RNA-binding proteins (RBPs), long non-coding RNAs (lncRNAs), and small nucleolar RNAs (snoRNAs) were found to play crucial regulatory roles in ischemic injury. Based on GEO databases and our experimental results, we selected Dcp2, lncRNA-RNCR3, Dkc1, and Snora62 and Foxh1 as research candidates. We found that expression levels of Dcp2, RNCR3, Dkc1, Snora62, and Foxh1 were upregulated in oxygen glucose deprivation-treated HT22 cells and hippocampal tissues subject to chronic cerebral ischemia (CCI). Silencing of Dcp2, RNCR3, Dkc1, Snora62, and Foxh1 all inhibited apoptosis of oxygen glucose deprivation-treated HT22 cells. Moreover, Dcp2 promoted RNCR3 expression by increasing its stability. Importantly, RNCR3 may act as a molecular skeleton to bind to Dkc1 and recruit Dck1 to promote snoRNP assembly. Snora62 was responsible for pseudouridylation at 28S rRNA U3507 and U3509 sites. Pseudouridylation levels of 28S rRNA were reduced after knockdown of Snora62. Decreased pseudouridylation levels inhibited the translational activity of its downstream target, Foxh1. Our study further confirmed that Foxh1 transcriptionally promoted the expression of Bax and Fam162a. Notably, experiments in vivo showed that Dcp2 knockdown combined with RNCR3 knockdown and Snora62 knockdown resulted in an anti-apoptosis effect. In conclusion, this study suggests that the axis Dcp2/RNCR3/Dkc1/Snora621 is important for the regulation of neuronal apoptosis induced by CCI.

Graphical Abstract

中文翻译：

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Dcp2/RNCR3/Dkc1/Snora62轴调控慢性脑缺血神经元凋亡的机制

发现 RNA 结合蛋白 (RBP)、长链非编码 RNA (lncRNA) 和小核仁 RNA (snoRNA) 在缺血性损伤中起着至关重要的调节作用。基于 GEO 数据库和我们的实验结果，我们选择 Dcp2、lncRNA-RNCR3、Dkc1、Snora62 和 Foxh1 作为研究候选对象。我们发现 Dcp2、RNCR3、Dkc1、Snora62 和 Foxh1 的表达水平在氧葡萄糖剥夺处理的 HT22 细胞和遭受慢性脑缺血 (CCI) 的海马组织中上调。Dcp2、RNCR3、Dkc1、Snora62 和 Foxh1 的沉默均抑制氧葡萄糖剥夺处理的 HT22 细胞的凋亡。此外，Dcp2 通过增加其稳定性来促进 RNCR3 的表达。重要的是，RNCR3 可能作为分子骨架与 Dkc1 结合并募集 Dck1 以促进 snoRNP 组装。Snora62 负责 28S rRNA U3507 和 U3509 位点的假尿苷化。敲除 Snora62 后，28S rRNA 的假尿苷化水平降低。降低的假尿苷化水平抑制了其下游靶标 Foxh1 的翻译活性。我们的研究进一步证实 Foxh1 转录促进 Bax 和 Fam162a 的表达。值得注意的是，体内实验表明，Dcp2 敲低与 RNCR3 敲低和 Snora62 敲低相结合可产生抗细胞凋亡作用。总之，本研究表明轴 Dcp2/RNCR3/Dkc1/Snora621 对于调节 CCI 诱导的神经细胞凋亡很重要。降低的假尿苷化水平抑制了其下游靶标 Foxh1 的翻译活性。我们的研究进一步证实 Foxh1 转录促进 Bax 和 Fam162a 的表达。值得注意的是，体内实验表明，Dcp2 敲低与 RNCR3 敲低和 Snora62 敲低相结合可产生抗细胞凋亡作用。总之，本研究表明轴 Dcp2/RNCR3/Dkc1/Snora621 对于调节 CCI 诱导的神经细胞凋亡很重要。降低的假尿苷化水平抑制了其下游靶标 Foxh1 的翻译活性。我们的研究进一步证实 Foxh1 转录促进 Bax 和 Fam162a 的表达。值得注意的是，体内实验表明，Dcp2 敲低与 RNCR3 敲低和 Snora62 敲低相结合可产生抗细胞凋亡作用。总之，本研究表明轴 Dcp2/RNCR3/Dkc1/Snora621 对于调节 CCI 诱导的神经细胞凋亡很重要。

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