Rbm25 governs embryonic stem cell identity and fate through transcriptional regulation of pluripotency and epigenetic programs

Embryonic stem cells (ESCs) can self-renew and differentiate into somatic cells. They can also adopt a totipotent-like state and become 2-cell-like cells (2CLCs). However, how these progresses are regulated remains poorly understood. Here, we define a novel role for Rbm25 (RNA-binding motif protein 25), previously known as a splicing regulator, in the maintenance of ESC identity. Rbm25 is highly expressed in ESCs and is downregulated during differentiation. Deletion or depletion of Rbm25 impairs ESC self-renewal and differentiation and promotes the transition toward 2CLCs. Mechanistically, RBM25 occupies pluripotency- and DNA methylation-related gene promoters and directly regulates their expression, thereby governing the gene expression program and the epigenetic state of ESCs. Together, our data indicate that Rbm25 controls stem cell fate specification at the transcription level and therefore uncover a new role of Rbm25 as a transcriptional regulator.