Histone lactylation couples cellular metabolism with developmental gene regulatory networks. This study shows that glycolysis-regulated histone lactylation links the metabolic state of embryonic cells to chromatin organization and gene regulatory network (GRN) activation. Lactylation marks genomic regions of glycolytic embryonic tissues, such as the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis, promoting enhancer accessibility and GRN activation. Reducing lactylation by targeting LDHA/B leads to downregulation of NC genes and impaired cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism involving transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism integrating cellular metabolism with GRNs that orchestrate embryonic development. Cell diversification involves the deployment of tissue-specific GRNs that determine cell identity and function. Differential gene expression is key for proper development. Embryonic cells exhibit heterogeneity in non-genetic factors, such as metabolism. Metabolic reprogramming is crucial for specific functions at various developmental stages. For example, embryonic stem cells (ESCs) have increased glycolysis, which decreases as they differentiate. These metabolic transitions affect cellular functions, as glycolysis inhibition in pluripotent stem cells interferes with their pluripotent state. In vitro studies show that metabolic switching is germ-layer-specific and controlled by transcription factors. Embryos also show spatial heterogeneity in metabolic states. Chick embryos have different glucose uptake patterns along the anterior-posterior and dorsal-ventral axes, indicating specific metabolic requirements for different tissues. The presomitic mesoderm (PSM) and neural crest have metabolism as an important determinant for development and gene expression. In the PSM, glycolytic flux influences Wnt signaling and cell motility. High glycolysis is important for neural crest cell migration. Disruptions in metabolic states in these cells lead to developmental defects, highlighting the importance of metabolic transitions for gene expression and cell behavior. The mechanisms coupling cellular metabolism with GRN activation remain largely unexplored. Lactate overproduction is a consequence of aerobic glycolysis in NCCs. In a 2019 study, Zhang et al. identified glycolysis-derived lysine lactylation (Kla) as a new histone mark. They showed that M1 macrophages have high lactylation levels, and during the M1 to M2 transition, lactylation is deposited around genes associated with M2 phenotypes. Histone Kla directly stimulates gene transcription. The regulatory effects of lactylation on gene expression are supported by findings that H3K18la marks promoters and active enhancers in a tissue-specific manner similar to H3K27ac. In a 2022 study, Dai et al.Histone lactylation couples cellular metabolism with developmental gene regulatory networks. This study shows that glycolysis-regulated histone lactylation links the metabolic state of embryonic cells to chromatin organization and gene regulatory network (GRN) activation. Lactylation marks genomic regions of glycolytic embryonic tissues, such as the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis, promoting enhancer accessibility and GRN activation. Reducing lactylation by targeting LDHA/B leads to downregulation of NC genes and impaired cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism involving transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism integrating cellular metabolism with GRNs that orchestrate embryonic development. Cell diversification involves the deployment of tissue-specific GRNs that determine cell identity and function. Differential gene expression is key for proper development. Embryonic cells exhibit heterogeneity in non-genetic factors, such as metabolism. Metabolic reprogramming is crucial for specific functions at various developmental stages. For example, embryonic stem cells (ESCs) have increased glycolysis, which decreases as they differentiate. These metabolic transitions affect cellular functions, as glycolysis inhibition in pluripotent stem cells interferes with their pluripotent state. In vitro studies show that metabolic switching is germ-layer-specific and controlled by transcription factors. Embryos also show spatial heterogeneity in metabolic states. Chick embryos have different glucose uptake patterns along the anterior-posterior and dorsal-ventral axes, indicating specific metabolic requirements for different tissues. The presomitic mesoderm (PSM) and neural crest have metabolism as an important determinant for development and gene expression. In the PSM, glycolytic flux influences Wnt signaling and cell motility. High glycolysis is important for neural crest cell migration. Disruptions in metabolic states in these cells lead to developmental defects, highlighting the importance of metabolic transitions for gene expression and cell behavior. The mechanisms coupling cellular metabolism with GRN activation remain largely unexplored. Lactate overproduction is a consequence of aerobic glycolysis in NCCs. In a 2019 study, Zhang et al. identified glycolysis-derived lysine lactylation (Kla) as a new histone mark. They showed that M1 macrophages have high lactylation levels, and during the M1 to M2 transition, lactylation is deposited around genes associated with M2 phenotypes. Histone Kla directly stimulates gene transcription. The regulatory effects of lactylation on gene expression are supported by findings that H3K18la marks promoters and active enhancers in a tissue-specific manner similar to H3K27ac. In a 2022 study, Dai et al.