近日，德国欧洲分子生物学实验室Agnese Loda及其小组的最新研究揭示了Xist非编码RNA直接调控X失活逃逸。这一研究成果于2025年12月15日发表在国际顶尖学术期刊《自然—细胞生物学》上。

通过增加其内源性水平，课题组发现Xist RNA可以在体外、分化细胞以及体内、无主题植入前和植入后胚胎的早期胚胎发生中沉默逃逸者。课题组进一步证明，Xist RNA在消除跨越逃逸细胞的拓扑相关结构域样结构中发挥作用，这依赖于SPEN。Xist在逃逸体沉默和消除拓扑结构域中的功能最初是完全可逆的，但持续的Xist上调会导致逃逸体的不可逆沉默和CpG岛DNA甲基化。因此，基因活性和无活性X染色体的三维拓扑结构是由Xist直接控制的，远远超出了早期发育时间窗口。

据介绍，在胎盘XX雌性中，一条X染色体在一个狭窄的发育时间窗口中被X染色体失活而沉默，这是由Xist非编码RNA介导的。虽然大多数X连锁基因在X染色体失活过程中沉默，但一些基因可以逃脱。

附：英文原文

Title: Escape from X inactivation is directly modulated by Xist noncoding RNA

Author: Hauth, Antonia, Panten, Jasper, Kneuss, Emma, Picard, Christel, Servant, Nicolas, Rall, Isabell, Prez-Rico, Yuvia A., Clerquin, Lena, Servaas, Nila, Villacorta, Laura, Jung, Ferris, Luong, Christy, Chang, Howard Y., Zaugg, Judith B., Stegle, Oliver, Odom, Duncan T., Heard, Edith, Loda, Agnese

Issue&Volume: 2025-12-15

Abstract: In placental XX females, one X chromosome is silenced during a narrow developmental time window by X-chromosome inactivation, which is mediated by Xist noncoding RNA. Although most X-linked genes are silenced during X-chromosome inactivation, some genes can escape. Here, by increasing its endogenous level, we show that Xist RNA can silence escapees well beyond early embryogenesis both in vitro, in differentiated cells, as well as in vivo, in mouse pre- and post-implantation embryos. We further demonstrate that Xist RNA plays a role in eliminating topologically associating domain-like structures spanning clusters of escapees, and this is dependent on SPEN. The function of Xist in silencing escapees and eliminating topological domains is initially fully reversible, but sustained Xist upregulation leads to irreversible silencing and CpG island DNA methylation of escapees. Thus, gene activity and three-dimensional topology of the inactive X chromosome are directly controlled by Xist, well beyond an early developmental time window.

DOI: 10.1038/s41556-025-01823-6

Source: https://www.nature.com/articles/s41556-025-01823-6