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Cell. 2018 Jul 26;174(3):536-548.e21. doi: 10.1016/j.cell.2018.06.004. Epub 2018 Jun 28.

Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness.

Author information

1
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Inflammation Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2
Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
3
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Genomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
5
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
6
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Inflammation Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. Electronic address: botond-banfi@uiowa.edu.

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.

KEYWORDS:

DFNA27; NRSF; REST; alternative splicing; cochlear hair cells; deafness; gene expression regulation; histone deacetylase inhibitors; inner ear; vestibular hair cells

PMID:
29961578
DOI:
10.1016/j.cell.2018.06.004

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