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| Status |
Public on Jun 28, 2018 |
| Title |
Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse cultured organ of Corti]. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The DNA-binding protein REST forms complexes with histone deacetylases (HDACs) to repress neuronal genes in non-neuronal cells. In differentiating neurons, REST is downregulated predominantly by transcriptional silencing. Here we report that post-transcriptional inactivation of REST by alternative splicing is required for hearing in humans and mice. We show that in the mechanosensory hair cells of the mouse ear, regulated alternative splicing of a frameshift-causing exon into the Rest mRNA is essential for the derepression of many neuronal genes. Heterozygous deletion of this alternative exon of mouse Rest causes hair cell degeneration and deafness, and the HDAC inhibitor SAHA (Vorinostat) rescues the hearing of these mice. In humans, inhibition of the frameshifting splicing event by a novel REST variant is associated with dominantly inherited deafness. Our data reveal the necessity for alternative splicing-dependent regulation of REST in hair cells, and identify a potential treatment for a group of hereditary deafness cases.
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| Overall design |
RNA-seq analysis of the mRNA profiles of FK228- and solvent-incubated organ of Corti cultures. These organ cultures were derived from wild-type (WT) mice and mutant mice that are heterozygous for the deletion of exon 4 of Rest (Rest[+/deltaExon4]).
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| Contributor(s) |
Nakano Y, Kelly MC, Rehman AU, Boger ET, Morell RJ, Kelley MW, Friedman TB, Bánfi B |
| Citation(s) |
29961578 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 DC010152 |
Functional characterization of the Bronx waltzer deafness gene |
THE UNIVERSITY OF IOWA |
BOTOND BANFI |
| R01 DC014953 |
Transcriptional regulation by a novel deafness gene in the DFNA27 locus |
THE UNIVERSITY OF IOWA |
BOTOND BANFI |
|
| Submission date |
Mar 08, 2018 |
| Last update date |
Nov 21, 2022 |
| Contact name |
Robert Morell |
| E-mail(s) |
morellr@nidcd.nih.gov
|
| Organization name |
National Institute on Deafness and Other Communication Disorders
|
| Street address |
35A Convent Drive, Room 1F-103
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL18480 |
Illumina HiSeq 1500 (Mus musculus) |
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| Samples (16)
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| This SubSeries is part of SuperSeries: |
| GSE111606 |
Defects in the alternative splicing-dependent regulation of REST cause deafness |
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| Relations |
| BioProject |
PRJNA437533 |
| SRA |
SRP134574 |
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