Embryonic cells exhibit diverse metabolic states. Recent studies have demonstrated that metabolic reprogramming drives changes in cell identity by affecting gene expression. However, the connection between cellular metabolism and gene expression remains poorly understood. Here we report that glycolysis-regulated histone lactylation couples the metabolic state of embryonic cells with chromatin organization and gene regulatory network (GRN) activation. We found that lactylation marks genomic regions of glycolytic embryonic tissues, like the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis. This process promotes the accessibility of active enhancers and the deployment of the NC GRN. Reducing the deposition of the mark by targeting LDHA/B leads to the downregulation of NC genes and the impairment of cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism that involves transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism that integrates cellular metabolism with the GRNs that orchestrate embryonic development.

胚胎细胞表现出不同的代谢状态。最近的研究表明，代谢重编程通过影响基因表达来驱动细胞身份的变化。然而，细胞代谢和基因表达之间的联系仍然知之甚少。在这里，我们报道糖酵解调节的组蛋白乳酰化将胚胎细胞的代谢状态与染色质组织和基因调控网络（GRN）激活结合起来。我们发现乳酰化标记了糖酵解胚胎组织的基因组区域，例如神经嵴（NC）和前体节中胚层。当这些细胞上调糖酵解时，组蛋白乳酰化发生在 NC 基因位点中。这一过程促进了活性增强剂的可及性和 NC GRN 的部署。通过靶向 LDHA/B 来减少标记的沉积会导致 NC 基因下调和细胞迁移受损。乳酰辅酶 A 在 NC 增强子组蛋白上的沉积得到了涉及转录因子 SOX9 和 YAP/TEAD 的机制的支持。这些发现定义了一种表观遗传机制，该机制将细胞代谢与协调胚胎发育的 GRN 整合起来。