SRRM2 splicing factor modulates cell fate in early development [RNA-Seq]

Srrm2 splicing factor is a novel gene implicated in developmental disorders and diseases. However, the role of Srrm2 in early mammalian development remains unexplored. Here, we show that Srrm2 expression dosage is critical for maintaining embryonic stem cell pluripotency and cell identity. Srrm2 heterozygosity promotes loss of stemness characterized by the coexistence of cells expressing naive and formative markers, together with large gene expression shifts, including in serum-response transcription factor targets and differentiation-related genes. Depletion of Srrm2 by RNA interference in embryonic stem cells identified splicing misregulation of specific genes, often linked to exon skipping. These results show that Srrm2 dosage is key in controlling stemness and cell fate decisions. Our findings unveil Srrm2’s molecular and cellular implications in development, shedding light on the involvement of splicing regulators in early embryogenesis, developmental diseases and tumorigenesis. To investigate the acute role of Srrm2 depletion in mouse embryonic stem cells (mESC), we treated mESC E14tg2a.4 with RNA interference targetting Srrm2 and a control region (GL2). siRNA-treated samples were collected 24 or 72 h upon treatment, in three independent experiments. We then performed gene expression profilling analysis by mRNA-seq of 3 replicates for each condition.