UTX/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration.
UTX/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration.
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UTX/KDM6A 缺失通过表观遗传触发内在神经再生促进脊髓损伤的恢复
DOI：
10.1016/j.omtm.2020.12.004
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发表时间：
2021-03-12
期刊：
影响因子：
--
通讯作者：
Lu H
中科院分区：
文献类型：
--
作者：
Guo Z;Li C;Cao Y;Qin T;Jiang L;Xu Y;Li M;Luo Z;Hu J;Lu H
中断的轴突不能再生，主要是脊髓损伤(SCI)后恢复不佳。神经元对损伤的表观遗传反应决定了轴突的内在生长能力。然而，脊髓损伤后轴突再生的表观遗传调控机制仍然很大程度上不清楚。在这项研究中，我们阐明了涉及染色体X(UTX)/microRNA-24(miR-24)/NeuroD1上普遍转录的四肽重复序列的表观遗传调控网络在小鼠脊髓损伤后轴突再生和功能恢复中的作用。我们的结果表明，UTX显著增加了脊髓损伤后的轴突再生并抑制了体外培养的轴突再生。而下调UTX则显著促进轴突再生。此外，脊髓损伤后miR-24表达增加，且受UTX正向调节。MIR-24也抑制轴突再生。染色质免疫沉淀(ChIP)结果表明，UTX与miR-24启动子结合并调节miR-24的表达。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。双荧光素酶报告分析表明miR-24与NeuroD1结合；此外，它通过调节微管稳定性来负性调节NeuroD1的表达，从而抑制轴突再生。体内UTX缺失显著促进脊髓损伤后轴突再生和功能恢复，沉默NeuroD1可恢复UTX功能。我们的发现表明UTX可能是脊髓损伤的潜在靶点。郭美美等人。描述了脊髓损伤(SCI)后轴突再生的表观遗传调控机制。UTX和miR-24形成表观遗传复合体，调节NeuroD1的表达，进而影响脊髓损伤后微管的稳定性和轴突再生。这为脊髓损伤的治疗策略开辟了新的可能性。
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 in vitro. 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 in vivo 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. Guo et al. described an epigenetic regulatory mechanism of axon regeneration after spinal cord injury (SCI). UTX and miR-24 form an epigenetic complex to regulate expression of NeuroD1, which further influences microtubule stability and axon regeneration after SCI. This opens new possibilities for therapeutic strategies of SCI.
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影响因子：
64.5
作者：
Cho Y;Sloutsky R;Naegle KM;Cavalli V
通讯作者：
Cavalli V
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
自噬诱导可稳定微管并促进脊髓损伤后轴突再生。
DOI：
10.1073/pnas.1611282113
发表时间：
2016-10-04
影响因子：
11.1
作者：
He, Miao;Ding, Yuetong;Luo, Zhen-Ge
通讯作者：
Luo, Zhen-Ge
影响因子：
16.2
作者：
Lee, Jae K.;Geoffroy, Cedric G.;Chan, Andrea F.;Tolentino, Kristine E.;Crawford, Michael J.;Leal, Marisa A.;Kang, Brian;Zheng, Binhai
通讯作者：
Zheng, Binhai
DOI：
10.1038/nrn.2017.46
发表时间：
2017-05-18
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Hwang JY;Aromolaran KA;Zukin RS
通讯作者：
Zukin RS