Corticosterone-mediated regulation and functions of miR-218-5p in rat brain.
Corticosterone-mediated regulation and functions of miR-218-5p in rat brain.
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DOI：
10.1038/s41598-021-03863-y
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发表时间：
2022-01-07
影响因子：
4.6
通讯作者：
Dwivedi Y
中科院分区：
文献类型：
--
作者：
Yoshino Y;Roy B;Dwivedi Y
慢性应激是重性抑郁障碍（MDD）的重要促发因素之一。压力相关研究强调了表观遗传主要参与者如microRNA（miRNAs）在临床前和临床水平上在抑郁症病理生理学中的机制作用。此前，我们曾报道过皮质酮（CORT）诱导的慢性应激反应中miR-218- 5 p表达的变化。MiR-218- 5 p是慢性应激条件下大鼠前额叶皮层（PFC）中最显著诱导的miRNAs之一。在本报告中，我们研究了慢性CORT暴露如何机械地影响大鼠脑中miR-218- 5 p的表达，以及miR-218如何触发其下游调控途径的分子变化。在皮质醇治疗的大鼠PFC中发现miR-218- 5 p的表达升高。糖皮质激素受体（GR）靶向染色质免疫沉淀（ChIP）试验显示，在其第3内含子中的miR-218-2所在的Slit 3基因的启动子区域上存在高GR占用率。在SH-SY 5 Y细胞中，基于AGO 2的RNA诱导沉默复合物免疫沉淀（RISC-IP）的RNA测序数据检测到miR-218- 5 p的六个一致的靶基因（APOL 4、DTWD 1、BNIP 1、胃L22、SNAPC 1和HDAC 6）。除APOL 4外，所有五个基因的表达都在CORT处理的大鼠PFC中成功地用qPCR进行了验证。此外，基于Hdac 6的ChIP-seq实验有助于定位CORT处理的大鼠PFC中富含基因间区域的主要基因组位点。基于邻近性的基因本体论（GO）分析显示，大多数的基因间位点是涉及中枢神经系统功能的关键基因的一部分，特别是突触组织，神经元投射形态发生和轴突发生。我们的研究结果表明，皮质醇处理大鼠PFC中miR-218- 5 p的上调可能是由于GR结合在Slit 3基因的启动子区。有趣的是，Hdac 6是可能发现的通过染色质修饰调节CNS相关基因的一致靶基因之一。总的来说，这些发现确立了miR-218- 5 p在慢性应激中的作用，以及它在引发应激诱导的疾病（包括抑郁症）中诱导几种CNS基因的基于染色质的转录变化中发挥的表观遗传功能。这也为理解miR-218- 5 p作为临床抑郁症非编码RNA治疗的潜在靶点的作用开辟了范围。
Chronic stress is one of the key precipitating factors in major depressive disorder (MDD). Stress associated studies have underscored the mechanistic role of epigenetic master players like microRNAs (miRNAs) in depression pathophysiology at both preclinical and clinical levels. Previously, we had reported changes in miR-218-5p expression in response to corticosterone (CORT) induced chronic stress. MiR-218-5p was one of the most significantly induced miRNAs in the prefrontal cortex (PFC) of rats under chronic stress. In the present report, we have investigated how chronic CORT exposure mechanistically affected miR-218-5p expression in the rat brain and how miR-218 could trigger molecular changes on its downstream regulatory pathways. Elevated expression of miR-218-5p was found in the PFC of CORT-treated rats. A glucocorticoid receptor (GR) targeted Chromatin-Immunoprecipitation (ChIP) assay revealed high GR occupancy on the promoter region of Slit3 gene hosting miR-218-2 in its 3rd intron. RNA-sequencing data based on RNA Induced silencing Complex Immunoprecipitation (RISC-IP) with AGO2 in SH-SY5Y cells detected six consistent target genes of miR-218-5p (APOL4, DTWD1, BNIP1, METTL22, SNAPC1, and HDAC6). The expression of all five genes, except APOL4, was successfully validated with qPCR in CORT-treated rat PFC. Further, Hdac6-based ChIP-seq experiment helped in mapping major genomic loci enriched for intergenic regions in the PFC of CORT-treated rat. A proximity-based gene ontology (GO) analysis revealed a majority of the intergenic sites to be part of key genes implicated in central nervous system functions, notably synapse organization, neuron projection morphogenesis, and axonogenesis. Our results suggest that the upregulation of miR-218-5p in PFC of CORT-treated rats possibly resulted from GR biding in the promoter region of Slit3 gene. Interestingly, Hdac6 was one of the consistent target genes potentially found to regulate CNS related genes by chromatin modification. Collectively, these findings establish the role of miR-218-5p in chronic stress and the epigenetic function it plays to induce chromatin-based transcriptional changes of several CNS genes in triggering stress-induced disorders, including depression. This also opens up the scope to understand the role of miR-218-5p as a potential target for noncoding RNA therapeutics in clinical depression.
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影响因子：
4.8
作者：
Gao, L;Cueto, MA;Atadja, P
通讯作者：
Atadja, P
影响因子：
3.3
作者：
Dwivedi, Y.;Rizavi, H. S.;Pandey, G. N.
通讯作者：
Pandey, G. N.
影响因子：
3.7
作者：
Glessner JT;Wang K;Sleiman PM;Zhang H;Kim CE;Flory JH;Bradfield JP;Imielinski M;Frackelton EC;Qiu H;Mentch F;Grant SF;Hakonarson H
通讯作者：
Hakonarson H
影响因子：
6.6
作者：
Cutano, Valentina;Di Giorgio, Eros;Brancolini, Claudio
通讯作者：
Brancolini, Claudio
影响因子：
4.8
作者：
Hobara, Teruyuki;Uchida, Shusaku;Watanabe, Yoshifumi
通讯作者：
Watanabe, Yoshifumi