Trans-splicing of the C. elegans let-7 primary transcript developmentally regulates let-7 microRNA biogenesis and let-7 family microRNA activity

let-7 is a microRNA whose sequence and roles in developmental progression are conserved Generally, transcription of let-7 primary transcript (pri-let-7) occurs early in development, whilst processing of the mature let-7 microRNA arises during cellular differentiation. In C. elegans and other animals, the RNA binding protein LIN-28 post-transcriptionally inhibits let-7 biogenesis at early developmental stages, but the mechanisms by which LIN-28 does this are not fully understood. Nor is it understood how the developmental regulation of let-7 might influence the expression or activities of other microRNAs of the same seed family. Here we show that pri-let-7 is trans-spliced to the SL1 splice leader downstream of the let-7 precursor stem-loop, producing a short, polyadenylated downstream mRNA, and that this trans-splicing event negatively impacts the biogenesis of mature let-7 microRNA in cis. Moreover, this trans-spliced mRNA contains sequences complementary to multiple the let-7 seed family (let-7fam) and negatively regulates let-7fam function in trans. Thus, this study provides evidence for a mechanism by which splicing of a microRNA primary transcript can negatively regulate said microRNA in cis as well as other microRNAs in trans.