Disruption of OCT4 Ubiquitination Increases OCT4 Protein Stability and ASH2L-B-Mediated H3K4 Methylation Promoting Pluripotency Acquisition

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.