Xiao Manjun, Wang Xiaohong, Xiao Enhua, Ming Qianwen
Department of Radiology, The Second Xiangya Hospital of Central South University, No. 139, Renmin Middle Road, Furong District, Changsha City, Hunan Province, 410011, China.
Funct Integr Genomics. 2025 Jan 18;25(1):17. doi: 10.1007/s10142-024-01522-9.
Post-traumatic epilepsy (PTE) is a debilitating chronic outcome of traumatic brain injury (TBI). Although FTO has been reported as a possible intervention target of TBI, its precise roles in the PTE remain incompletely understood. Here we used mild or serious mice TBI model to probe the role and molecular mechanism of FTO in PTE. The results of electroencephalography showed that frequency of epilepsy in serious TBI model mice was more obvious. Using quantitative PCR (qPCR) and western blot analysis, we demonstrated that FTO and NR4A2 were downregulated, while m6A level of NR4A2 mRNA was upregulated in the hippocampus of serious TBI mice. Functionally, FTO overexpression was found to reduce epilepsy susceptibility, blood-brain barrier (BBB) disruption and neuronal damage in TBI mice, suggested a role for FTO in PTE. In addition, RNA-binding protein immunoprecipitation and dual-luciferase assay experiment showed that NR4A2 was a target of FTO, and FTO upregulated NR4A2 expression through m6A-YTHDF2 manner. Furthermore, the molecular and histological changes caused by FTO overexpression are markedly reversed by NR4A2 knockdown in TBI mice. Collectively, our results demonstrate that FTO alleviates epilepsy susceptibility and brain injury after TBI by mediating epigenetic up-regulation of NR4A2, which implicates it as a potential therapeutic target for PTE.
创伤后癫痫（PTE）是创伤性脑损伤（TBI）导致的一种使人衰弱的慢性后果。尽管已报道FTO可能是TBI的干预靶点，但其在PTE中的精确作用仍未完全明确。在此，我们使用轻度或重度小鼠TBI模型来探究FTO在PTE中的作用及分子机制。脑电图结果显示，重度TBI模型小鼠的癫痫发作频率更为明显。通过定量PCR（qPCR）和蛋白质免疫印迹分析，我们证明在重度TBI小鼠的海马体中，FTO和NR4A2表达下调，而NR4A2 mRNA的m6A水平上调。在功能上，发现FTO过表达可降低TBI小鼠的癫痫易感性、血脑屏障（BBB）破坏及神经元损伤，提示FTO在PTE中发挥作用。此外，RNA结合蛋白免疫沉淀和双荧光素酶报告基因实验表明NR4A2是FTO的靶点，且FTO通过m6A - YTHDF2方式上调NR4A2表达。此外，在TBI小鼠中，NR4A2基因敲低可显著逆转FTO过表达所引起的分子和组织学变化。总体而言，我们的结果表明，FTO通过介导NR4A2的表观遗传上调来减轻TBI后的癫痫易感性和脑损伤，这表明它可能是PTE的一个潜在治疗靶点。
