PLX174615

GSE111603: Defects in the alternative splicing-dependent regulation of REST cause deafness - [mouse cultured organ of Corti].

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Robert,James,Morell (morellr@nidcd.nih.gov) - Laboratory of Molecular Genetics National Institute on Deafness and Other Communication Disorders (NIDCD)