Sink into the Epigenome: Histones as Repositories That Influence Cellular Metabolism

Abstract

Epigenetic modifications on chromatin are most commonly thought to be involved in the transcriptional regulation of gene expression. Due to their dependency on small-molecule metabolites, these modifications can relay information about cellular metabolic state to the genome for the activation or repression of particular sets of genes. In this review we discuss emerging evidence that these modifications might also have a metabolic purpose. Due to their abundance, the histones have the capacity to store substantial amounts of useful metabolites or to enable important metabolic transformations. Such metabolic functions for histones could help to explain the widespread occurrence of particular modifications that may not always be strongly correlated with transcriptional activity.

Keywords: SAM; acetate; acetyl-CoA; epigenetics; histone acetylation; histone methylation.

Figure 1. Pathways for methionine and SAM metabolism

SAM synthesized from methionine donates methyl groups to various methyl recipients. Alternatively, SAM can be decarboxylated for the synthesis of polyamines, and the recycling of the byproduct methylthioadenosine is known as the methionine salvage pathway. SAM-dependent methylation generates SAH, and the subsequent hydrolysis of SAH produces adenosine and homocysteine, which can feed purine metabolism and transsulfuration for cysteine and glutathione synthesis, respectively. Homocysteine can also be recycled for methionine synthesis. Folate and choline are metabolized to provide necessary methyl groups for remethylating homocysteine.

Figure 2. Pathways for acetyl-CoA metabolism

Acetyl-CoA can be synthesized via at least four routes: 1) decarboxylation of pyruvate by the pyruvate dehydrogenase complex (PDC); 2) cleavage of citrate by ATP citrate lyase (ACLY); 3) fatty acid β-oxidation; and 4) synthesis from acetate by acetyl-CoA synthetase enzymes (ACSS).

Figure 3. Dynamics of methylation and acetylation of histones

The methylation status of histones is determined by opposing methylation and demethylation reactions. Histone methyltransferases (HMTs) catalyze the methylation of histones using SAM as the methyl donor, while histone demethylases catalyze the removal of methyl groups. Jumonji-domain containing demethylases (JHDM) consume α-KG in the demethylation reaction, while the LSD1 family of demethylases utilize FAD as a cofactor. The histones serve as a methyl sink and take methyl groups from SAM to facilitate its conversion to cysteine and glutathione through the transsulfuration pathway. The acetylation status of histones is determined by opposing acetylation and deacetylation reactions. Histone acetyltransferases (HATs) catalyze the acetylation of histones using acetyl-CoA as the acetyl donor, while histone deacetylases catalyze the removal of acetyl groups to release free acetate (HDACs) or as O-acetyl-ADP-ribose (sirtuins). The released acetate can be converted back to acetyl-CoA to elicit metabolic or signaling functions.