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.

体细胞重编程提供了对细胞命运确定的基本原理的深入了解，目前尚不清楚。在这里，我们显示了转录因子Glis1在干细胞中诱导多水平的表观遗传和代谢重构，从而促进了多能性的诱导。我们发现，Glis1能够将衰老细胞重编程为多能细胞并改善基因组稳定性。在重编程的早期阶段，Glis1直接结合并打开糖酵解基因上的染色质，而它关闭体细胞基因上的染色质以上调糖酵解。随后，更高的糖酵解通量提高了细胞的乙酰辅酶A和乳酸水平，从而增强了所谓的“第二波”和多能性基因位点的乙酰化（H3K27Ac）和乳酸化（H3K18la），将它们打开以促进细胞重编程。