The spatiotemporal control of gene expression exerted by promoters and enhancers is central for organismal development, physiology and behaviour. These two types of regulatory elements have long been distinguished from each other based on their function, but recent work highlighted common architectural and functional features. It also suggested that inheritable alterations in the epigenetic and sequence context of regulatory elements might underlie evolutionary changes of their principal activity, which could result in changes in the transcriptional profile of genes under their control or even facilitate the birth of new genes. Here, based on integrated cross-mammalian analyses of DNase hypersensitivity, chromatin modification and transcriptional data, we provide support for this hypothesis by detecting 445 regulatory elements with signatures of activity turnover in sister species from the primate and rodent lineages (termed "P/E" elements). Through the comparison with outgroup species, we defined the directionality of turnover events, which revealed that most instances represent transformations of putative ancestral enhancers into promoters, leading to the emergence of species-specific transcribed loci or 5' exons. Notably, P/E elements have distinct GC sequence compositions and stabilizing 5' splicing (U1) regulatory motif patterns, which may predispose them to functional repurposing during evolution. Moreover, we trace changes in the U1 and polyadenylation signal densities and distributions that accompanied and likely drove the evolutionary activity switches. Overall, our work highlights functional repurposing as a notable mechanism that likely facilitated regulatory innovation and the origination of new genes and exons during mammalian evolution.
Overall design: 78 single-end strand-specific RNA-seq libraries were generated from polyA-selected RNA from four organs (brain, heart, kidney and liver) from human, macaque, marmoset, mouse, rat and rabbit samples.
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