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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Aminoglycoside-induced histone deacetylation and hair cell death in the mouse cochlea.
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Aminoglycoside-induced histone deacetylation and hair cell death in the mouse cochlea.

机译：氨基糖苷诱导的小鼠耳蜗中的组蛋白脱乙酰化和毛细胞死亡。

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Post-translational modification of histones is an important form of chromatin regulation impacting transcriptional activation. Histone acetyltransferases, for example, acetylate lysine residues on histone tails thereby enhancing gene transcription, while histone deacetylases (HDACs) remove those acetyl groups and repress gene transcription. Deficient histone acetylation is associated with pathologies, and histone deacetylase inhibitors have been studied in the treatment of cancer and neurodegenerative diseases. Here we explore histone acetylation in cochlear sensory cells following a challenge with gentamicin, an aminoglycoside antibiotic known to cause loss of auditory hair cells and hearing. The addition of the drug to organotypic cultures of the mouse organ of Corti decreased the acetylation of histone core proteins (H2A Ack5, H2B Ack12, H3 Ack9, and H4 Ack8) followed by a loss of sensory cells. Protein levels of HDAC1, HDAC3 and HDAC4 were increased while the histone acetyltransferases such as CREB-binding protein and p300 remained unchanged. We next hypothesized that protecting histone acetylation should prevent cell death and tested the effects of HDAC-inhibitors on the actions of gentamicin. Co-treatment with trichostatin A maintained near-normal levels of acetylation of histone core proteins in cochlear hair cells and attenuated gentamicin-induced cell death. The addition of sodium butyrate also rescued hair cells from damage by gentamicin. The results are consistent with an involvement of deficient histone acetylation in aminoglycoside-induced hair cell death and point to the potential value of HDAC-inhibitors in protection from the side effects of these drugs.
机译：组蛋白的翻译后修饰是影响转录激活的染色质调节的重要形式。组蛋白乙酰转移酶，例如，乙酰化组蛋白尾巴上的赖氨酸残基，从而增强基因转录，而组蛋白脱乙酰基酶（HDAC）去除那些乙酰基并抑制基因转录。缺乏的组蛋白乙酰化与病理相关，并且已经研究了组蛋白脱乙酰基酶抑制剂在癌症和神经退行性疾病的治疗中。在这里，我们探讨了庆大霉素的挑战后，在耳蜗感觉细胞中的组蛋白乙酰化，庆大霉素是一种已知会导致听觉毛细胞和听力丧失的氨基糖苷类抗生素。将药物添加到Corti小鼠器官的器官型培养物中会降低组蛋白核心蛋白（H2A Ack5，H2B Ack12，H3 Ack9和H4 Ack8）的乙酰化程度，随后会导致感觉细胞丢失。 HDAC1，HDAC3和HDAC4的蛋白质水平增加，而组蛋白乙酰基转移酶（如CREB结合蛋白和p300）保持不变。接下来我们假设保护组蛋白乙酰化应该可以防止细胞死亡，并测试了HDAC抑制剂对庆大霉素的作用。与曲古抑菌素A共同处理可保持耳蜗毛细胞中组蛋白核心蛋白的乙酰化水平接近正常水平，并减轻了庆大霉素诱导的细胞死亡。丁酸钠的加入还可以使庆大霉素对毛细胞的伤害也得以挽救。结果与组蛋白乙酰化不足参与氨基糖苷诱导的毛细胞死亡有关，并指出了HDAC抑制剂在保护这些药物的副作用方面的潜在价值。

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