美国加州大学洛杉矶分校Kathrin Plath团队发现，XIST直接调控初始人类多能细胞中的X连锁基因和常染色体基因。2024年1月4日出版的《细胞》杂志发表了这项成果。
研究人员表示，X染色体失活（XCI）是RNA介导的基因表达调控范例，其中长非编码RNA XIST顺式遍布X染色体，介导全染色体的基因沉默。在雌性初始人类多能干细胞（hPSC）中，XIST处于分散配置状态，XCI不会发生，这引发了对XIST功能的质疑。
研究人员发现，XIST在X染色体上扩散，并诱导抑制初始hPSC中X连锁基因的表达。令人惊讶的是，XIST还以特定的常染色体区域为目标，在这些区域诱导抑制性染色质变化和基因表达抑制。因此，XIST使雌雄细胞的X连锁基因剂量相等，同时诱导常染色体的差异。在小鼠造血干细胞的XCI启动过程中，Xist的分散配置和常染色体定位也会短暂出现。
总之，这项研究确定了XIST是X染色体抑制的调节因子，发现了XIST/Xist在演化过程中保守的反式作用，并揭示了XIST/Xist分散与常染色体靶向之间的相关性。
附：英文原文
Title: XIST directly regulates X-linked and autosomal genes in naive human pluripotent cells
Author: Iris Dror, Tsotne Chitiashvili, Shawn Y.X. Tan, Clara T. Cano, Anna Sahakyan, Yolanda Markaki, Constantinos Chronis, Amanda J. Collier, Weixian Deng, Guohao Liang, Yu Sun, Anna Afasizheva, Jarrett Miller, Wen Xiao, Douglas L. Black, Fangyuan Ding, Kathrin Plath
Issue&Volume: 2024/01/04
Abstract: X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome in cis to mediate gene silencing chromosome-wide. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration, and XCI does not occur, raising questions about XIST’s function. We found that XIST spreads across the X chromosome and induces dampening of X-linked gene expression in naive hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences in autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting.
DOI: 10.1016/j.cell.2023.11.033
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01319-3