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Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis

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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.

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Acknowledgments

The authors would like to thank Min Yu and Shaoyang Sun for their technical assistance and Yalin Huang for help with the confocal microscope. This work was supported by grants from the Major State Basic Research Development Program of China (973 Program) (2011CB504506, 2010CB945503) and the National Natural Science Foundation of China (Nos. 81070793, 81230019, 81300825), the Program for Changjiang Scholars and Innovative Research Team in University (IRT1010), the Specialized Research Fund for the Doctor Program of Higher Education (20120071110077), the Program of Outstanding Shanghai Academic Leader (11XD1401300), the Program of Leading Medical Personnel in Shanghai, the Fundamental Research Funds for the Central Universities (2242014R30022, NO2013WSN085), and the China Postdoctoral Science Foundation Funded Project (No. 2014M551328)

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Otolaryngology, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China

    Yingzi He, Huiqian Yu, Shan Sun & Huawei Li

  2. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Huawei Li

  3. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Huawei Li

  4. Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital, Xiamen University, Xiamen, Fujian, 361003, China

    Chengfu Cai

  5. Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, 210096, China

    Renjie Chai

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  1. Yingzi He
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Correspondence to Huawei Li.

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Yingzi He, Huiqian Yu, and Chengfu Cai contributed equally to this work.

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He, Y., Yu, H., Cai, C. et al. Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis. Mol Neurobiol 52, 196–205 (2015). https://doi.org/10.1007/s12035-014-8841-3

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