Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade
Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade
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Glis1 通过表观基因组-代谢组-表观基因组信号级联促进多能性的诱导。
DOI：
10.1038/s42255-020-0267-9
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发表时间：
2020-09-01
影响因子：
20.8
通讯作者：
Liu, Xingguo
中科院分区：
文献类型：
--
作者：
Li, Linpeng;Chen, Keshi;Liu, Xingguo
体细胞重编程提供了对细胞命运决定的基本原理的深入了解，但人们对此仍知之甚少。在这里，我们证明转录因子 Glis1 诱导干细胞进行多级表观遗传和代谢重塑，从而促进多能性的诱导。我们发现 Glis1 能够将衰老细胞重编程为多能细胞并提高基因组稳定性。在重编程的早期阶段，Glis1 直接结合并打开糖酵解基因的染色质，而关闭体细胞基因的染色质以上调糖酵解。随后，更高的糖酵解通量增强细胞乙酰辅酶A和乳酸水平，从而增强所谓的“第二波”和多能性基因位点的乙酰化（H3K27Ac）和乳酰化（H3K18la），打开它们以促进细胞重编程。我们的工作强调了 Glis1 作为一种强大的重编程因子，并揭示了表观基因组-代谢组-表观基因组信号级联，涉及细胞命运决定背景下糖酵解驱动的组蛋白乙酰化和乳酰化协调。
Somatic cell reprogramming provides insight into basic principles of cell fate determination, which remain poorly understood. Here we show that the transcription factor Glis1 induces multi-level epigenetic and metabolic remodelling in stem cells that facilitates the induction of pluripotency. We find that Glis1 enables reprogramming of senescent cells into pluripotent cells and improves genome stability. During early phases of reprogramming, Glis1 directly binds to and opens chromatin at glycolytic genes, whereas it closes chromatin at somatic genes to upregulate glycolysis. Subsequently, higher glycolytic flux enhances cellular acetyl-CoA and lactate levels, thereby enhancing acetylation (H3K27Ac) and lactylation (H3K18la) at so-called 'second-wave' and pluripotency gene loci, opening them up to facilitate cellular reprogramming. Our work highlights Glis1 as a powerful reprogramming factor, and reveals an epigenome-metabolome-epigenome signalling cascade that involves the glycolysis-driven coordination of histone acetylation and lactylation in the context of cell fate determination.