UTX/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration

Zhu Guo; Chengjun Li; Yong Cao; Tian Qin; Liyuan Jiang; Yan Xu; Miao Li; Zixiang Luo; Jianzhong Hu; Hongbin Lu

doi:10.1016/j.omtm.2020.12.004

UTX/KDM6A deletion promotes the recovery of spinal cord injury by epigenetically triggering intrinsic neural regeneration

Mol Ther Methods Clin Dev. 2020 Dec 10:20:337-349. doi: 10.1016/j.omtm.2020.12.004. eCollection 2021 Mar 12.

Authors

Zhu Guo^{1

2

3}, Chengjun Li^{1

4}, Yong Cao^{1

4}, Tian Qin^{1

4}, Liyuan Jiang^{1

4}, Yan Xu^{4

5}, Miao Li^{1

4}, Zixiang Luo^{1

4}, Jianzhong Hu^{1

4}, Hongbin Lu^{4

5}

Affiliations

¹ Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China.
² Spine Surgery Department of the Affiliated Hospital of Qingdao University, Qingdao 266000, China.
³ Traumatic Orthopedic Institute of Shandong Province, Affiliated Hospital of Qingdao University, Qingdao 266000, China.
⁴ Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha 410008, China.
⁵ Department of Sports Medicine, Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.

Abstract

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.

Keywords: NeuroD1; UTX; epigenetic regulation; microRNA-24; microtubule stability; spinal cord injury.