Mechanistic study on Lnc-Gstm5 regulation of the SUV39H1/H3K9me3 axis in hyperbaric oxygen-mediated suppression of inflammatory response following spinal cord injury

Abstract

Hyperbaric oxygen (HBO) suppresses the inflammatory response following spinal cord injury (SCI). However, the underlying detailed mechanisms are still to be clarified. Here we explored the mechanism of long non-coding RNA (lncRNA) glutathione s-transferase mu 5 (Gstm5) regulating NF-κB signaling pathway in HBO-mediated suppression of inflammatory response following SCI. In the current study, SCI cell model was developed with lipopolysaccharides (LPS)-induced BV2 cells and processed with HBO treatment, si-NC, and si-Lnc-Gstm5. Lnc-Gstm5, NF-κB p65, IL-1β，IL-6, TNF-a, suppressor of variegation 3-9 homolog 1 (SUV39H1), histone 3 lysine 9 trimethylation (H3K9me3), YTH domain containing 2 (YTHDC2) expression level were measured. The mice SCI model was generated and treated with HBO treatment, shRNA-Lnc-Gstm5. Lnc-Gstm5 was identified and BMS score, histopathological injury score, and inflammatory factors were evaluated. We found that HBO suppresses inflammatory response through up-regulating Lnc-Gstm5 level in a manner of YTHDC2-dependent m6A modification. Lnc-Gstm5 recruits SUV39H1 to up-regulate H3K9me3 expression level and suppresses NF-κB signaling pathway by reducing p65 phosphorylation. HBO suppresses the inflammatory response via YTHDC2/Lnc-Gstm5/SUV39H1/H3K9me3/NF-κB axis following SCI in mice. These results reveal a Lnc-Gstm5-driven epigenetic regulation mechanism, and targeting Lnc-Gstm5 represents a promising therapeutic strategy for SCI patients.

Keywords: Histone methylation; Hyperbaric oxygen; Inflammatory response; N6- methyladenosine; Spinal cord injury; lncRNA Gstm5.