Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models

Qiumin Tan, Hari Krishna Yalamanchili, Jeehye Park, Antonia De Maio, Hsiang Chih Lu, Ying Wooi Wan, Joshua J. White, Vitaliy V. Bondar, Layal S. Sayegh, Xiuyun Liu, Yan Gao, Roy V. Sillitoe, Harry T. Orr, Zhandong Liu, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Splicing regulation is an important step of post-transcriptional gene regulation. It is a highly dynamic process orchestrated by RNA-binding proteins (RBPs). RBP dysfunction and global splicing dysregulation have been implicated inmany human diseases, but the in vivo functions ofmost RBPs and the splicing outcome upon their loss remain largely unexplored. Here we report that constitutive deletion of Rbm17, which encodes an RBP with a putative role in splicing, causes early embryonic lethality inmice and that its loss in Purkinje neurons leads to rapid degeneration. Transcriptome profiling of Rbm17-deficient and control neurons and subsequent splicing analyses using CrypSplice, a newcomputationalmethod that we developed, revealed thatmore than half of RBM17-dependent splicing changes are cryptic. Importantly, RBM17 represses cryptic splicing of genes that likely contribute tomotor coordination and cell survival. This finding prompted us to re-analyze published datasets froma recent report on TDP-43, an RBP implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as it was demonstrated that TDP-43 represses cryptic exon splicing to promote cell survival. We uncovered a large number of TDP-43-dependent splicing defects that were not previously discovered, revealing that TDP-43 extensively regulates cryptic splicing. Moreover, we found a significant overlap in genes that undergo both RBM17-and TDP-43-dependent cryptic splicing repression, many of which are associated with survival. We propose that repression of cryptic splicing by RBPs is critical for neuronal health and survival. CrypSplice is available at www.liuzlab.org/CrypSplice.

Original languageEnglish (US)
Pages (from-to)5083-5093
Number of pages11
JournalHuman molecular genetics
Volume25
Issue number23
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
We thank Dr. Nathaniel Heintz for the generous gift of Pcp2-BacTRAP line (Tg (Pcp2-EGFP/Rpl10a) DR166 Htz), and members of the Zoghbi and Liu laboratory for helpful suggestions and discussions. The project was supported in part by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the cores used were the RNA In Situ Hybridization Core Facility, Mouse Behavioral Core and the Genomic and RNA Profiling Core at Baylor College of Medicine. Development of the GFP monoclonal antibodies used in this study was supported in part through the NIH/NCI Cancer Center Support Grant GrantP30 CA008748 which funds the Antibody and Bioresource Core Facility at Memorial Sloan Kettering Cancer Center. This work was supported by National Institute of Health (F32 NS083091 to Q. T., F31 NS092264 to J. J. W., R01 NS089664 to R. V. S., R37 NS22920 to H. T. O., and R37 NS027699 to H. Y. Z.) This work was also supported by National Science Foundation (DMS-1263932 to Z. L.).

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