Exon-Mediated Activation of Transcription Starts

The processing of RNA transcripts from mammalian genes occurs in proximity to their transcription. Here, we describe a phenomenon affecting thousands of genes that we call exon-mediated activation of transcription starts (EMATS), in which the splicing of internal exons impacts promoter choice and the expression level of the gene. We observed that evolutionary gain of internal exons is associated with gain of new transcription start sites (TSSs) nearby and increased gene expression. Inhibiting exon splicing reduced transcription from nearby promoters, and creation of new spliced exons activated transcription from cryptic promoters. The strongest effects occurred for weak promoters located proximal and upstream of efficiently spliced exons. Together, our findings support a model in which splicing recruits transcription machinery locally to influence TSS choice and identify exon gain, loss, and regulatory change as major contributors to the evolution of alternative promoters and gene expression in mammals. [Display omitted] •New promoters arise near evolutionarily new internal exons•Splicing of internal exons activates proximal upstream weak promoters•Splicing may recruit transcription machinery locally to influence promoter selection•These impacts of splicing on transcription are widespread Fiszbein et al. show that splicing of internal exons activates transcription from nearby upstream promoters, especially those that are weak or even cryptic, suggesting that regulation of splicing can be used to alter the transcriptional output of mammalian genes.