BackgroundNeuron apoptosis is a pivotal process for brain damage in cerebral ischemia. Dot1L (disruptor of telomeric silencing 1‐like) is only known histone H3K79 methyltransferase. It is not clear whether the role and mechanism of Dot1L on cerebral ischemia is related to regulate neuron apoptosis.Methods and ResultsWe use a combination of mice middle cerebral artery occlusion stroke and neurons exposed to oxygen‐glucose deprivation followed by reoxygenation to investigate the role and mechanism of Dot1L on cerebral ischemia. We find knockdown or inhibition of Dot1L reversed ischemia‐induced neuronal apoptosis and attenuated the neurons injury treated by oxygen‐glucose deprivation followed by reoxygenation. Further, blockade of Dot1L prevents RIPK1 (receptor‐interacting protein kinase 1)‐dependent apoptosis through increased RIPK1 K63‐ubiquitylation and decreased formation of RIPK1/Caspase 8 complexes. In line with this, H3K79me3 enrichment in the promoter region of deubiquitin‐modifying enzyme A20 and deubiquitinase cylindromatosis gene promotes the increasing expression in oxygen‐glucose deprivation followed by reoxygenation ‐induced neuronal cells, on the contrary, oxygen‐glucose deprivation followed by reoxygenation decreases H3K79me3 level in the promoter region of ubiquitin‐modifying enzyme cIAP1 (cellular inhibitors of apoptosis proteins), and both these factors ultimately cause K63‐deubiquitination of RIPK1. Importantly, knockdown or inhibition of Dot1L in vivo attenuates apoptosis in middle cerebral artery occlusion mice and reduces the extent of middle cerebral artery occlusion ‐induced brain injury.ConclusionsThese data support for the first time, to our knowledge, that Dot1L regulating RIPK1 to the apoptotic death trigger contributes to cerebral ischemia injury. Therefore, targeting Dot1L serves as a new therapeutic strategy for ischemia stroke.

中文翻译：

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组蛋白甲基转移酶 Dot1L 有助于脑缺血/再灌注中的 RIPK1 激酶依赖性细胞凋亡

背景神经元凋亡是脑缺血脑损伤的关键过程。Dot1L（端粒沉默 1 样的干扰物）是唯一已知的组蛋白 H3K79 甲基转移酶。尚不清楚Dot1L在脑缺血中的作用和机制是否与调节神经元凋亡有关。方法与结果我们结合小鼠大脑中动脉闭塞性卒中和暴露于氧葡萄糖剥夺再氧合的神经元来研究其作用和机制。 Dot1L对脑缺血的作用机制 我们发现 Dot1L 的敲低或抑制可逆转缺血诱导的神经元凋亡，并减轻通过氧-葡萄糖剥夺和复氧处理的神经元损伤。更远，Dot1L 的阻断通过增加 RIPK1 K63 泛素化和减少 RIPK1/Caspase 8 复合物的形成来防止 RIPK1（受体相互作用蛋白激酶 1）依赖性细胞凋亡。与此一致，去泛素修饰酶 A20 和去泛素酶圆柱瘤病基因的启动子区域中 H3K79me3 富集促进了氧-葡萄糖剥夺和复氧诱导的神经元细胞的表达增加，相反，氧-葡萄糖剥夺随后复氧减少泛素修饰酶 cIAP1（细胞凋亡蛋白的细胞抑制剂）启动子区域的 H3K79me3 水平，这两个因素最终导致 RIPK1 的 K63 去泛素化。重要的，体内 Dot1L 的敲低或抑制减弱了大脑中动脉闭塞小鼠的细胞凋亡，并降低了大脑中动脉闭塞引起的脑损伤的程度。结论据我们所知，这些数据首次支持 Dot1L 调节 RIPK1 对凋亡死亡触发因素的影响有助于脑缺血损伤。因此，靶向 Dot1L 可作为缺血性卒中的新治疗策略。