Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development

Fei Chen; Yu Zhou; Yingchuan B. Qi; Vishal Khivansara; Hairi Li; Sang Young Chun; John K. Kim; Xiang-Dong Fu; Yishi Jin

doi:10.1101/gad.266650.115

Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development

¹Neurobiology Section, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093, USA;
²Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA;
³Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
⁴Life Sciences Institute, Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
⁵Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA

Corresponding author: yijin{at}ucsd.edu

↵Present addresses: ⁶Institute of Developmental and Regenerative Biology, School of Life and Environmental Sciences, Hangzhou Normal University, 310036 Hangzhou, China; ⁷Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; ⁸Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.

Abstract

Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathway controlling APA in the Caenorhabditis elegans nervous system. Loss of function in ssup-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) C-terminal domain (CTD), dampens transcription termination at a strong intronic polyadenylation site (PAS) in unc-44/ankyrin yet promotes termination at the weak intronic PAS of the MAP kinase dlk-1. A nuclear protein, SYDN-1, which regulates neuronal development, antagonizes the function of SSUP-72 and several nuclear polyadenylation factors. This regulatory pathway allows the production of a neuron-specific isoform of unc-44 and an inhibitory isoform of dlk-1. Dysregulation of the unc-44 and dlk-1 mRNA isoforms in sydn-1 mutants impairs neuronal development. Deleting the intronic PAS of unc-44 results in increased pre-mRNA processing of neuronal ankyrin and suppresses sydn-1 mutants. These results reveal a mechanism by which regulation of CTD phosphorylation controls coding region APA in the nervous system.

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Footnotes

Supplemental material is available for this article.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.266650.115.

Received June 1, 2015.
Accepted October 16, 2015.

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