SETD2 epidermal deficiency promotes cutaneous wound healing via activation of AKT/mTOR Signalling.
SETD2 epidermal deficiency promotes cutaneous wound healing via activation of AKT/mTOR Signalling.
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SETD2 表皮缺陷通过激活 AKT/mTOR 信号促进皮肤伤口愈合
DOI：
10.1111/cpr.13045
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发表时间：
2021-06
影响因子：
8.5
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Li X;Liu C;Zhu Y;Rao H;Liu M;Gui L;Feng W;Tang H;Xu J;Gao WQ;Li L
皮肤伤口愈合是世界范围内的主要医学问题之一。表观遗传修饰剂已被确定为皮肤发育、体内平衡和伤口修复的重要参与者。 SET 结构域包含 2 (SETD2) 是唯一已知的组蛋白 H3K36 三甲基化酶；然而，它在皮肤伤口愈合中的作用仍不清楚。为了阐明 SETD2 在伤口愈合中的生物学作用，使用条件基因靶向来产生表皮特异性 Setd2 缺陷小鼠。在小鼠背部进行伤口愈合实验，收集受伤的皮肤组织并通过苏木精和伊红（H&E）和免疫组织化学染色进行分析。在体外，对 Setd2 敲低和 Setd2 过表达人类永生化角质形成细胞系 (HaCaT) 进行 CCK8 和划痕伤口愈合测定。此外，还进行了 RNA-seq 和 H3K36me3 ChIP-seq 分析，以确定 SETD2 调节的失调基因。最后，结果在使用 AKT 和 mTOR 抑制剂（MK2206 和雷帕霉素）的功能性救援实验中得到了验证。成功建立了表皮特异性Setd2缺陷小鼠，SETD2缺陷通过促进角质形成细胞增殖和迁移，导致皮肤伤口愈合过程中加速上皮化。此外，SETD2的缺失增强了体外角质形成细胞的划痕闭合和增殖。从机制上讲，Setd2 的缺失导致 AKT/mTOR 信号通路的激活，而分别用 MK2206 和雷帕霉素对 AKT 和 mTOR 进行药理学抑制，延迟伤口闭合。我们的结果表明 SETD2 缺失通过激活 AKT/mTOR 信号传导促进皮肤伤口愈合。表皮特异性 Setd2 缺陷小鼠在皮肤伤口愈合过程中通过促进角质形成细胞增殖和迁移而加速上皮化。从机制上讲，Setd2 的缺失导致 AKT/mTOR 信号通路激活，MK2206 和雷帕霉素分别对 AKT 和 mTOR 进行药理抑制，延迟伤口闭合。
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. 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). 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. Our results showed that SETD2 loss promoted cutaneous wound healing via the activation of AKT/mTOR signalling. The epidermis‐specific Setd2‐deficient mice showed accelerated re‐epithelialization during cutaneous wound healing by promoting keratinocytes proliferation and migration. Mechanistically, deletion of Setd2 resulted in the activation the AKT/mTOR signalling pathway and pharmacological inhibitions of AKT and mTOR with MK2206 and rapamycin delayed wound closure, respectively.
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影响因子：
16.6
作者：
Miao, Qi;Ku, Amy T.;Nishino, Yudai;Howard, Jeffrey M.;Rao, Ajay S.;Shaver, Timothy M.;Garcia, Gloria E.;Le, Diep N.;Karlin, Kristen L.;Westbrook, Thomas F.;Poli, Valeria;Nguyen, Hoang
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影响因子：
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