An extreme chronic wound tissue microenvironment causes epigenetic gene silencing. Unbiased whole-genome methylome was studied in the wound-edge (WE) tissue of chronic wound patients. A total of 4689 differentially methylated regions (DMRs) were identified in chronic WE compared to unwounded (UW) human skin. Hypermethylation was more frequently observed (3661 DMRs) in the chronic WE compared to hypomethylation (1028 DMRs). Twenty-six hypermethylated DMRs were involved in epithelial to mesenchymal transition (EMT). Bisulfite sequencing validated hypermethylation of a predicted specific upstream regulator TP53. RNA sequencing analysis was performed to qualify findings from methylome analysis. Analysis of the downregulated genes identified the TP53 signaling pathway as being significantly silenced. Direct comparison of hypermethylation and downregulated genes identified four genes, ADAM17, NOTCH, TWIST1 and SMURF1, that functionally represent the EMT pathway. Single-cell RNA sequencing studies identified that these effects on gene expression were limited to the keratinocyte cell compartment. Experimental murine studies established that tissue ischemia potently induces WE gene methylation and that 5'-azacytidine, inhibitor of methylation, improved wound closure. To specifically address the significance of TP53 methylation, keratinocyte-specific editing of TP53 methylation at the WE was achieved by a tissue nanotransfection (TNT) based CRISPR/dCas9 approach. This work identified that reversal of methylation-dependent keratinocyte gene-silencing represents a productive therapeutic strategy to improve wound closure.