Metabolism and epigenetics - PubMed (original) (raw)

Review

Metabolism and epigenetics

Ryan Janke et al. Annu Rev Cell Dev Biol. 2015.

Abstract

Epigenetic mechanisms by which cells inherit information are, to a large extent, enabled by DNA methylation and posttranslational modifications of histone proteins. These modifications operate both to influence the structure of chromatin per se and to serve as recognition elements for proteins with motifs dedicated to binding particular modifications. Each of these modifications results from an enzyme that consumes one of several important metabolites during catalysis. Likewise, the removal of these marks often results in the consumption of a different metabolite. Therefore, these so-called epigenetic marks have the capacity to integrate the expression state of chromatin with the metabolic state of the cell. This review focuses on the central roles played by acetyl-CoA, S-adenosyl methionine, NAD(+), and a growing list of other acyl-CoA derivatives in epigenetic processes. We also review how metabolites that accumulate as a result of oncogenic mutations are thought to subvert the epigenetic program.

Keywords: S-adenosyl methionine; acetylation; chromatin modification; folate; methylation; oncometabolite.

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Figures

Figure 1

Figure 1

The one-carbon pathway (brown arrows) is important for the production of methionine and cysteine, as well as the SAM used in DNA and histone methylation reactions. Several inputs into the pathway replenish metabolites consumed during one-carbon metabolism. In cells expressing threonine dehydrogenase, threonine is oxidized to produce glycine, which is converted to methylene-THF (blue arrows). Folate obtained through diet or by de novo synthesis is converted into THF. Abbreviations: Me, methyl; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; THF, tetrahydrofolate.

Figure 2

Figure 2

Potential roles of ascorbate and oncometabolites in regulating the activity of FeII- and α-ketoglutarate–dependent dioxygenases. (a) Following the oxidative decarboxylation of α-ketoglutarate, the dioxygenase can regain enzyme activity either by hydroxylating a substrate such as 5mC or by oxidizing ascorbate. (b) Mutations in IDH, SDH, and FH genes can result in high levels of oncometabolites (red) known to inhibit FeII- and α-ketoglutarate–dependent dioxygenases competitively with respect to α-ketoglutarate (green). Abbreviations: 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; FH, fumarate hydratase; IDH, isocitrate dehydrogenase; SDH, succinate dehydrogenase.

Figure 3

Figure 3

Metabolic pathways used for synthesis of NAD+ in yeast and mammals. (a) The de novo NAD+ synthesis pathway converts tryptophan to quinolinate (blue box), which is then converted into NAMN, a precursor to NAD+. The NAD+ salvage pathway (light brown arrows) converts NAM, one of the by-products of sirtuin-mediated deacetylation, back into NAD+. Yeast converts NAM into NAD+ through the generation of NA. (b) Mammals are able to process NA in the same manner as yeast to generate NAD+. However, the mammalian salvage pathway does not generate NA; instead, NAM is converted into NMN and then directly back into NAD+. NAD+ is consumed during the deacetylation of histones catalyzed by sirtuins. Abbreviations: NA, nicotinic acid; NaAD, nicotinic acid adenine dinucleotide; NAD+, nicotinamide adenine dinucleotide; NAM, nicotinamide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NMN, nicotinamide mononucleotide; OAAR, _O-_acetyl ADP-ribose.

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