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JMJD3 and NF-?B-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing.

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-?B 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-?B 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-?B-Notch pathway in keratinocyte wound healing.

SUBMITTER: Na J

PROVIDER: S-EPMC5529578 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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JMJD3 and NF-κB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing.

Na Jungtae J Shin Jee Yoon JY Jeong Hayan H Lee Jee Youn JY Kim Beom Joon BJ Kim Won Sun WS Yune Tae Young TY Ju Bong-Gun BG

Scientific reports 20170726 1

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 keratinocyte ...[more]

PMID: 28747631

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Project description:Background and purposeIn addition to its analgesic functions, the peripheral opioid receptor system affects skin homeostasis by influencing cell differentiation, migration and adhesion; also, wound healing is altered in δ-opioid receptor knockout mice (DOPr(-/-) ). Hence, we investigated δ-opioid receptor effects on the expression of several proteins of the desmosomal junction complex and on the migratory behaviour of keratinocytes.Experimental approachExpression levels of desmosomal cadherins in wild-type and DOPr(-/-) mice, and the morphology of intercellular adhesion in human keratinocytes were analysed by immunofluorescence. To investigate the δ-opioid receptor activation pathway, protein expression was studied using Western blot and its effect on cellular migration determined by in vitro live cell migration recordings from human keratinocytes.Key resultsExpression of the desmosomal cadherins, desmogleins 1 and 4, was up-regulated in skin from DOPr(-/-) mice, and down-regulated in δ-opioid receptor-overexpressing human keratinocytes. The localization of desmoplakin expression was rearranged from linear arrays emanating from cell borders to puncta in cell periphery, resulting in less stable intercellular adhesion. Migration and wound recovery were enhanced in human keratinocyte monolayers overexpressing δ-opioid receptors in vitro. These δ-opioid receptor effects were antagonized by specific PKCα/β inhibition indicating they were mediated through the PKC signalling pathway. Finally, cells overexpressing δ-opioid receptors developed characteristically long but undirected protrusions containing filamentous actin and δ-opioid receptors, indicating an enhanced migratory phenotype.Conclusion and implicationsOpioid receptors affect intercellular adhesion and wound healing mechanisms, underlining the importance of a cutaneous neuroendocrine system in wound healing and skin homeostasis.Linked articlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Dataset Information

JMJD3 and NF-?B-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing.

Publications

JMJD3 and NF-κB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing.

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