M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats.
M6A RNA Methylation-Based Epitranscriptomic Modifications in Plasticity-Related Genes via miR-124-C/EBPα-FTO-Transcriptional Axis in the Hippocampus of Learned Helplessness Rats.
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DOI：
10.1093/ijnp/pyac068
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发表时间：
2022-12-12
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突触可塑性受损与基因调控网络的动态变化有关。最近，随着独特的基于N6-甲基腺苷(M6A)的可逆转录甲基化的概念的出现，基因调控被引入。在这项研究中，我们测试了m6A RNA甲基化是否可能作为应激性侮辱和可塑性相关基因表达变化之间的联系。用定量聚合酶链式反应方法检测了易感应激性抑郁(习得性无助)大鼠海马区可塑性基因NR3c1、CREb1、NTRK2、M6A修饰酶FTO、甲基转移酶样蛋白(Mett1)-3和14、DNA甲基化酶DNMT1、DNMT3A、转录因子C/eBP-α和miRNA124-3p的表达。免疫沉淀后检测可塑性相关基因M6A甲基化。染色质免疫沉淀法检测C/eBP-α与FTO启动子的内源性结合。用体外模型研究了MIR-124通过C/EBPα对FTO的转录后抑制作用。习得性无助大鼠的海马区表现出NR3C1、Creb1和NTRK2的下调以及它们的m6A甲基化的丰富。脱甲基酶FTO表达下调，甲基化酶METTL3表达上调。由于DNMT1和DNMT3A的低表达，FTO启动子发生了低甲基化。同时，转录因子C/eBPα在FTO启动子上的占有率较低。反之，通过诱导miR-124-3p的表达，C/eBP-α转录本表达下调。我们的研究从机制上连接了缺陷C/EBP-α-FTO轴，受miR-124-3p诱导表达的表观遗传学影响，改变了可塑性相关基因中m6A的丰富。这可能与抑郁症的神经元可塑性异常有关。
Impaired synaptic plasticity has been linked to dynamic gene regulatory network changes. Recently, gene regulation has been introduced with the emerging concept of unique N6-methyladenosine (m6A)-based reversible transcript methylation. In this study, we tested whether m6A RNA methylation may potentially serve as a link between the stressful insults and altered expression of plasticity-related genes. Expression of plasticity genes Nr3c1, Creb1, Ntrk2; m6A-modifying enzymes Fto, methyltransferase like (Mettl)-3 and 14; DNA methylation enzymes Dnmt1, Dnmt3a; transcription factor C/ebp-α; and miRNA-124-3p were determined by quantitative polymerase chain reaction (qPCR) in the hippocampus of rats that showed susceptibility to develop stress-induced depression (learned helplessness). M6A methylation of plasticity-related genes was determined following m6A mRNA immunoprecipitation. Chromatin immunoprecipitation was used to examine the endogenous binding of C/EBP-α to the Fto promoter. MiR-124–mediated post-transcriptional inhibition of Fto via C/EBPα was determined using an in vitro model. Hippocampus of learned helplessness rats showed downregulation of Nr3c1, Creb1, and Ntrk2 along with enrichment in their m6A methylation. A downregulation in demethylating enzyme Fto and upregulation in methylating enzyme Mettl3 were also noted. The Fto promoter was hypomethylated due to the lower expression of Dnmt1 and Dnmt3a. At the same time, there was a lower occupancy of transcription factor C/EBPα on the Fto promoter. Conversely, C/ebp-α transcript was downregulated via induced miR-124-3p expression. Our study mechanistically linked defective C/EBP-α-FTO-axis, epigenetically influenced by induced expression of miR-124-3p, in modifying m6A enrichment in plasticity-related genes. This could potentially be linked with abnormal neuronal plasticity in depression.
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