| Title | SETD2 epidermal deficiency promotes cutaneous wound healing via activation of AKT/mTOR Signalling |
| Authors | Li, Xiaoxue Liu, Changwei Zhu, Yiwen Rao, Hanyu Liu, Min Gui, Liming Feng, Wenxin Tang, Huayuan Xu, Jin Gao, Wei-Qiang Li, Li |
| Affiliation | Shanghai Jiao Tong Univ, Ren Ji Hosp, State Key Lab Oncogenes & Related Genes, Sch Med,Renji Med X Clin Stem Cell Res Ctr, Shanghai, Peoples R China Shanghai Jiao Tong Univ, Ren Ji Hosp, Renji Med X Clin Stem Cell Res Ctr, Sch Biomed Engn, Shanghai, Peoples R China Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai, Peoples R China Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai, Peoples R China Shanghai Univ Tradit Chinese Med, Sch Rehabil Sci, Shanghai, Peoples R China Peking Univ, Sch Chem Biol & Biotechnol, State Key Lab Chem Oncogen, Shenzhen Grad Sch, Shenzhen, Peoples R China |
| Keywords | HISTONE METHYLTRANSFERASE SETD2 KERATINOCYTE MIGRATION EPIGENETIC REGULATION SKIN GENE REPAIR REEPITHILIALIZATION IDENTIFICATION METHYLATION SUPPRESSOR |
| Issue Date | May-2021 |
| Publisher | CELL PROLIFERATION |
| Abstract | Objectives Cutaneous wound healing is one of the major medical problems worldwide. Epigenetic modifiers have been identified as important players in skin development, homeostasis and wound repair. SET domain-containing 2 (SETD2) is the only known histone H3K36 tri-methylase; however, its role in skin wound healing remains unclear. Materials and Methods To elucidate the biological role of SETD2 in wound healing, conditional gene targeting was used to generate epidermis-specific Setd2-deficient mice. Wound-healing experiments were performed on the backs of mice, and injured skin tissues were collected and analysed by haematoxylin and eosin (H&E) and immunohistochemical staining. In vitro, CCK8 and scratch wound-healing assays were performed on Setd2-knockdown and Setd2-overexpression human immortalized keratinocyte cell line (HaCaT). In addition, RNA-seq and H3K36me3 ChIP-seq analyses were performed to identify the dysregulated genes modulated by SETD2. Finally, the results were validated in functional rescue experiments using AKT and mTOR inhibitors (MK2206 and rapamycin). Results Epidermis-specific Setd2-deficient mice were successfully established, and SETD2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing by promoting keratinocyte proliferation and migration. Furthermore, the loss of SETD2 enhanced the scratch closure and proliferation of keratinocytes in vitro. Mechanistically, the deletion of Setd2 resulted in the activation of AKT/mTOR signalling pathway, while the pharmacological inhibition of AKT and mTOR with MK2206 and rapamycin, respectively, delayed wound closure. Conclusions Our results showed that SETD2 loss promoted cutaneous wound healing via the activation of AKT/mTOR signalling. |
| URI | http://hdl.handle.net/20.500.11897/613097 |
| ISSN | 0960-7722 |
| DOI | 10.1111/cpr.13045 |
| Indexed | SCI(E) |
| Appears in Collections: | 化学生物学与生物技术学院 å å¦ä¸ å å å·¥ç¨ å¦é ¢ |
