Dermatology and Venereology Division, Department of Medicine (Solna), Center for Molecular Medicine, Karolinska Institute, 17176 Stockholm, Sweden.
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 17176 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2019 May 7;116(19):9443-9452. doi: 10.1073/pnas.1814097116. Epub 2019 Apr 24.
An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-β signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed "wound and keratinocyte migration-associated lncRNA 1" (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.
越来越多的研究揭示了长非编码 RNA（lncRNAs）在许多生理和病理过程中的基因表达调控中的重要性。然而，它们在皮肤伤口愈合中的作用仍知之甚少。我们的研究集中在一种皮肤特异性 lncRNA，LOC105372576，其表达在生理伤口愈合过程中增加。然而，在人类非愈合性伤口中，与再上皮化的正常伤口相比，其水平显著降低。我们将 LOC105372576 表征为核定位、RNAPII 转录和多聚腺苷酸化的 lncRNA。在角质形成细胞中，其表达受 TGF-β 信号诱导。LOC105372576 的敲低和其内源性转录的激活分别降低和增加了角质形成细胞的迁移和人离体皮肤伤口的再上皮化。因此，LOC105372576 被命名为“伤口和角质形成细胞迁移相关 lncRNA1”（WAKMAR1）。进一步的研究表明，WAKMAR1 通过通过将 DNA 甲基转移酶隔离来干扰 E2F1 启动子甲基化，从而调节细胞迁移的重要蛋白编码基因网络。从机制上讲，WAKMAR1 通过干扰 E2F1 启动子甲基化来增强 E2F1 的表达。总之，我们已经确定了一种对角质形成细胞迁移很重要的 lncRNA，其缺乏可能与慢性伤口的发病机制有关。
