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

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

PROVIDER: PRJNA437491 | ENA |

REPOSITORIES: ENA

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Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse utricles].

Project description: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.

2018-06-28 | GSE111604 | GEO

Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse brain cortex].

2018-06-28 | GSE111602 | GEO

Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse utricles].

Project description:Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse utricles].

| PRJNA437494 | ENA

Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse cultured organ of Corti].

2018-06-28 | GSE111603 | GEO

Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse brain cortex].

Project description:Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse brain cortex].

| PRJNA437534 | ENA

Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse cultured organ of Corti].

Project description:Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse cultured organ of Corti].

| PRJNA437533 | ENA

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

Project description: Not available

| S-EPMC6370011 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-06-28 | GSE111606 | GEO

A mutation in the Srrm4 gene causes pre-mRNA splicing defects and deafness in Bronx waltzer mice.

Project description:The spontaneous mutant Bronx waltzer (bv) mouse line is characterized by deafness and balance defect. We located the bv mutation to the Srrm4 gene which encodes a regulator of alternative pre-mRNA splicing. We found that Srrm4 is expressed in balance and hearing organs (i.e. in the vestibular maculas and the cochlea). Srrm4 is also expressed in the central nervous system including the cerebellum. To identify potential splicing defects in bv/bv mice, we analyzed RNA samples from the vestibular maculas and cerebellums of bv/bv mice and control (bv/+) littermates, using mouse exon junction microarrays (MJAY). In this dataset, we include probe-set level data obtained from cerebellar samples. The processed data represent probe-set intensities that have been normalized to gene expression levels. 8 total samples were analyzed in this series: cerebellums from 4 heterozygous (bv/+) and 4 homozygous (bv/bv) mice at P15.

2012-10-21 | E-GEOD-33589 | biostudies-arrayexpress