Abstract
Alternative splicing (AS) is involved in cell fate decisions and embryonic development. However, regulation of these processes is poorly understood. Here, we have identified the serine threonine kinase receptor-associated protein (STRAP) as a putative spliceosome-associated factor. Upon Strap deletion, there are numerous AS events observed in mouse embryoid bodies (EBs) undergoing a neuroectoderm-like state. Global mapping of STRAP-RNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP-seq) reveals that STRAP preferably targets transcripts for nervous system development and regulates AS through preferred binding positions, as demonstrated for two neuronal-specific genes, Nnat and Mark3. We have found that STRAP involves in the assembly of 17S U2 snRNP proteins. Moreover, in Xenopus, loss of Strap leads to impeded lineage differentiation in embryos, delayed neural tube closure, and altered exon skipping. Collectively, our findings reveal a previously unknown function of STRAP in mediating the splicing networks of lineage commitment, alteration of which may be involved in early embryonic lethality in mice.
Highlights
Alternative splicing (AS) is involved in cell fate decisions and embryonic development
We identified 896 genes differentially expressed at the isoform level (Supplementary Data 1), as exemplified by Etl4, Nin, and Lmna (Supplementary Fig. 1b), suggesting that variants of genes contribute to transcriptional diversity in a developmentally regulated manner
We show that, for mice, the deletion of Strap leads to early embryonic lethality and, in embryoid bodies (EBs), to abnormal differentiation (Fig. 2 and Supplementary Fig. 4c, d), indicating an essential role of serine threonine kinase receptor-associated protein (STRAP) in mouse early embryo development and differentiation of ESCs
Summary
Alternative splicing (AS) is involved in cell fate decisions and embryonic development. Regulation of these processes is poorly understood. Global mapping of STRAPRNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP-seq) reveals that STRAP preferably targets transcripts for nervous system development and regulates AS through preferred binding positions, as demonstrated for two neuronal-specific genes, Nnat and Mark. We have found that STRAP involves in the assembly of 17S U2 snRNP proteins. Our findings reveal a previously unknown function of STRAP in mediating the splicing networks of lineage commitment, alteration of which may be involved in early embryonic lethality in mice. ECLIP-seq reveals that STRAP associates with a broad set of transcripts involved in nervous system development. Our study deciphers the role of STRAP in modulating splicing programs associated with lineage-specific commitment
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