Polycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. Two distinct PRC2 complexes, PRC2.1 and PRC2.2, contain respectively MTF2 and JARID2 in embryonic stem cells (ESCs). In this study, we explored their roles in lineage specification and commitment, using single-cell transcriptomics and mouse embryoid bodies derived from Mtf2 and Jarid2 null ESCs. We observe that the loss of Mtf2 results in enhanced and faster differentiation towards cell fates from all germ layers, while the Jarid2 null cells are predominantly directed towards early differentiating precursors, with reduced efficiency towards mesendodermal lineages. These effects are caused by derepression of developmental regulators that are poised for activation in pluripotent cells and gain H3K4me3 at their promoters in the absence of PRC2 repression. Upon lineage commitment, the differentiation trajectories are relatively similar to those of wild-type cells. Together, our results uncover a major role for MTF2-containing PRC2.1 in balancing poised lineage-specific gene activation, whereas the contribution of JARID2-containing PRC2 is more selective in nature compared to MTF2. These data explain how PRC2 imposes thresholds for lineage choice during the exit of pluripotency.

Polycomb Repressive Complex 2 (PRC2) 对于早期胚胎发育过程中基因的协调表达至关重要，可催化组蛋白 H3 赖氨酸 27 三甲基化。两个不同的 PRC2 复合体 PRC2.1 和 PRC2.2 在胚胎干细胞 (ESC) 中分别包含 MTF2 和 JARID2。在这项研究中，我们使用单细胞转录组学和源自Mtf2和Jarid2无效 ESC 的小鼠胚状体探索了它们在谱系规范和承诺中的作用。我们观察到Mtf2的缺失导致所有胚层向细胞命运的分化增强和更快，而Jarid2无效细胞主要针对早期分化前体，对中内胚层谱系的效率降低。这些影响是由发育调节因子的去阻遏引起的，这些调节因子准备在多能细胞中激活，并在没有 PRC2 抑制的情况下在其启动子处获得 H3K4me3。在谱系承诺后，分化轨迹与野生型细胞的分化轨迹相对相似。总之，我们的结果揭示了包含 MTF2 的 PRC2.1 在平衡平衡谱系特异性基因激活中的主要作用，而与 MTF2 相比，包含 JARID2 的 PRC2 的贡献在本质上更具选择性。这些数据解释了 PRC2 如何在多能性退出期间为谱系选择施加阈值。