Defects in the alternative splicing-dependent regulation of REST cause deafness

Yoko Nakano; Michael C Kelly; Atteeq U Rehman; Erich T Boger; Robert J Morell; Matthew W Kelley; Thomas B Friedman; Botond Bánfi

doi:10.1016/j.cell.2018.06.004

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Defects in the alternative splicing-dependent regulation of REST cause deafness

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Defects in the alternative splicing-dependent regulation of REST cause deafness

Yoko Nakano, Michael C Kelly, Atteeq U Rehman, Erich T Boger, Robert J Morell, Matthew W Kelley, Thomas B Friedman and Botond Bánfi

Cell (Cambridge), Vol.174(3), pp.536-548.e21

07/26/2018

DOI: 10.1016/j.cell.2018.06.004

PMCID: PMC6370011

PMID: 29961578

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Abstract

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 they identify a potential treatment for a group of hereditary deafness cases.

Details

Title: Subtitle: Defects in the alternative splicing-dependent regulation of REST cause deafness
Creators: Yoko Nakano - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Michael C Kelly - Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Atteeq U Rehman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Erich T Boger - Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Robert J Morell - Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Matthew W Kelley - Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Thomas B Friedman - Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA
Botond Bánfi - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Cell (Cambridge), Vol.174(3), pp.536-548.e21
DOI: 10.1016/j.cell.2018.06.004
PMID: 29961578
PMCID: PMC6370011
ISSN: 0092-8674
eISSN: 1097-4172
Grant note: name: NIDCD/NIH, award: R01DC010152, R01DC014953; name: NIDCD Division of Intramural Research/NIH, award: DC000048, DC000086, DC000059
Language: English
Date published: 07/26/2018
Academic Unit: Anatomy and Cell Biology; Otolaryngology; Internal Medicine
Record Identifier: 9984025353002771

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