Shou, Jianyong (2013) Inhibition of H3K9 Methyltransferase G9a/GLP Prevents Ototoxic and Ongoing Hair Cell Death. Cell Death and Diseases, 4 (e506). ISSN 2041-4889

Abstract

Sensorineural hearing loss (SNHL) is one of the most common sensory defects in humans. Considering the susceptibility of hair cells to many vulnerabilities and the important role of histone modifications in cell development and injury, we examined the roles of G9a/GLP in hair cell protection by using pharmacological inhibitors. We observed a transient increase of H3K9me2 upon hair cell damage in organotypic cochlear cultures. Treatment with BIX01294 or UNC0638, specific inhibitors to G9a/GLP, prevented hair cell loss accompanying the reduced level of H3K9me2. Using fluorescent labelling, we demonstrated that BIX01294 does not interfere with aminoglycoside uptake, indicating the otoprotective role of BIX01294 does not likely function through the regulation of aminoglycoside absorption. Moreover, local delivery of BIX01294 prevented neomycin-induced in vivo auditory hair cell loss in the organ of Corti in a mouse mode, as measured by histological and functional auditory brainstem response (ABR) analyses. Transcritptome profiling analysis indicated that G9a/GLP inhibition may up-regulate the expression of to Pcdh8 and Insm1 execute its otoprotection roles. These data revealed a novel role of histone modification in otoprotection. The reduced susceptibility of the hair cells to stress by the downregulation of H3K9me2 may be of potential therapeutic value for those suffering from SNHL.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:14
Last Modified:	13 Oct 2015 13:14
URI:	https://oak.novartis.com/id/eprint/8501