Metabolic mechanisms of epigenetic regulation

Abstract

Chromatin modifications have been well-established to play a critical role in the regulation of genome function. Many of these modifications are introduced and removed by enzymes that utilize cofactors derived from primary metabolism. Recently, it has been shown that endogenous cofactors and metabolites can regulate the activity of chromatin-modifying enzymes, providing a direct link between the metabolic state of the cell and epigenetics. Here we review metabolic mechanisms of epigenetic regulation with an emphasis on their role in cancer. Focusing on three core mechanisms, we detail and draw parallels between metabolic and chemical strategies to modulate epigenetic signaling, and highlight opportunities for chemical biologists to help shape our knowledge of this emerging phenomenon. Continuing to integrate our understanding of metabolic and genomic regulatory mechanisms may help elucidate the role of nutrition in diseases such as cancer, while also providing a basis for new approaches to modulate epigenetic signaling for therapeutic benefit.

Figure 1

Regulation of genome function by cofactor-dependent enzymes. (a) Chromatin-modifying enzymes modulate the posttranslational modifications of histone amino acids and cytosine methylation state. These modifications can affect the physical accessibility of genomic loci, provide specific binding surfaces for effector proteins, or influence posttranslational modification of neighboring residues. (b) Enzyme cofactors, their associated chromatin modifiers, and examples of metabolic pathways that produce and consume each cofactor. Enzymes are abbreviated according to nomenclature established by Allis et al. KAT, lysine acetyltransferase; HDAC, sirtuin histone deacetylase; KMT, lysine methyltransferase; KDM, lysine demethylase; DNMT, DNA methyltransferase; TET, cytosine hydroxylase.

Figure 2

Regulation of epigenetic signaling by cofactor competition. Diverse mechanisms of genomic regulation including transcription factor stability, and histone and cytosine methylation status are regulated by α-ketoglutarate-dependent dioxygenases (green arrow). Inactivating mutations in the TCA cycle enzymes FH and SDH or missense mutations in cytosolic IDH1 result in the production of high concentrations of fumarate, succinate, and (R)-2-hydroxyglutarate, which compete with α- ketoglutarate for enzyme active sites (red arrow). Metabolic enzymes are color-coded light blue, with those proteins mutated or overexpressed in cancer outlined in bold red. HIF, hypoxia-inducible factor; SDH, succinate dehydrogenase; FH, fumarate hydratase; IDH, isocitrate dehydrogenase.

Figure 3

Regulation of epigenetic signaling by cofactor depletion. SAM functions as a universal methyl donor for methylation of macromolecules and metabolites. Overactivity of metabolic methyltransferases such as NNMT can result in depletion of SAM and decreased SAM/SAH ratios, thereby reducing KMT/DNMT activity and genomic methylation. Replenishment of SAM requires the activity of the folate and SAM cycles, which utilize methyl groups derived from folate or choline (not shown) to replenish intracellular methionine for SAM biosynthesis. Disruption of the SAM cycle by inhibitors has been shown to decrease the activity of KMT enzymes in cancer. Cofactors and byproducts of most enzymatic reactions have been omitted for simplicity. NNMT, nicotinamide N-methyltransferase; SAHase, S-adenosylhomocysteine hydrolase; MTR, 5-methyltetrahydrofolate-homocysteine methyltransferase; MTHFR, methylenetetrahydrofolate reductase; SHMT, serine hydroxymethyltransferase; MAT, methionine adenosyltransferase; DZNep, 3-deazaneplanocin A.

Figure 4

Regulation of epigenetic signaling by subcellular localization of cofactor biosynthesis. The SAM biosynthetic enzyme MAT associates with transcription factors at specific genomic loci, producing SAM that is used by KMT enzymes to methylate histones and establish a repressive heterochromatin state. Notably, addition of exogenous SAM does not stimulate the same effect, suggesting genomic-localized biosynthesis of SAM is required for transcriptional repression.

Figure 5

Mimicking metabolic mechanisms of epigenetic regulation with small molecules. (a) Synthetic cofactors applied for inhibition of chromatin-modifying enzymes. Cofactor-derived portions of each molecule are highlighted in gold. (b) NAD+ salvage pathway and NAMPT inhibitors. Blockade of NAD+ salvage has been shown to deplete cellular NAD+ levels and inhibit SIRT HDAC activity. (c) Chemical inducer of dimerization approach used to localize genomic function of HP1, which stimulates local KMT and DNMT activity. NAMPT, nicotinamide phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenyltransferase; HP-1, heterochromatin binding protein.