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 journalArticle

31 Citations (Scopus)

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 - Jan 1 2016

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RNA-Binding Proteins
Cell Survival
Protein Splicing
Genes
Survival
Purkinje Cells
Gene Expression Profiling
Exons
Neurons
Health

Cite this

Tan, Q., Yalamanchili, H. K., Park, J., De Maio, A., Lu, H. C., Wan, Y. W., ... Zoghbi, H. Y. (2016). Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Human molecular genetics, 25(23), 5083-5093. https://doi.org/10.1093/hmg/ddw337

Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. / Tan, Qiumin; Yalamanchili, Hari Krishna; Park, Jeehye; De Maio, Antonia; Lu, Hsiang Chih; Wan, Ying Wooi; White, Joshua J.; Bondar, Vitaliy V.; Sayegh, Layal S.; Liu, Xiuyun; Gao, Yan; Sillitoe, Roy V.; Orr, Harry T.; Liu, Zhandong; Zoghbi, Huda Y.

In: Human molecular genetics, Vol. 25, No. 23, 01.01.2016, p. 5083-5093.

Research output: Contribution to journalArticle

Tan, Q, Yalamanchili, HK, Park, J, De Maio, A, Lu, HC, Wan, YW, White, JJ, Bondar, VV, Sayegh, LS, Liu, X, Gao, Y, Sillitoe, RV, Orr, HT, Liu, Z & Zoghbi, HY 2016, 'Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models', Human molecular genetics, vol. 25, no. 23, pp. 5083-5093. https://doi.org/10.1093/hmg/ddw337
Tan Q, Yalamanchili HK, Park J, De Maio A, Lu HC, Wan YW et al. Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Human molecular genetics. 2016 Jan 1;25(23):5083-5093. https://doi.org/10.1093/hmg/ddw337
Tan, Qiumin ; Yalamanchili, Hari Krishna ; Park, Jeehye ; De Maio, Antonia ; Lu, Hsiang Chih ; Wan, Ying Wooi ; White, Joshua J. ; Bondar, Vitaliy V. ; Sayegh, Layal S. ; Liu, Xiuyun ; Gao, Yan ; Sillitoe, Roy V. ; Orr, Harry T. ; Liu, Zhandong ; Zoghbi, Huda Y. / Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. In: Human molecular genetics. 2016 ; Vol. 25, No. 23. pp. 5083-5093.
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AU - Liu, Xiuyun

AU - Gao, Yan

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