HDAC1通过H3K27ac重塑抑制NRF2转录，从而加重新霉素诱导的耳蜗毛细胞损伤

文献信息

中文摘要

背景： 氨基糖苷类诱导的听力损失与耳蜗毛细胞中的氧化应激和线粒体功能障碍密切相关，但其上游表观遗传机制仍不完全清楚。方法：本研究探讨了组蛋白去乙酰化酶1（HDAC1）是否通过转录抑制NRF2参与新霉素诱导的耳蜗损伤。结果：在HEI-OC1细胞中，新霉素增加了细胞凋亡、活性氧蓄积、线粒体去极化和线粒体超氧化物产生，并伴有HDAC1上调和NRF2抑制。沉默HDAC1可减轻这些改变并恢复NRF2表达。ChIP-qPCR显示，新霉素暴露后HDAC1在NRF2近端启动子处的占据增加，而H3K27ac富集减少，HDAC1敲低则逆转了这些变化。一致地，沉默HDAC1增加了NRF2启动子活性，而HDAC1过表达进一步抑制NRF2转录并降低H3K27ac水平。敲低HDAC1还恢复了核内NRF2丰度，并增加了下游抗氧化蛋白HO-1和NQO1。重要的是，NRF2过表达部分挽救了HDAC1过表达引起的细胞活力和ATP含量下降，支持NRF2在HDAC1下游发挥功能作用。在体内，丙戊酸部分保留了新霉素处理小鼠的听阈，减少了耳蜗毛细胞凋亡，恢复了NRF2表达，并改善了线粒体超微结构损伤。结论：总之，这些发现确定了NRF2启动子处HDAC1相关的H3K27ac重塑是导致新霉素诱导耳蜗毛细胞损伤的一种表观遗传机制，并支持HDAC1-NRF2调控作为耳保护的一个潜在靶点。

英文摘要

Aminoglycoside-induced hearing loss is closely associated with oxidative stress and mitochondrial dysfunction in cochlear hair cells, but the upstream epigenetic mechanisms remain incompletely understood. This study investigated whether histone deacetylase 1 (HDAC1) contributes to neomycin-induced cochlear injury through transcriptional repression of NRF2. In HEI-OC1 cells, neomycin increased apoptosis, reactive oxygen species accumulation, mitochondrial depolarization, and mitochondrial superoxide production, accompanied by HDAC1 upregulation and NRF2 suppression. HDAC1 silencing attenuated these alterations and restored NRF2 expression. ChIP-qPCR demonstrated increased HDAC1 occupancy and reduced H3K27ac enrichment at the proximal NRF2 promoter after neomycin exposure, whereas HDAC1 knockdown reversed these changes. Consistently, HDAC1 silencing increased NRF2 promoter activity, while HDAC1 overexpression further suppressed NRF2 transcription and reduced H3K27ac levels. HDAC1 knockdown also restored nuclear NRF2 abundance and increased the downstream antioxidant proteins HO-1 and NQO1. Importantly, NRF2 overexpression partially rescued the reductions in cell viability and ATP content caused by HDAC1 overexpression, supporting a functional role for NRF2 downstream of HDAC1. In vivo, valproic acid partially preserved auditory thresholds, reduced cochlear hair cell apoptosis, restored NRF2 expression, and ameliorated mitochondrial ultrastructural damage in neomycin-treated mice. Collectively, these findings identify HDAC1-associated H3K27ac remodeling at the NRF2 promoter as an epigenetic mechanism contributing to neomycin-induced cochlear hair cell injury and support HDAC1-NRF2 regulation as a potential target for otoprotection.