Xiao RJ, Wang TJ, Wu DY, Yang SF, Gao H, Gan PD, Yi YY, Zhang YL. N6-methyladenosine methyltransferase Wilms tumor 1-associated protein impedes diabetic wound healing through epigenetically activating DNA methyltransferase 1. World J Diabetes 2025; 16(3): 102126 [DOI: 10.4239/wjd.v16.i3.102126]
Corresponding Author of This Article
You-Lai Zhang, PhD, Associate Chief Physician, Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, No. 32 Fuzhou Road, Donghu District, Nanchang 330006, Jiangxi Province, China. youlaizhang@163.com
Research Domain of This Article
Cell Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ren-Jie Xiao, Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China
Tian-Jiao Wang, State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China
Tian-Jiao Wang, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education and College of Life Sciences, Nankai University, Tianjin 300071, China
Dan-Yin Wu, Shui-Fa Yang, Hai Gao, Pei-Dong Gan, Yang-Yan Yi, You-Lai Zhang, Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China
Author contributions: Xiao RJ and Zhang YL designed the research study; Xiao RJ, Wang TJ, Wu DY and Yang SF performed the experiments; Xiao RJ, Gao H and Gan PD collected the data; Xiao RJ, Yi YY and Zhang YL analyzed the data and wrote the manuscript; All authors have read and approved the final manuscript.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University on March 6, 2024.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: You-Lai Zhang, PhD, Associate Chief Physician, Department of Plastic and Cosmetic Surgery, The Second Affiliated Hospital, Jiangxi Medical College of Nanchang University, No. 32 Fuzhou Road, Donghu District, Nanchang 330006, Jiangxi Province, China. youlaizhang@163.com
Received: October 11, 2024 Revised: December 7, 2024 Accepted: January 8, 2025 Published online: March 15, 2025 Processing time: 102 Days and 18.8 Hours
Abstract
BACKGROUND
Diabetic wound injury is a significant and common complication in individuals with diabetes. N6-methyladenosine (m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complications. However, the function of m6A methyltransferase Wilms tumor 1-associated protein (WTAP) in diabetic wound healing remains elusive.
AIM
To investigate the potential epigenetic regulatory mechanism of WTAP during diabetic wound healing.
METHODS
Human umbilical vein endothelial cells (HUVECs) were induced with high glucose (HG) to establish in vitro cell model. Male BALB/c mice were intraperitoneally injected with streptozotocin to mimic diabetes, and full-thickness excision was made to mimic diabetic wound healing. HG-induced HUVECs and mouse models were treated with WTAP siRNAs and DNA methyltransferase 1 (DNMT1) overexpression vectors. Cell viability and migration ability were detected by cell counting kit-8 and Transwell assays. In vitro angiogenesis was measured using a tube formation experiment. The images of wounds were captured, and re-epithelialization and collagen deposition of skin tissues were analyzed using hematoxylin and eosin staining and Masson’s trichrome staining.
RESULTS
The expression of several m6A methyltransferases, including METTL3, METTL14, METTL16, KIAA1429, WTAP, and RBM15, were measured. WTAP exhibited the most significant elevation in HG-induced HUVECs compared with the normal control. WTAP depletion notably restored cell viability and enhanced tube formation ability and migration of HUVECs suppressed by HG. The unclosed wound area of mice was smaller in WTAP knockdown-treated mice than in control mice at nine days post-wounding, along with enhanced re-epithelialization rate and collagen deposition. The m6A levels on DNMT1 mRNA in HUVECs were repressed by WTAP knockdown in HUVECs. The mRNA levels and expression of DNMT1 were inhibited by WTAP depletion in HUVECs. Overexpression of DNMT1 in HUVECs notably reversed the effects of WTAP depletion on HG-induced HUVECs.
CONCLUSION
WTAP expression is elevated in HG-induced HUVECs and epigenetically regulates the m6A modification of DNMT1 to impair diabetic wound healing.
Core Tip: Diabetes mellitus is significantly correlated with non-healing wounds, which cause physiological and psychological distress to patients. N6-methyladenosine (m6A)-associated epigenetic regulation plays a crucial role in diabetes mellitus. However, the function of m6A methyltransferase tumor 1-associated protein (WTAP) in diabetic wound healing remains unclear. Our study demonstrated that WTAP was elevated in high glucose-induced human umbilical vein endothelial cells and epigenetically regulates the m6A modification of DNA methyltransferase 1, repressing diabetic wound healing. This study provides novel insights into the mechanisms by which the m6A regulator WTAP inhibits diabetic wound healing.
