在特定的健康人类 B 细胞亚群中逃避 XCI,并且人类 SLE B 细胞表现出 X 连锁基因和 XIST RNA 相互作用基因的异常表达。我们的数据显示,错误定位的 XIST RNA,加上 SLE 中 Xi 处异染色质修饰的显着减少,容易导致 Xi 的异常 X 连锁基因表达,

更新日期:2021-06-09
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