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

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Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways
STEM CELLS ( IF 4.0 ) Pub Date : 2020-05-05 , DOI: 10.1002/stem.3188
Qi Jiang ₁ , Xingwei Huang ₁ , Xinglin Hu ₁ , Zhiyan Shan ₁ , Yanshuang Wu ₁ , Guangming Wu ₂ , Lei Lei _{1,

3}

Affiliation

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 induced pluripotent stem cell (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. Furthermore, 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 the metabolic pattern in a demethylation‐activity‐dependent manner. These results may provide an insight into the relationship between epigenomics, transcriptomics, metabolomics, and reprogramming.

中文翻译：

组蛋白去甲基化酶 KDM6A 通过表观遗传调节 PTEN 和 IL-6 信号通路促进体细胞重编程

异常的表观遗传重编程是体细胞重编程的主要障碍之一。虽然我们之前的研究表明 H3K27me3 去甲基化酶 KDM6A 可以提高核重编程效率，但机制尚不清楚。在这项研究中，我们证明了 Kdm6a 的过表达可以以去甲基酶活性依赖的方式提高诱导多能干细胞 (iPSC) 的重编程效率。KDM6A 清除了多能性和代谢相关基因上的 H3K27me3，从而促进了将基因表达谱和代谢模式改变为中间状态。此外，KDM6A 可能促进 IL-6 表达，分泌的 IL-6 可能进一步提高 iPSC 重编程效率。此外，KDM6A 可能促进 PTEN 表达以降低 p-AKT 和 p-mTOR 水平，这反过来又促进了重新编程。总的来说，我们的结果表明，KDM6A 可能通过以去甲基化活性依赖的方式加速基因表达谱和代谢模式的变化来提高 iPSC 重编程效率。这些结果可能有助于深入了解表观基因组学、转录组学、代谢组学和重编程之间的关系。

更新日期：2020-05-05

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