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KV-JDBT230227_AuthorCorr_AttachmentsFolder_Yang et al DIABETES_supplemental information 11.9.2023 clean copy[AU].pdf (1.4 MB)

Re-epithelialization of Diabetic Skin and Mucosal Wounds is Rescued by Treatment with Epigenetic Inhibitors

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Version 2 2023-11-27, 17:32
Version 1 2023-10-24, 16:11
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posted on 2023-11-27, 17:32 authored by Bo Yang, Stella Alimperti, Michael V. Gonzalez, Tzvete Dentchev, Minjung Kim, Justin Suh, Paul M. Titchenell, Kang I. Ko, John Seykora, Manju Benakanakere, Dana T. Graves

Wound healing is a complex, highly regulated process and is substantially disrupted by diabetes. We show here that human wound healing induces specific epigenetic changes that are exacerbated by diabetes in an animal model. We identified epigenetic changes and gene expression alterations that significantly reduce re-epithelialization of skin and mucosal wounds in an in vivo model of diabetes, which were dramatically rescued in vivo by blocking these changes. We demonstrate that high glucose altered FOXO1-MMP9 promoter interactions through increased demethylation and reduced methylation of DNA at FOXO1 binding sites and also by promoting permissive histone-3 methylation. Mechanistically, high glucose promotes interaction between FOXO1 and RNA polymerase-II (Pol-II) to produce high expression of MMP9 that limits keratinocyte migration. The negative impact of diabetes on re-epithelialization in vivo was blocked by specific DNA demethylase inhibitors in vivo and by blocking permissive histone-3 methylation, which rescues FOXO1-impaired keratinocyte migration. These studies point to novel treatment strategies for delayed wound healing in individuals with diabetes. They also indicate that FOXO1 activity can be altered by diabetes through epigenetic changes that may explain other diabetic complications linked to changes in diabetes-altered FOXO1-DNA interactions.

Funding

This work was funded by grants R01DE019108, R01DE017732 from the National Institute of Dental and Craniofacial Research (DTG), R01DE031046 from the National Institute of Dental and Craniofacial Research (SA), and R01DE030415 from the National Institute of Dental and Craniofacial Research (KIK).

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