The RNA polymerase II CTD phosphatase SSUP-72 regulates alternative polyadenylation in C. elegans neurons.. Caenorhabditis elegans

Alternative polyadenylation (APA) plays important roles in generating transcriptomediversity. In the nervous system widespread APA are observed in development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. Through systematic genetic studies and genome-wide survey of transcriptional landscape, here, we report a mechanism controlling APA of two neuronal genes, UNC-44/Ankyrin and DLK-1/MAPKK, during development of C. elegans nervous system. We show that SSUP-72, a Ser5 phosphatase for RNA polymerase II (Pol II) Carboxyl-Terminal Domain (CTD), differentially affects the usage of poly(A) sites (PASs) in the coding regions of unc-44 and dlk-1. A novel nuclear protein SYDN-1 interacts with both SSUP-72 and RNA pol II, and inhibits the function of SSUP-72 and nuclear polyadenylation factors. This regulatory pathway dampens the usage of a strong internal PAS of unc-44 for the production of neuron-specific ankyrin, and promotes the usage of a weak PAS of dlk-1 to control its activity. Deregulation of unc-44 and dlk-1 mRNA isoforms impairs neuronal development. Our data illustrate the high degree selectivity of APA regulation in complex nervous systems. Overall design: Two (2) wildtype N2 libraries and two (2) sydn-1 mutant libraries.