Human Skin Long Non-coding Rna Wakmar1 Regulates Wound Healing By Enhancing Keratinocyte Migration
Dongqing Li1, Lara Kular1, Manika Vij1, Eva K. Herter1, Xi Li1, Aoxue Wang2, Tongbin Chu2, Maria-Alexandra Toma1, Letian Zhang1, Eleni Liapi1, Lennart Blomqvist1, Irène Gallais Sérézal1, Ola Rollman3, Jakob D. Wikstrom1, David Berglund4, Mona Ståhle1, Pehr Sommar5, Maja Jagodic1, Ning Xu Landén1.
1Karolinska Institute, Stockholm, Sweden, 2The Second Hospital of Dalian Medical University, Dalian, China, 3Academic University Hospital, Uppsala, Sweden, 4Uppsala University, Uppsala, Sweden, 5Karolinska University Hospital, Stockholm, Sweden.
BACKGROUND: Increasing number of studies reveals the importance of long non-coding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. METHODS: We focused on a skin specific lncRNA LOC105372576, and studied its expression and function in human wounds. RESULTS: We found that LOC105372576 expression was increased during physiologic wound healing. In human non-healing wounds, however, its level was significantly lower compared to normal wounds under re-epithelization. LOC105372576 was characterized 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 re-epithelization of human ex vivo skin wounds. Therefore, LOC105372576 was termed as 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. CONCLUSIONS: Collectively, we have identified a novel lncRNA important for keratinocyte migration which deficiency may be involved in the pathogenesis of chronic wounds.
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