Function of deubiquitinase USP21 in mouse embryonic stem cell [ChIP-Seq]

Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is required to maintain the stemness of ESCs, although Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system (UPS). Here, we report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog and therefore maintains the protein level of Nanog in mouse-ESCs (mESCs). Loss of USP21 results in Nanog destruction, mESCs differentiation and reduced the somatic cell reprogramming efficiency. USP21 is a transcriptional target of the LIF/STAT3 pathway and is downregulated upon differentiation. Moreover, differentiation cues promote ERK-mediated phosphorylation and dissociation of USP21 from Nanog, thus leading to Nanog degradation. Additionally, USP21 is recruited to gene promoters by Nanog to deubiquitinate histone H2A at K119 and thus facilitates Nanog-mediated gene expression. Together, our findings provide a regulatory mechanism by which extrinsic signals regulate mESC fate via deubiquitinating Nanog.