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

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.

Microglia-Derived Exosomal microRNA-151-3p Enhances Functional Healing After Spinal Cord Injury by Attenuating Neuronal Apoptosis via Regulating the p53/p21/CDK1 Signaling Pathway

“…Primary cortical neurons were isolated from fetal mice (E14-16) as previously described ( Guo Z. et al, 2021 ). Briefly, the cortical brains of the fetal mice were removed and placed into a cold PBS solution.…”

“…Microglia could interact with almost all CNS cells during normal status and diseased development by transferring a large number of factors that are crucial for CNS function. One emerging novel propagating model of such cell-to-cell communication is through the release of exosomes ( Guo Z. et al, 2021 ). Microglia-released exosomes can be taken up by neurons and affect recipient cell neurogenesis and neuronal cell apoptosis.…”

Bone Marrow Mesenchymal Stem Cell-Derived Exosome-Educated Macrophages Promote Functional Healing After Spinal Cord Injury

“…Tests were performed three times with an interval of 10 min before model induction and on days 1, 3, and 7 and once per week thereafter for 8 weeks post SCI. The hindlimb motor evoked potential (MEP) and latent period were obtained as previously described ( Guo et al, 2021 ). Briefly, recording needle electrodes were inserted intramuscularly into the tibialis anterior muscle of the hindlimbs.…”

Comprehensive analysis of m6A methylation modification in chronic spinal cord injury in mice

“…10 It has been reported that knockdown of the epigenetic factor Ubiquitously Transcribed tetratricopeptide repeat on chromosome X (UTX) can facilitate axon regeneration and angiogenesis after acute spinal cord injury by targeting microRNA-24. 11,12 Epigenetic modifications are also involved in angiogenesis after chronic compressive spinal cord injury through the Xist/miR-32-5p/Notch-1 axis. 13 Among epigenetic modifications, N6-methyladenosine (m6A) is the most common and abundant mRNA modification.…”

“…Inhibiting HDAC1 was found to promote neuronal loss and DNA damage, which further deteriorated behavioral outcomes after stroke 10 . It has been reported that knockdown of the epigenetic factor Ubiquitously Transcribed tetratricopeptide repeat on chromosome X (UTX) can facilitate axon regeneration and angiogenesis after acute spinal cord injury by targeting microRNA‐24 11,12 . Epigenetic modifications are also involved in angiogenesis after chronic compressive spinal cord injury through the Xist/miR‐32‐5p/Notch‐1 axis 13 …”