Histone acylation marks respond to metabolic perturbations and enable cellular adaptation

Cellular adaptation: chromosomal protein modification acts as metabolic stress sensor Tracking the modification of a protein essential to chromosome structure could indicate the metabolic state of cells. Histone proteins provide structural support for chromosomes, and their modification influences metabolic signaling and gene expression. One possible modification adds an acyl group to the histone (acylation). Eun-Jung Cho at Sungkyunkwan University, Suwon, South Korea, and co-workers explored acylation of histone H3K23 under specific metabolic challenges, including reduced availability of glucose and metabolic enzymes. Mammalian cells rapidly alter gene expression in response to nutrient availability, enabling them to adapt under stress. The team found that H3K23 modifications were directly linked with nutrient availability and metabolic enzyme levels. H3K23 acylation specifically reprogrammed gene expression under stress conditions, suggesting that histone acylation is part of a critical sensor system that helps cells adapt to stress. Acetylation is the most studied histone acyl modification and has been recognized as a fundamental player in metabolic gene regulation, whereas other short-chain acyl modifications have only been recently identified, and little is known about their dynamics or molecular functions at the intersection of metabolism and epigenetic gene regulation. In this study, we aimed to understand the link between nonacetyl histone acyl modification, metabolic transcriptional regulation, and cellular adaptation. Using antibodies specific for butyrylated, propionylated, and crotonylated H3K23, we analyzed dynamic changes of H3K23 acylation upon various metabolic challenges. Here, we show that H3K23 modifications were highly responsive and reversibly regulated by nutrient availability. These modifications were commonly downregulated by the depletion of glucose and recovered based on glucose or fatty acid availability. Depletion of metabolic enzymes, namely, ATP citrate lyase, carnitine acetyltransferase, and acetyl-CoA synthetase, which are involved in Ac-CoA synthesis, resulted in global loss of H3K23 butyrylation, crotonylation, propionylation, and acetylation, with a profound impact on gene expression and cellular metabolic states. Our data indicate that Ac-CoA/CoA and central metabolic inputs are important for the maintenance of histone acylation. Additionally, genome-wide analysis revealed that acyl modifications are associated with gene activation. Our study shows that histone acylation acts as an immediate and reversible metabolic sensor enabling cellular adaptation to metabolic stress by reprogramming gene expression.