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.