Mbd2 Mediates Retinal Cell Apoptosis by Targeting the lncRNA Mbd2-AL1/miR-188-3p/Traf3 Axis in Ischemia/Reperfusion Injury
Mbd2 Mediates Retinal Cell Apoptosis by Targeting the lncRNA Mbd2-AL1/miR-188-3p/Traf3 Axis in Ischemia/Reperfusion Injury
复制标题
Mbd2 在缺血/再灌注损伤中通过靶向 lncRNA Mbd2-AL1/miR-188-3p/Traf3 轴介导视网膜细胞凋亡
DOI：
10.1016/j.omtn.2020.01.011
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发表时间：
2020-03-06
影响因子：
8.8
通讯作者：
Li, Huiling
中科院分区：
文献类型：
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作者：
Ge, Yanni;Zhang, Ran;Li, Huiling
最近的研究报道，DNA甲基化参与视网膜细胞死亡。甲基化CpG结合域蛋白2（Methyl-CpG binding domain protein 2，Mbd 2）是DNA甲基化的一种。其作用和监管机制仍不清楚。本研究采用原代培养视网膜神经节细胞（RGC）和Mbd 2基因敲除（Mbd 2-KO）小鼠的缺血/再灌注（I/R）模型。我们证明Mbd 2介导I/R损伤引起的RGC凋亡。从机制上讲，数据表明Mbd 2通过其启动子的去甲基化上调Mbd 2相关的长非编码RNA 1（Mbd 2-AL 1）。此外，Mbd 2-AL 1海绵microRNA（miR）-188-3p，从而阻止肿瘤坏死因子（TNF）受体相关因子3（Traf 3）下调，并诱导RGC凋亡。抑制miR-188- 3 p降低了Mbd 2-AL 1小干扰RNA（siRNA）的抗凋亡作用，这一事实进一步证明了这一点。最后，显示Mbd 2-KO小鼠视网膜细胞凋亡减弱，视觉功能保留，这与Mbd 2-AL 1/miR-188- 3 p/Traf 3轴相关。本研究揭示了Mbd 2在RGC凋亡中的作用，为视网膜缺血性疾病的治疗提供了新的思路。
Recent studies reported that DNA methylation was involved in retinal cell death. Methyl-CpG binding domain protein 2 (Mbd2) is one of the DNA methylation readers. Its role and mechanism of regulation remain unclear. The ischemia/reperfusion (I/R) model in mice primary culture retinal ganglion cells (RGCs) and Mbd2 knockout (Mbd2-KO) mice was used in the current study. We demonstrated that Mbd2 mediates RGC apoptosis caused by I/R injury. Mechanistically, the data suggested that Mbd2 upregulated Mbd2-associated long noncoding RNA 1 (Mbd2-AL1) via demethylation of its promoter. Furthermore, Mbd2-AL1 sponged microRNA (miR)-188-3p, thus preventing tumor necrosis factor (TNF) receptor-associated factor 3 (Traf3) downregulation and inducing RGC apoptosis. This was further demonstrated by the fact that inhibition of miR-188-3p diminished the anti-apoptosis role of Mbd2-AL1 small interfering RNA (siRNA). Finally, it showed that the apoptosis of retinal cells was attenuated, and the visual function was preserved in Mbd2-KO mice, which were associated with the Mbd2- AL1/miR-188-3p/Traf3 axis. Our present study revealed the role of Mbd2 in RGC apoptosis, which may provide a novel therapeutic strategy for retinal ischemic diseases.