DNA hydroxymethylation mediated traumatic spinal injury by influencing cell death–related gene expression

Spinal cord injury (SCI) is a serious neurological disease, often leading to segmental injury following severe limb dysfunction. Recent studies showed that epigenetic regulation is involved in the pathogenesis of SCI. In this study, we examined the change in 5‐hydroxymethylcytosine (5hmC), a mechanism of demethylation, and its role in SCI in rats. We found that global 5hmC modification significantly increased in traumatic spinal cord tissues. Ten‐eleven translocation (Tet) enzymes are the limiting‐rate enzyme to catalyze the conversion of 5‐methylcytosine to 5hmC. In our study, the data indicated that Tet2, but not Tet1 and Tet3, significantly increased in traumatic spinal cord tissues. Further, we treated rats with SC‐1, a Tet2 expression inhibitor. SC‐1 increased necrotic volume after SCI. To further demonstrate that the damage caused by SC‐1 was related to DNA 5hmC, we examined the messenger RNA (mRNA) expression of many genes that related to cell death and cell survival. Our data showed that the 5hmC levels were related to the mRNA levels of these genes. In conclusion, targeting Tet2 to cause change in 5hmC levels in cell death–related genes may be new therapeutic strategy for the treatment of SCI. Ten‐eleven translocation (Tet)2 and DNA 5‐hydroxymethylcytosine (5hmC) significantly increased in traumatic spinal cord tissues; Inhibition of Tet2 increased necrotic volume after spinal injury; Cell death–related gene expression was strongly associated with DNA 5hmC.