459 Regulation of the keratinocyte progenitor to differentiation switch by alternative mRNA splicing

Alternative splicing (AS) of messenger RNAs diversifies gene function by generating protein isoforms with different biological properties. Over 95% human genes are alternatively spliced, but the functional consequences most AS events still not known. Here, using long-read RNA sequencing, we identified 5,826 associated epidermal differentiation (percent spliced index >10%, FDR <0.01). were enriched in histone modification and phosphorylation (p < 0.001). The common type was cassette exon splicing, which an intervening between two other exons is included or skipped mRNA sequence. We functionally characterized a mitogen-activated kinase (MAP3K7), had been previously studied epidermis. Basal progenitors preferentially express shorter MAP3K7 isoform switch to longer suprabasal, differentiated epidermis inclusion additional 81 bp exon. Using isoform-specific knockdown overexpression, demonstrate that single necessary sufficient transition keratinocytes from replicating progenitor state high clonogenic capacity into post-mitotic state. also performed binding motif analysis sequences adjacent 26 proteins predicted mediate keratinocytes, including ten unstudied roles skin. In summary, our study defines repertoire alternative demonstrates potential this resource identify RBPs regulate differentiation.