Abstract
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.
Highlights
The posttranslational modification of histone proteins plays a crucial role in the regulation of a wide range of biological processes[1]
Recent studies have demonstrated that major metabolic enzymes, such as ATP citrate lyase (ACLY) and carnitine acetyltransferase (CRAT), which convert citrate or mitochondrial acetate to cytosolic acetyl-coenzyme A (Ac-CoA), and acetyl-CoA synthetase 2 (ACSS2), which
Our transcriptome analysis showed that a total of 1643 genes were significantly affected by glucose deprivation (934 downregulated, 709 upregulated, |fold change (FC) | ≥ 2), and their expression was partially rescued by glucose addition (Fig. 1b)
Summary
The posttranslational modification of histone proteins plays a crucial role in the regulation of a wide range of biological processes[1]. Histone acetylation has been intimately linked to cellular metabolism because of its sensitivity to the abundance of acetyl-coenzyme A (Ac-CoA)[2]. Ac-CoA is a central metabolic intermediate produced primarily from glycolysis and various metabolic. Metabolic enzymes, especially those that supply AcCoA, play critical roles in the maintenance of histone acetylation. Recent studies have demonstrated that major metabolic enzymes, such as ATP citrate lyase (ACLY) and carnitine acetyltransferase (CRAT), which convert citrate or mitochondrial acetate to cytosolic Ac-CoA, and acetyl-CoA synthetase 2 (ACSS2), which
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