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 language | English (US) |
|---|---|
| Pages (from-to) | 5083-5093 |
| Number of pages | 11 |
| Journal | Human molecular genetics |
| Volume | 25 |
| Issue number | 23 |
| DOIs | |
| State | Published - Jan 1 2016 |
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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 journal › Article
}
TY - JOUR
T1 - Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models
AU - Tan, Qiumin
AU - Yalamanchili, Hari Krishna
AU - Park, Jeehye
AU - De Maio, Antonia
AU - Lu, Hsiang Chih
AU - Wan, Ying Wooi
AU - White, Joshua J.
AU - Bondar, Vitaliy V.
AU - Sayegh, Layal S.
AU - Liu, Xiuyun
AU - Gao, Yan
AU - Sillitoe, Roy V.
AU - Orr, Harry T.
AU - Liu, Zhandong
AU - Zoghbi, Huda Y.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85011285424&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddw337
DO - 10.1093/hmg/ddw337
M3 - Article
VL - 25
SP - 5083
EP - 5093
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 23
ER -