Post-injury stress signals alter epigenetic profile of cytosine methylation in the proviral genome of endogenous retroviruses

The majority of epigenetic methylation events at cytosine residues of the genome are reported to occur in transposable elements, as a result, it contributes to genome stability by repressing their transposition activity. Our recent studies demonstrated that the expression of certain murine endogenous retroviruses (MuERVs), a family of retrotransposons, is modulated in the liver after burn injury and sepsis. In this study, we investigated whether burn-elicited stress signals alter epigenetic methylation profile of cytosine residues of the MuERV proviral genome. Female C57BL/6J mice were subjected to ~ 18% total body surface area burn. The genomic DNAs from the livers, which were collected at 3 and 24 h after burn, were treated with bisulfite to convert unmethylated cytosines (C) to thymines (T). From four experimental groups (no burn-3 h, burn-3 h, no burn-24 h, and burn-24 h), 91, 98, 94, and 86 unique U3 sequences (from sense or antisense strand) were cloned, respectively and a total of 16 different U3 sizes were identified among them. The survey of C to T conversions in these U3 sequences revealed that the epigenetic profiles of cytosine methylation are differentially affected (increase or decrease in demethylated cytosine residues) by stress signals from burn and/or anesthesia-resuscitation in a position of cytosine residue and/or size of U3 sequence-specific manner. In addition, the methylation characteristics of the majority of cytosine residues of the different U3 sequences within each size group were conserved. The findings from this study suggest that burn-elicited stress signals contribute to a transient or permanent alteration in cytosine methylation characteristics of certain MuERV loci in the genome, potentially modulating transcription activity of their own as well as neighboring genes.