Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways.

Aberrant epigenetic reprogramming is one of the major barriers for somatic cell reprogramming. Although our previous study has indicated that H3K27me3 demethylase KDM6A can improve the nuclear reprogramming efficiency, the mechanism remains unclear. In this study, we demonstrate that the overexpression of Kdm6a may improve iPSC reprogramming efficiency in a demethylase enzymatic activity-dependent manner. KDM6A erased H3K27me3 on pluripotency- and metabolism-related genes, and consequently facilitated changing the gene expression profile and metabolic pattern to an intermediate state. Further, KDM6A may promote IL-6 expression, and the secreted IL-6 may further improve iPSC reprogramming efficiency. In addition, KDM6A may promote PTEN expression to decrease p-AKT and p-mTOR levels, which in turn facilitates reprogramming. Overall, our results reveal that KDM6A may promote iPSC reprogramming efficiency by accelerating changes in the gene expression profile and metabolic pattern in a demethylation-activity-dependent manner. These results may provide an insight into the relationship between epigenomics, transcriptomics, metabolomics and reprogramming. (c) AlphaMed Press 2020 SIGNIFICANCE STATEMENT: iPSC-based treatment allows potential therapy for multiple diseases; however, its low efficiency limits its further application. In the present study, we demonstrated that KDM6A may improve iPSC reprogramming efficiency in a demethylase enzymatic activity-dependent manner. Further, KDM6A-induced H3K27me3 distribution may alter the gene expression profile and metabolic pattern of MEFs. We ultimately found that the PTEN and IL-6 pathways contributed to improving reprogramming.