TOBF1 modulates mouse embryonic stem cell fate through regulating alternative splicing of pluripotency genes

Embryonic stem cells (ESCs) can undergo lineage-specific differentiation, giving rise to different cell types that constitute an organism. Although roles of transcription factors and chromatin modifiers in these cells have been described, how the alternative splicing (AS) machinery regulates their expression has not been sufficiently explored. Here, we show that the long non-coding RNA (lncRNA)-associated protein TOBF1 modulates the AS of transcripts necessary for maintaining stem cell identity in mouse ESCs. Among the genes affected is serine/arginine splicing factor 1 (SRSF1), whose AS leads to global changes in splicing and expression of a large number of downstream genes involved in the maintenance of ESC pluripotency. By overlaying information derived from TOBF1 chromatin occupancy, the distribution of its pluripotency-associated OCT-SOX binding motifs, and transcripts undergoing differential expression and AS upon its knockout, we describe local nuclear territories where these distinct events converge. Collectively, these contribute to the maintenance of mouse ESC identity. [Display omitted] •TOBF1 maintains mouse ESC identity through regulation of alternate splicing•This happens cotranscriptionally in discrete nuclear foci and impacts multiple genes•Among them, alternate isoform usage of SRSF1 leads to global splicing changes•Loss and gain of TOBF1 lead to concomitant changes in the levels of pluripotency genes Aich et al. elucidate the role of a previously uncharacterized protein, TOBF1, in the stabilization of mouse embryonic pluripotency. Their study reveals that TOBF1 regulates the alternative splicing of multiple pluripotency regulatory transcripts through cotranscriptional splicing in discrete nuclear foci in ESCs.