UTX/KDM6A Deletion Promotes Recovery of Spinal Cord Injury by Epigenetically Regulating Vascular Regeneration

Abstract

The regeneration of the blood vessel system post spinal cord injury (SCI) is essential for the repair of neurological function. As a significant means to regulate gene expression, epigenetic regulation of angiogenesis in SCI is still largely unknown. Here, we found that Ubiquitously Transcribed tetratricopeptide repeat on chromosome X (UTX), the histone H3K27 demethylase, increased significantly in endothelial cells post SCI. Knockdown of UTX can promote the migration and tube formation of endothelial cells. The specific knockout of UTX in endothelial cells enhanced angiogenesis post SCI accompanied with improved neurological function. In addition, we found regulation of UTX expression can change the level of microRNA 24 (miR-24) in vitro . The physical binding of UTX to the promotor of miR-24 was indicated by chromatin immunoprecipitation (ChIP) assay. Meanwhile, methylation sequencing of endothelial cells demonstrated that UTX could significantly decrease the level of methylation in the miR-24 promotor. Furthermore, miR-24 significantly abolished the promoting effect of UTX deletion on angiogenesis in vitro and in vivo . Finally, we predicted the potential target mRNAs of miR-24 related to angiogenesis. We indicate that UTX deletion can epigenetically promote the vascular regeneration and functional recovery post SCI by forming a regulatory network with miR-24.

LncRNA Xist Contributes to Endogenous Neurological Repair After Chronic Compressive Spinal Cord Injury by Promoting Angiogenesis Through the miR-32-5p/Notch-1 Axis

“…Here, we confirm that angiogenesis serves as a beneficial factor to improve neurological function after CCSCI, which is supported by many other published studies. For instance, the ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX)/lysine demethylase 6A (KDM6A) deletion in a mouse SCI model has been shown to promote neurological function by epigenetically regulating vascular regeneration (Ni et al, 2019). Moreover, hepatocyte growth factor was demonstrated to enhance endogenous repair and functional recovery in a rat SCI model by promoting neuron and oligodendrocyte survival, angiogenesis, and axonal regrowth (Kitamura et al, 2007).…”

“…This evidence confirms that angiogenesis plays a key role in the progress of neurological repair after SCI, especially during the chronic injury phase. Many factors and pathways have been shown to be important in the regulation of angiogenesis (Casella et al, 2002;Kitamura et al, 2007;Acar et al, 2012;Yang et al, 2017;Ni et al, 2019). Notch-1 is a well-known factor that can alter the level of angiogenesis in various diseases including rheumatoid arthritis (Gao et al, 2012), cancer (Dos Santos et al, 2017;Jin et al, 2017), and psoriasis (Rooney et al, 2014) by regulating downstream genes.…”

Overexpression of Rictor in the injured spinal cord promotes functional recovery in a rat model of spinal cord injury

“…Effective tissue repair of the injured spinal cord is closely related to functional recovery after SCI 42 . The motor recovery analysis using BBB scores in SCI model rats clearly show that an increased score reflects a biologically significant change 24 .…”

Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis

“…The MEPSs of the hindlimb were assessed by electromyography at 8 weeks postsurgery as previously described [16]. After effective anesthesia, the stimulating electrodes were secured onto the surface of the skull corresponding to the motor cortex area, and recording electrodes were inserted into the tibialis anterior muscle in the contralateral hindlimb.…”