Epigenetic predisposition and pathogenic mechanisms of recessive dystrophic epidermolysis bullosa

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Abstract Fragility of the skin, development of poorly healing and chronic wounds, fibrosis, and squamous cell carcinoma (SSC) are common features in patients suffering from hereditary Recessive Dystrophic Epidermolysis Bullosa (RDEB). The disease is caused by mutations in Col7A1 gene, which lead to lack or dysfunction of type VII collagen and poor anchorage of epidermis to dermis. Multiple investigations, including studies from our group, addressed both RDEB pathophysiology and therapy, and defined factors contributing to RDEB moribund symptoms. It remains unclear why some RDEB skin lesions heal, while other progress to non-healing wounds in the same patient, or why patients harboring same molecular defect in Col7A1 gene may have drastically different cutaneous manifestations. Here, we hypothesize that epigenetic changes occurring in RDEB epidermis affect wound healing, fibrosis, and SCC development and that epigenetic changes could be pharmacologically attenuated to facilitate restoration of RDEB skin integrity after injury and reduction of morbid consequences. Our preliminary data showing drastically reduced H3 histone acetylation and highly significant levels of 5-mC DNA methylation in the RDEB epidermis as well as methylation of promoters of specific genes involved in fibrosis, cell cycle control, and cancer in the primary RDEB-derived keratinocytes strongly support proposed hypothesis. Our exploratory project is designed to define the role of epigenetic regulation of gene expression in RDEB epidermis, outline target genes, and define molecular mechanism(s) responsible for epigenetic changes. In this project, we will also assess whether pharmacological intervention can be used to lessen moribund factors and alleviate moribund RDEB symptoms. The Specific Aims of the project are: 1) To investigate molecular mechanism of epigenetic control, epigenetic changes, and specific targets in RDEB epidermis; and 2) To investigate the contribution of epigenetics to RDEB pathogenesis and evaluate the utility of epigenetic inhibitors to reduce RDEB-associated cutaneous manifestations. It is anticipated that completion of the current project will provide us with the crucial information regarding the role of epigenetic factors in RDEB, and illuminate the path to better management of RDEB-associated painful and moribund manifestations and define molecular pathways controlling epigenetic gene regulation as relevant to wound healing, fibrosis, and SCC susceptibility.