Neuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100
Capponi, Simona; Stöffler, Nadja; Irimia, Manuel; Van Schaik, Frederik M.A.; Ondik, Mercedes M.; Biniossek, Martin L.; Lehmann, Lisa; Mitschke, Julia; Vermunt, Marit W.; Creyghton, Menno P.; Graybiel, Ann M.; Reinheckel, Thomas; Schilling, Oliver; Blencowe, Benjamin J.; Crittenden, Jill R.; Timmers, H. Th Marc
(2020) RNA biology, volume 17, issue 1, pp. 62 - 74
(Article)
Abstract
Neuronal microexons represent the most highly conserved class of alternative splicing events and their timed expression shapes neuronal biology, including neuronal commitment and differentiation. The six-nt microexon 34ʹ is included in the neuronal form of TAF1 mRNA, which encodes the largest subunit of the basal transcription factor TFIID. In this study,
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we investigate the tissue distribution of TAF1-34ʹ mRNA and protein and the mechanism responsible for its neuronal-specific splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34ʹ have different distributions in the brain, which distinguish proliferating from post-mitotic neurons. Knockdown and ectopic expression experiments demonstrate that the neuronal-specific splicing factor SRRM4/nSR100 promotes the inclusion of microexon 34ʹ into TAF1 mRNA, through the recognition of UGC sequences in the poly-pyrimidine tract upstream of the regulated microexon. These results show that SRRM4 regulates temporal and spatial expression of alternative TAF1 mRNAs to generate a neuronal-specific TFIID complex.
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Keywords: Alternative mRNA splicing, microexons, neuronal transcription, neurogenesis, basal transcription factors, TAF1, X-linked Dystonia Parkinsonism, Molecular Biology, Cell Biology
ISSN: 1547-6286
Publisher: Landes Bioscience
Note: Funding Information: We thank the present and past members of the Timmers laboratory for their support, discussions and critical reading of this manuscript. This work also benefitted from discussions with Dr. Paul Coffer and his group members (University Medical Center Utrecht, The Netherlands). We also thank Samitha Venu, Tomoko Yoshida, Marie Follo and Courtney Anderson, Emily Park, Mindy Wang, and Wei Wei from ACDBio for technical assistance. We thank Marcel Leist (University of Konstanz, Germany) for providing the LUHMES cells. This work was financially supported by the Collaborative Center for X-linked Dystonia Parkinsonism (CCXDP). We are particularly grateful for the stimulating discussions with all members of the CC-XDP and its inspirational leaders. Publisher Copyright: © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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