Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis
Inhibition of H3K4me2 Demethylation Protects Auditory Hair Cells from Neomycin-Induced Apoptosis
复制标题
抑制 H3K4me2 去甲基化可保护听觉毛细胞免受新霉素诱导的细胞凋亡
DOI：
10.1007/s12035-014-8841-3
复制
发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
He, Yingzi;Yu, Huiqian;Li, Huawei
氨基糖苷类引起的毛细胞损失是儿童听力障碍的主要原因，值得医学研究更多关注。表观遗传机制已被证明可以保护毛细胞免受耳毒性药物的影响。在本研究中，我们重点研究二甲基化组蛋白 H3K4 (H3K4me2) 在毛细胞存活中的作用。为了研究赖氨酸特异性去甲基化酶 1 (LSD1)（主要负责 H3K4me2 去甲基化的组蛋白去甲基化酶）对新霉素诱导的毛细胞损失的影响，用 LSD1 抑制剂对分离的耳蜗进行预处理，然后暴露于新霉素。接触新霉素后，柯蒂氏器中的毛细胞严重丧失，抑制 LSD1 可显着防止新霉素诱导的毛细胞丧失。接触新霉素后，毛细胞核中的 H3K4me2 表达减少，用 LSD1 抑制剂阻断 H3K4me2 表达的减少可防止毛细胞损失。这些抑制剂在体内的局部递送还可以保护毛细胞免受新霉素诱导的耳毒性，并维持小鼠的听力阈值（根据听觉脑干反应确定）。这种对新霉素诱导的细胞凋亡的抑制是通过减少 caspase-3 的激活来实现的。总之，我们的研究结果证明了 H3K4me2 对新霉素诱导的毛细胞损失和听力损失的保护作用。
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.