Ezh2 Mediates Regulation Of Mechanotransduction And Skin Regeneration For The Treatment Of Skin Defect
Jing Wang, M.D., Ph.D., Qingfeng Li, M.D.,Ph.D., Shuangbai Zhou, M.D.,Ph.D..
Shanghai 9th People’s Hospital, Schoolof Medicine, ShanghaiJiao Tong University, Shanghai, China.
For massive skin defect, skin tissue expansion has been demonstrated to be an effective and predominant treatment by inducing skin regeneration through mechanical stretch. However, the mechanotransduction in interfollicular epidermal stem cells (IFESCs) and the mechanism controlling the organized growth of IFESCs under stretch have not been explored.
Using the mechanical stretch model of humans, mice in vivo and IFESCs in vitro, we examined the proliferation status, mechanotransduction (the expression and location of YAP and its target genes) and epigenetic status (DNA methylation and histone methylation) of epidermal stem cells during a long-term stretch.
Here, we report that mechanical stretch promotes short-term skin cell growth followed by long-term cell-growth arrest. In patients undergoing long-term skin tissue expansion, the levels of histone H3 lysine 27 trimethylation (H3K27me3) and its histone methyltransferase, EZH2, are significantly elevated with suppressed Jagged-1 (JAG1), a pro-proliferation target gene of mechano-sensor yes-associated protein (YAP), in the epidermal basal cells of patients’ skin. Under long-term mechanical stimulation, EZH2 is elevated and recruited to the nucleus where it competes with YAP for the binding of TEAD3, a DNA-binding protein facilitating the binding of YAP to the promoter region of JAG1 under short-term stretch, and forms repressive H3K27me3 suppressing JAG1 transcription. Small-molecule inhibitor of EZH2 significantly rescues the long-term stretch-induced cell growth control in IFESCs.
These findings reveal for the first time the involvement of an EZH2-mediated feedback mechanism underlying temporal mechanotransduction in IFESCs and provide a strategy for promoting skin regeneration.
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