Exon-mediated activation of transcription starts

Abstract

The processing of transcripts from mammalian genes often occurs near in time and space to their transcription. Here we describe a phenomenon we call exon-mediated activation of transcription starts (EMATS) that affects thousands of mammalian genes in which the splicing of internal exons impacts the spectrum of promoters used and expression level of the host gene. We observed that evolutionary gain of new internal exons is associated with gain of new TSSs nearby and increased gene expression. Inhibiting exon splicing reduced transcription from nearby promoters. Conversely, creation of new splice sites and enable splicing of new exons activated transcription from cryptic promoters. The strongest effects were associated with weak promoters located proximal and upstream of efficiently spliced exons. Together, our findings support a model in which splicing factors recruit 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 altered gene expression in mammals.