Guo Zhu, Li Chengjun, Cao Yong, Qin Tian, Jiang Liyuan, Xu Yan, Li Miao, Luo Zixiang, Hu Jianzhong, Lu Hongbin
Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China.
Spine Surgery Department of the Affiliated Hospital of Qingdao University, Qingdao 266000, China.
Mol Ther Methods Clin Dev. 2020 Dec 10;20:337-349. doi: 10.1016/j.omtm.2020.12.004. eCollection 2021 Mar 12.
Interrupted axons that fail to regenerate mainly cause poor recovery after spinal cord injury (SCI). How neurons epigenetically respond to injury determines the intrinsic growth ability of axons. However, the mechanism underlying epigenetic regulation of axonal regeneration post-SCI remains largely unknown. In this study, we elucidated the role of the epigenetic regulatory network involving ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX)/microRNA-24 (miR-24)/NeuroD1 in axonal regeneration and functional recovery in mice following SCI. Our results showed that UTX was significantly increased post-SCI and repressed axonal regeneration . However, downregulation of UTX remarkably promoted axonal regeneration. Furthermore, miR-24 was increased post-SCI and positively regulated by UTX. miR-24 also inhibited axonal regeneration. Chromatin immunoprecipitation (ChIP) indicated that UTX binds to the miR-24 promoter and regulates miR-24 expression. Genome sequencing and bioinformatics analysis suggested that NeuroD1 is a potential downstream target of UTX/miR-24. A dual-luciferase reporter assay indicated that miR-24 binds to NeuroD1; moreover, it represses axonal regeneration by negatively regulating the expression of NeuroD1 via modulation of microtubule stability. UTX deletion prominently promoted axonal regeneration and improved functional recovery post-SCI, and silencing NeuroD1 restored UTX function. Our findings indicate that UTX could be a potential target in SCI.
未能再生的中断轴突是脊髓损伤（SCI）后恢复不佳的主要原因。神经元如何通过表观遗传对损伤做出反应决定了轴突的内在生长能力。然而，SCI后轴突再生的表观遗传调控机制仍 largely 未知。在本研究中，我们阐明了涉及X染色体上普遍转录的四肽重复序列（UTX）/微小RNA-24（miR-24）/神经分化因子1（NeuroD1）的表观遗传调控网络在SCI后小鼠轴突再生和功能恢复中的作用。我们的结果表明，SCI后UTX显著增加并抑制轴突再生。然而，UTX的下调显著促进了轴突再生。此外，miR-24在SCI后增加并受UTX正向调控。miR-24也抑制轴突再生。染色质免疫沉淀（ChIP）表明UTX与miR-24启动子结合并调节miR-24表达。基因组测序和生物信息学分析表明NeuroD1是UTX/miR-24的潜在下游靶点。双荧光素酶报告基因测定表明miR-24与NeuroD1结合；此外，它通过调节微管稳定性负向调节NeuroD1的表达来抑制轴突再生。UTX缺失显著促进了SCI后轴突再生并改善了功能恢复，而沉默NeuroD1恢复了UTX功能。我们的研究结果表明UTX可能是SCI的一个潜在靶点。
