Abstract
It has been shown that epigenetic regulation plays an important role in skin wound healing. We previously found that histone H3K27me3 demethylase JMJD3 regulates inflammation and cell migration in keratinocyte wound healing. In this study, we identified Notch1 as a direct target of JMJD3 and NF-κB in wounded keratinocytes using in vitro cell and in vivo animal models. We found that Notch1 is up-regulated in the wound edge and its expression is dependent on JMJD3 and NF-κB in wounded keratinocytes. We also found that Notch1 activates the expression of RhoU and PLAU gene, which are critical regulators of cell migration. Consistently, depletion or inactivation of Notch1 resulted in decreased filopodia formation, increased focal adhesion and actin stress fiber, leading to reduced keratinocyte migration and skin wound healing. Thus, our findings provide the molecular mechanism involving JMJD3/NF-κB-Notch pathway in keratinocyte wound healing.
Highlights
The skin forms physical and immunological barriers from the external environment to maintain water balance, body temperature, insulation, sensation, and immunity[1, 2]
We demonstrated that JMJD3 and NF-κB-dependent Notch[1] activation is required for the regulation of focal adhesion, filopodia, and stress fiber formation though RhoU and uPA gene expressions, leading to keratinocyte migration during the early phase of skin wound healing
Notch signaling plays an important role in epidermal differentiation and skin maintenance, the molecular mechanism underlying Notchmediated keratinocyte wound healing has not been fully elucidated
Summary
The skin forms physical and immunological barriers from the external environment to maintain water balance, body temperature, insulation, sensation, and immunity[1, 2]. The skin wound healing process occurs in four overlapping stages: haemostasis, inflammation, migration and proliferation, and remodeling[3, 4]. Keratinocytes distant from the wound edge actively proliferate, resulting in the filling of the wound gap. Accumulation evidences have revealed that Notch signaling plays an important role in skin development, homeostasis, and wound healing by the regulation of differentiation, proliferation, and apoptosis[8,9,10,11]. To activate Notch signaling, the interaction between a transmembrane Notch receptor and a transmembrane ligand is required on two adjacent cells. Abnormal Notch signaling results in impaired epidermal differentiation, proliferation, and inflammation, leading to a variety of skin diseases including skin cancer, psoriasis, and atopic dermatitis[10, 11, 17]
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