Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Obstetrics and Gynecology, Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2024 Nov 26;43(11):114887. doi: 10.1016/j.celrep.2024.114887. Epub 2024 Oct 24.
The seamless transition through stages of pluripotency relies on a balance between transcription factor networks and epigenetic mechanisms. Here, we reveal the crucial role of the transgene activation suppressor (TASOR), a component of the human silencing hub (HUSH) complex, in maintaining cell viability during the transition from naive to primed pluripotency. TASOR loss in naive pluripotent stem cells (PSCs) triggers replication stress, disrupts H3K9me3 heterochromatin, and impairs silencing of LINE-1 (L1) transposable elements, with more severe effects in primed PSCs. Notably, the survival of Tasor knockout PSCs during this transition can be restored by inhibiting caspase or deleting the mitochondrial antiviral signaling protein (MAVS). This suggests that unscheduled L1 expression activates an innate immune response, leading to cell death specifically in cells exiting naive pluripotency. Our findings highlight the importance of epigenetic programs established in naive pluripotency for normal development.
多能性阶段的无缝过渡依赖于转录因子网络和表观遗传机制之间的平衡。在这里，我们揭示了转基因激活抑制因子（TASOR）在维持从原始多能性向初始多能性过渡期间细胞活力方面的关键作用，TASOR 是人类沉默中心（HUSH）复合物的一个组成部分。在原始多能干细胞（PSCs）中缺失 TASOR 会引发复制应激，破坏 H3K9me3 异染色质，并损害 LINE-1（L1）转座元件的沉默，在初始 PSCs 中则更为严重。值得注意的是，在这个过渡过程中，Tasor 敲除 PSCs 的存活可以通过抑制半胱天冬酶或删除线粒体抗病毒信号蛋白（MAVS）来恢复。这表明非计划性的 L1 表达激活了先天免疫反应，导致仅在退出原始多能性的细胞中发生细胞死亡。我们的研究结果强调了在原始多能性中建立的表观遗传程序对正常发育的重要性。
