The protein level of OCT4, a core pluripotency transcription factor, is vital for embryonic stem cell (ESC) maintenance, differentiation, and somatic cell reprogramming. However, how OCT4 protein levels are controlled during reprogramming remains largely unknown. Here, we identify ubiquitin conjugation sites of OCT4 and report that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction from mouse embryonic fibroblasts. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process. Furthermore, we reveal that OCT4 directly activates expression of Ash2l-b, and that ASH2L-B is a major isoform of ASH2L highly expressed in ESCs and required for somatic cell reprogramming. Together, this study emphasizes the importance of ubiquitination manipulation of the reprogramming factor and its interplay with the epigenetic regulator for successful reprogramming, opening a new avenue to improve the efficiency of pluripotency induction.

OCT4（一种核心的多能性转录因子）的蛋白水平对于胚胎干细胞（ESC）的维持，分化和体细胞重编程至关重要。但是，在重编程期间如何控制OCT4蛋白质水平仍然未知。在这里，我们确定OCT4的泛素结合位点，并报告WWP2催化的OCT4泛素化或Wwp2消融的破坏显着提高了小鼠胚胎成纤维细胞诱导多能性的效率。从机制上讲，在重新编程过程中，WWP2介导的OCT4泛素化作用的破坏会提高OCT4蛋白质的稳定性和H3K4甲基化水平。此外，我们发现OCT4直接激活Ash2l-b的表达，并且ASH2L-B是ASH2L的主要同工型，在ESC中高度表达，是体细胞重编程所必需的。总之，这项研究强调了重编程因子的泛素化操纵及其与表观遗传调节剂相互作用以成功进行重编程的重要性，为提高多能性诱导效率开辟了一条新途径。