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首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >Inhibition of histone methyltransferases SUV39H1 and G9a leads to neuroprotection in an in vitro model of cerebral ischemia
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Inhibition of histone methyltransferases SUV39H1 and G9a leads to neuroprotection in an in vitro model of cerebral ischemia

机译:组蛋白甲基转移酶SUV39H1和G9a的抑制在脑缺血的体外模型中导致神经保护

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摘要

Cerebral ischemia induces a complex transcriptional response with global changes in gene expression. It is essentially regulated by transcription factors as well as epigenetic players. While it is well known that the inhibition of transcriptionally repressive histone deacetylases leads to neuroprotection, the role of histone methyltransferases in the postischemic transcriptional response remains elusive. We investigated the effects of inhibition of the repressive H3K9 histone methyltransferases SUV39H1 and G9a on neuronal survival, H3K9 promoter signatures and gene expression. Their inhibition either with the specific blocker chaetocin or by use of RNA interference promoted neuronal survival in oxygen glucose deprivation (OGD). Brain-derived neurotrophic factor (BDNF) was upregulated and BDNF promoter regions showed an increase in histone marks characteristic for active transcription. The BDNF blockade with K252a abrogated the protective effect of chaetocin treatment. In conclusion, inhibition of histone methyltransferases SUV39H1 and G9a confers neuroprotection in a model of hypoxic metabolic stress, which is at least in part mediated by BDNF.
机译:脑缺血诱导复杂的转录反应,基因表达发生整体变化。它基本上受转录因子以及表观遗传参与者的调节。众所周知,抑制转录抑制性组蛋白脱乙酰基酶可导致神经保护作用,但组蛋白甲基转移酶在缺血后转录应答中的作用仍然难以捉摸。我们研究了抑制性抑制H3K9组蛋白甲基转移酶SUV39H1和G9a对神经元存活,H3K9启动子签名和基因表达的影响。通过特定的阻断剂脂蛋白或通过使用RNA干扰对它们的抑制促进了氧葡萄糖剥夺(OGD)中神经元的存活。脑源性神经营养因子(BDNF)被上调,并且BDNF启动子区域显示出用于主动转录的组蛋白标记增加。用K252a进行的BDNF阻断取消了Chaetocin治疗的保护作用。总之,在缺氧代谢应激模型中,组蛋白甲基转移酶SUV39H1和G9a的抑制作用赋予神经保护作用,该模型至少部分是由BDNF介导的。

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