Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Structural and Chemical Biology & Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK.
Cell. 2024 Jan 4;187(1):110-129.e31. doi: 10.1016/j.cell.2023.11.033.
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.
X 染色体失活 (XCI) 是 RNA 介导的基因表达调控的典范，其中长非编码 RNA XIST 在顺式中跨越 X 染色体扩散，介导全染色体范围的基因沉默。在女性原始人多能干细胞 (hPSC) 中，XIST 呈弥散状态，XCI 不会发生，这引发了对 XIST 功能的质疑。我们发现 XIST 会跨越 X 染色体并诱导原始 hPSC 中 X 连锁基因表达的抑制。令人惊讶的是，XIST 还靶向特定的常染色体区域，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 在雄性和雌性细胞之间平衡 X 连锁基因剂量，同时诱导常染色体的差异。在小鼠 PSC 中 XCI 起始期间，分散的 Xist 构型和常染色体定位也会短暂出现。总之，我们的研究确定了 XIST 是 X 染色体抑制的调节因子，揭示了 XIST/Xist 的进化保守的反式作用，以及 XIST/Xist 弥散与常染色体靶向之间的相关性。
