Department of Pharmacology, The Fourth Military Medical University, Xi'an, China.
Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Exp Neurol. 2018 Oct;308:132-142. doi: 10.1016/j.expneurol.2018.07.007. Epub 2018 Jul 18.
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 downstream Bax and Caspase-3 genes. Silencing Jmjd3 improved neurological deficit and reduced infarct volume following ischemic injury in vivo. The present study suggested that JMJD3 was a critical promoter of neuronal apoptosis by regulating the expression of Bax and Caspase-3, and inhibition of JMJD3 might provide a new therapeutic intervention for treating cerebral ischemia.
组蛋白甲基化对缺血性脑卒中后神经元凋亡中 p53 的控制密切相关。在哺乳动物细胞中，组蛋白赖氨酸残基的去甲基化由含有 Jumonji 结构域的蛋白（JMJD）家族催化。其中，JMJD3 被报道为缺氧靶基因，在包括神经元在内的大脑所有细胞类型中表达。然而，JMJD3 在缺血性脑卒中后神经元凋亡过程中的作用在很大程度上仍然未知。PCR、免疫染色和 Western blot 结果表明，在氧葡萄糖剥夺（OGD）损伤下，培养神经元中的 JMJD3 表达上调。Jmjd3 神经元表现出抑制细胞凋亡和对 OGD 损伤的耐受性。染色质免疫沉淀和启动子报告基因分析表明，其潜在机制是通过转录激活 p53，从而改变下游 Bax 和 Caspase-3 基因。体内沉默 Jmjd3 可改善缺血性损伤后的神经功能缺损和梗死体积减少。本研究表明，JMJD3 通过调节 Bax 和 Caspase-3 的表达，是神经元凋亡的关键启动子，抑制 JMJD3 可能为治疗脑缺血提供新的治疗干预。
