title: Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis.
abstract: Aminoglycoside-induced hair cell loss is a major cause of hearing impairment in children and deserves more attention in medical research. Epigenetic mechanisms have been shown to protect hair cells from ototoxic drugs. In this study, we focused on the role of dimethylated histone H3K4 (H3K4me2) in hair cell survival. To investigate the effects of lysine-specific demethylase 1 (LSD1)--the histone demethylase primarily responsible for demethylating H3K4me2--on neomycin-induced hair cell loss, isolated cochleae were pretreated with LSD1 inhibitors followed by neomycin exposure. There was a severe loss of hair cells in the organ of Corti after neomycin exposure, and inhibition of LSD1 significantly protected against neomycin-induced hair cell loss. H3K4me2 expression in the nuclei of hair cells decreased after exposure to neomycin, and blocking the decreased expression of H3K4me2 with LSD1 inhibitors prevented hair cell loss. Local delivery of these inhibitors in vivo also protected hair cells from neomycin-induced ototoxicity and maintained the hearing threshold in mice as determined by auditory brain stem response. This inhibition of neomycin-induced apoptosis occurs via reduced caspase-3 activation. Together, our findings demonstrate the protective role for H3K4me2 against neomycin-induced hair cell loss and hearing loss.
authors.affiliation: Department of Otolaryngology, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, 200031, People's Republic of China.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: He
authors.forename: Huiqian
authors.initials: H
authors.lastname: Yu
authors.forename: Chengfu
authors.initials: C
authors.lastname: Cai
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.forename: Renjie
authors.initials: R
authors.lastname: Chai
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001550:Benzamidines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D006198:Hair Cells, Auditory / Q000473:pathology*; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009355:Neomycin / Q000494:pharmacology*; D009925:Organ of Corti / Q000187:drug effects / Q000201:enzymology; D010647:Phenyl Ethers / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D001550:Benzamidines; C000604717:CBB1007; D003521:Cyclopropanes; D006657:Histones; D010647:Phenyl Ethers; D010879:Piperazines; C000604718:S2101 compound; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D053148:Caspase 3; D009355:Neomycin; D008239:Lysine