Inhibiting Jumoji domain containing protein 3 (JMJD3) prevent neuronal apoptosis from stroke
Inhibiting Jumoji domain containing protein 3 (JMJD3) prevent neuronal apoptosis from stroke
复制标题
抑制含有 Jumoji 结构域的蛋白 3 (JMJD3) 可预防中风引起的神经元凋亡
DOI：
10.1016/j.expneurol.2018.07.007
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发表时间：
2018
影响因子：
5.3
通讯作者：
Mingkai Li
中科院分区：
文献类型：
--
作者：
Huinan Zhang;Jun Wang;Jing Huang;Tingyu Shi;Xue Ma;Xiaoxing Luo;Xia Li;Mingkai Li
组蛋白甲基化调控p53与缺血性脑卒中后神经细胞凋亡密切相关。在哺乳动物细胞中，组蛋白甲基化赖氨酸残基的去甲基化由Jumonji结构域蛋白（JMJD）家族催化。其中，JMJD3被报道为缺氧靶基因，并且在包括神经元在内的脑的所有细胞类型中表达。然而，JMJD 3在缺血性脑卒中后神经元凋亡过程中的作用仍不清楚。PCR、免疫组化和Western blotting结果显示，在培养的神经元中，Jmjd3表达上调，Jmjd3 −/−神经元对OGD损伤表现出耐受性和细胞凋亡抑制。染色质免疫沉淀和启动子报告基因分析表明，潜在的机制是通过转录激活p53，从而改变下游的p53和Caspase-3基因。沉默Jmjd3可改善缺血性脑损伤后的神经功能缺损并减少梗死体积。本研究提示，JMJD3可能通过调节caspase-3和caspase-3的表达而促进神经细胞凋亡，抑制JMJD3可能为脑缺血的治疗提供新的干预手段。
Control of p53 by histone methylation is closely related in the neuronal apoptosis following ischemic stroke. In mammalian cells, demethylation of methylated lysine residue of histones is catalyzed by Jumonji domain-containing proteins (JMJD) family. Among them, JMJD3 is reported to be a hypoxic target gene and expressed in all cell types of brain including neurons. However, the role of JMJD3 on process of neuronal apoptosis after ischemic stroke is still largely unknown. PCR, immunostaining and Western blotting results indicated that JMJD3 expression was upregulated in cultured neurons upon oxygen–glucose deprivation (OGD) injury.Jmjd3−/−neurons exhibited inhibited cell apoptosis and tolerance to the OGD injury. Chromatin immunoprecipitation and promoter reporter assays showed that the underlying mechanism was through transcriptional activation of p53, thus altering the downstreamBaxandCaspase-3genes. SilencingJmjd3improved neurological deficit and reduced infarct volume following ischemic injuryin vivo. The present study suggested that JMJD3 was a critical promoter of neuronal apoptosis by regulating the expression ofBaxandCaspase-3, and inhibition of JMJD3 might provide a new therapeutic intervention for treating cerebral ischemia.