Dux promotes metabolism-lactylation-MET cascaded network during early iPSC reprogramming with Brg1 as the histone lactylation reader [Cut & Tag]
The process of reprogramming induced pluripotent stem cells (iPSCs) involves several crucial events, including the shutdown of somatic genes, the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. These events intricately interact and influence each other, ultimately leading to the formation of iPSCs. However, the specific element that regulates the reprogramming network remains unclear. Dux, a factor known to promote totipotency during the transition from embryonic stem cells (ESCs) to 2C-like ESCs (2CLC), has not been extensively studied in the context of iPSC reprogramming. In this study, we demonstrate that the modification of H3K18la induced by Dux overexpression controls the metabolism-H3K18la-MET network, enhancing the efficiency of iPSC reprogramming through a metabolic switch and the recruitment of P300 via its C-terminal domain. Through the utilization of H3K18la regulators, we discover that H3K18la plays crucial roles in promoting MET. Furthermore, our proteomic analysis of H3K18la IP experiment uncover the specific recruitment of Brg1 during reprogramming, with both H3K18la and Brg1 being enriched on the promoters of genes associated with epithelial and pluripotency. In summary, our study has demonstrated the significant role of Dux-induced H3K18la in the early reprogramming process, highlighting its function as a potent trigger. Additionally, our research has revealed, for the first time, the binding of Brg1 to H3K18la, indicating its role as a reader of histone lactylation. Overall design: Comparative gene expression profiling analysis of CUT&Tag data for MEF, D4, D4-OE-DUX, and iPSC .