Jarid1b Promotes Epidermal Differentiation by Mediating Repression of Ship1 and Activation of AKT/Ovol1 Pathway

Abstract

The role of epigenetic regulators in the control of epithelial cell differentiation is largely undefined. Our studies showed that H3K4me3 was decreased during epidermal differentiation. Unexpectedly, both expression of histone methyltransferases and demethylases over H3K4me3 were elevated upon differentiation, suggesting the crucial role of demethylases in controlling of differentiation. Next we found that the demethylase Jarid1b positively regulated epidermal differentiation. ShRNA-mediated depletion of Jarid1b delayed the calcium induced HaCaT cell differentiation in vitro and impaired differentiation layer formation in reconstituted epidermis in vivo. Conversely, overexpression of Jarid1b increased epidermal differentiation gene expression and inhibited cell proliferation and migration in culture. Mechanistically, we found that Jarid1b substantially increased mesenchymal-epithelial transition (MET) gene expression, among which Ovol1 positively regulated differentiation gene expression. In addition，Ovol1 expression was repressed by PI3K-AKT pathway inhibitors and suppressor Ship1 overexpression. Knockdown of Ship1 activated downstream PI3K-AKT pathway and enhanced Ovol1 expression in HaCaT cells. Importantly, we found that Jarid1b negatively regulated Ship1 expression, but not of Pten, via directly binding to its promoter to modulate H3K4me3 enrichment. Taken together, our results indentify an essential role for Jarid1b in regulation of Ship1/AKT/Ovol1 pathway to promote epithelial cell differentiation. Funding Statement: This work was supported by National Natural Science Foundation of China (81672662, 81701381, 81770978 and 81774248), Key Research and Development Program of Shandong Province (2017GSF18193, 2018GSF118012), Natural Science Foundation of Shandong Province (ZR2014CM040) and Shandong Provincial Education Department Program (J14LK02). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All experimental protocols were approved by the ethics committee of animal care of Affiliated Hospital of Qingdao University. All animal studies were performed in strict accordance with the approved protocol.