Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming
Short-Term Mitochondrial Permeability Transition Pore Opening Modulates Histone Lysine Methylation at the Early Phase of Somatic Cell Reprogramming
复制标题
短期线粒体通透性转变孔开放在体细胞重编程的早期调节组蛋白赖氨酸甲基化。
DOI：
10.1016/j.cmet.2018.08.001
复制
发表时间：
2018-12-04
期刊：
影响因子：
29
通讯作者：
Liu, Xingguo
中科院分区：
文献类型：
--
作者：
Ying, Zhongfu;Xiang, Ge;Liu, Xingguo
体细胞重编程诱导多能干细胞重新配置染色质修饰。这一过程是否以及如何由源自线粒体的信号调节尚不清楚。在这里，我们发现线粒体通透性过渡孔（mPTP）是线粒体稳态的关键调节器，在重编程的早期阶段经历了短期的开放，这种短暂的激活增强了重编程。在小鼠胚胎成纤维细胞中，更大的mPTP开放与更高的重编程效率相关。mPTP打开的重编程促进功能是通过H3K9me2和H3K27me3的植物同源结构域手指蛋白8 （PHF8）去甲基化介导的，导致它们在多能基因启动子区域的占位减少。mPTP打开增加线粒体活性氧产生下游的PHF8蛋白水平和miR-101c，同时提高PHF8的辅助因子α -酮戊二酸的水平。我们的发现代表了一种新的线粒体到细胞核的途径，通过mptp介导的表观遗传调控来决定细胞的命运。
Reprogramming of somatic cells to induced pluripotent stem cells reconfigures chromatin modifications. Whether and how this process is regulated by signals originating in the mitochondria remain unknown. Here we show that the mitochondrial permeability transition pore (mPTP), a key regulator of mitochondrial homeostasis, undergoes short-term opening during the early phase of reprogramming and that this transient activation enhances reprogramming. In mouse embryonic fibroblasts, greater mPTP opening correlates with higher reprogramming efficiency. The reprogramming-promoting function of mPTP opening is mediated by plant homeodomain finger protein 8 (PHF8) demethylation of H3K9me2 and H3K27me3, leading to reduction in their occupancies at the promoter regions of pluripotency genes. mPTP opening increases PHF8 protein levels downstream of mitochondrial reactive oxygen species production and miR-101c and simultaneously elevates levels of PHF8's cofactor, alpha-ketoglutarate. Our findings represent a novel mitochondria-to-nucleus pathway in cell fate determination by mPTP-mediated epigenetic regulation.