AI Article Synopsis
- REST is a DNA-binding protein that interacts with histone deacetylases (HDACs) to silence neuronal genes in non-neuronal cells, and its downregulation is primarily due to transcriptional silencing in differentiating neurons.
- The study highlights the importance of post-transcriptional regulation through alternative splicing of REST, which is crucial for hearing in both humans and mice, especially in the hair cells of the ear.
- A mutation affecting alternative splicing of REST leads to hair cell degeneration and deafness in mice, but treatment with an HDAC inhibitor can restore hearing; this mechanism is also linked to a hereditary form of deafness in humans.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370011 | PMC |
| http://dx.doi.org/10.1016/j.cell.2018.06.004 | DOI Listing |
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