Journal
MOLECULAR NEUROBIOLOGY
Volume 52, Issue 1, Pages 196-205Publisher
SPRINGER
DOI: 10.1007/s12035-014-8841-3
Keywords
Hair cell; Neomycin; H3K4me2; LSD1
Categories
Funding
- Major State Basic Research Development Program of China (973 Program) [2011CB504506, 2010CB945503]
- National Natural Science Foundation of China [81070793, 81230019, 81300825]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT1010]
- Specialized Research Fund for the Doctor Program of Higher Education [20120071110077]
- Program of Outstanding Shanghai Academic Leader [11XD1401300]
- Fundamental Research Funds for the Central Universities [2242014R30022, NO2013WSN085]
- China Postdoctoral Science Foundation [2014M551328]
- Program of Leading Medical Personnel in Shanghai
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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.
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