Histone lactylation couples cellular metabolism with developmental gene regulatory networks

• Published in: Nature communications 2024-01, Vol.15 (1), p.90-19, Article 90
• Main Authors: Merkuri, Fjodor, Rothstein, Megan, Simoes-Costa, Marcos
• Format: Article
• Language: English
• Subjects: 13; 14; 14/63; 38; 38/109; 38/22; 38/91; 45; 45/23; 45/77; 49; 49/31; 49/39; 631/136/142; 631/136/756/1456; 631/337/100/2285; 631/337/176; Cell differentiation; Cell migration; Cellular communication; Chromatin; Deposition; Differentiation (biology); Embryogenesis; Embryonic growth stage; Enhancers; Epigenetics; Gene expression; Genes; Glycolysis; Histones; Humanities and Social Sciences; Mesoderm; Metabolism; multidisciplinary; Neural crest; Science; Science (multidisciplinary); Sox9 protein; Transcription factors; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44121-1

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. While metabolic reprogramming has been shown to drive changes in cell identity, the link between cellular metabolism and gene expression remains poorly characterized. Here they show that histone lactylation couples metabolism and transcription during neural crest cell differentiation in the early embryo.