Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Center for Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA.
Nat Commun. 2021 Mar 25;12(1):1865. doi: 10.1038/s41467-021-21910-0.
Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of "stemness" and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.
哺乳动物胚胎的多能性细胞在植入后为谱系分化做准备，经历广泛的染色质重塑。多梳抑制复合物 2（PRC2）沉积的抑制性 H3K27me3 从植入前胚胎中的大片段重新分配到发育基因的启动子，以标记它们。这种 H3K27me3 全局再分布的调控机制尚不清楚。本文报道了一种翻译后机制，该机制通过破坏 PRC2 来稳定 H3K27me3，从而在谱系分化过程中进行限制。使用一种生长素诱导的降解结构域系统，作者证明去泛素酶 Usp9x 是小鼠胚胎干细胞（ES 细胞）自我更新所必需的。Usp9x 高的 ES 细胞具有高水平的 PRC2，并且具有植入前胚胎的染色质和转录特征，而 Usp9x 低的 ES 细胞则类似于植入后、原肠胚期的上胚层。本文发现 Usp9x 与 PRC2 相互作用、去泛素化和稳定 PRC2。在植入后胚胎中删除 Usp9x 会导致通常在原肠胚后获得 H3K27me3 的基因去抑制，随后在 E9.5 出现形态异常，这表明 Usp9x 和 PRC2 在发育过程中存在反复联系。Usp9x 是“干性”的标志物，在各种神经发育障碍和癌症中发生突变。本文结果揭示了 Usp9x-PRC2 调控轴在植入前后至关重要，并且可能在其他干细胞命运转变和疾病状态中重新发挥作用。
