Epigenetic reprogramming during wound healing: loss of polycomb‐mediated silencing may enable upregulation of repair genes

Abstract

Tissue repair is a complex process that requires wound-edge cells to proliferate and migrate, which in turn necessitates induction of a large repair transcriptome. Epigenetic modifications have emerged as crucial regulators of gene expression. Here, we ask whether epigenetic reprogramming might contribute to the concerted induction of repair genes by wound-edge cells. Polycomb group proteins (PcGs) co-operatively silence genes by laying down repressive marks such as histone H3 lysine 27 trimethylation (H3K27me3), which can be removed by specific demethylases. We show that PcGs Eed, Ezh2 and Suz12 are significantly downregulated during murine skin repair, whereas the newly described demethylases Jmjd3 and Utx are markedly upregulated. Correspondingly, we find a striking reduction of repressive H3K27me3 in the wound epidermis. Quantitative chromatin immunoprecipitation studies have revealed that there is less Eed bound to the regulatory regions of two paradigm wound-induced genes, Myc and Egfr, suggesting that loss of polycomb-mediated silencing might contribute to the induction of repair genes.

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

“…Moreover, only full-thickness wounds induce the migration of cells from neighboring HFs to the place of injury. The molecular mechanism underlying both the attraction and homing of potential tumor-initiating cells or cells contributing to tumor formation remains an important topic for future studies and is likely to depend on the specific cytokine and growth factor milieu and involve alteration of epigenetic patterns (37).…”

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance

“…Recent genome-wide mapping of sites on chromatin that contain H3K27me3 and are bound by PcG proteins have identified hundreds of putative Polycomb target genes in Drosophila and several thousand in human cells (7)(8)(9)(10). In addition to their well-established role in maintaining cell identities, PcG proteins have been implicated in many processes relevant to aging, including stem cell pluripotency and self-renewal, regulation of cell cycle exit, regeneration and wound healing, tumorigenesis, and DNA repair, suggesting that PcG proteins may also modulate organismal life span (1,(11)(12)(13)(14)(15)(16).…”

The Epigenetic Regulation of Wound Healing

“…Shaw and Martin postulated that PcG proteins may play important roles in wound repair, and found that the expression of PRC2 complex components Ezh2, Suz12, and Eed was transiently downregulated during wound healing in in vivo murine models. 61 Additionally, immunohistochemical expression patterns illustrated a paucity of Eed and Ezh2 at the wound margin, while it was abundant further away from the wound. 61 In contrast, the expression of H3K27 histone demethylases JMJD3 and Utx was upregulated.…”

“…61 Additionally, immunohistochemical expression patterns illustrated a paucity of Eed and Ezh2 at the wound margin, while it was abundant further away from the wound. 61 In contrast, the expression of H3K27 histone demethylases JMJD3 and Utx was upregulated. Levels of both Eed and Ezh2 were, however, restored once re-epithelialization was complete, suggesting that there is a transient activation of repair genes via loss of PcG-proteinmediated silencing to permit epithelial closure.…”

“…Levels of both Eed and Ezh2 were, however, restored once re-epithelialization was complete, suggesting that there is a transient activation of repair genes via loss of PcG-proteinmediated silencing to permit epithelial closure. 61 Our unpublished observations demonstrate that histone deacetylases HDAC1 and HDAC2 are expressed in a human migrating wound epithelial tongue during skin regeneration, indicating their significant involvement during this process.…”