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 pluripotencyassociated 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.

Automated summary

This study reveals that the lncRNA-associated protein TOBF1 regulates the alternative splicing of transcripts necessary for maintaining stem cell identity in mouse ESCs. One of the affected genes is serine/arginine splicing factor 1 (SRSF1), whose splicing leads to global changes in splicing and expression of downstream genes involved in the maintenance of ESC pluripotency. The study shows that TOBF1 chromatin occupancy, pluripotency-associated OCT-SOX binding motifs, and transcripts undergoing differential expression and splicing converge in specific nuclear territories, collectively contributing to the maintenance of mouse ESC identity.