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Review
. 2020 Sep;45(9):731-747.
doi: 10.1016/j.tibs.2020.04.002. Epub 2020 May 6.

Metabolism and the Epigenome: A Dynamic Relationship

Spencer A Haws  1 , Cassandra M Leech  1 , John M Denu  2
Affiliations
Review

Metabolism and the Epigenome: A Dynamic Relationship

Spencer A Haws et al. Trends Biochem Sci. 2020 Sep.

Abstract

Many chromatin-modifying enzymes require metabolic cofactors to support their catalytic activities, providing a direct path for fluctuations in metabolite availability to regulate the epigenome. Over the past decade, our knowledge of this link has grown significantly. What began with studies showing that cofactor availability drives global abundances of chromatin modifications has transitioned to discoveries highlighting metabolic enzymes as loci-specific regulators of gene expression. Here, we cover our current understanding of mechanisms that facilitate the dynamic and complex relationship between metabolism and the epigenome, focusing on the roles of essential metabolic and chromatin associated enzymes. We discuss physiological conditions where availability of these epimetabolites is dynamically altered, highlighting known links to the epigenome and proposing other plausible connections.

Keywords: acetylation; acylation; chromatin; circadian cycles; dietary challenges; methylation.

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Figures

Figure 1:
Figure 1:. Central metabolites are essential cofactors for chromatin modifying enzymes.
Central metabolites from diverse metabolic pathways are essential cofactors for the chromatin modifying enzymes (in bold) that regulate the epigenome. Enzyme abbreviations: HMT (histone methyltransferase); HDM (histone demethylase); DNMT (DNA methyltransferase); TET (DNA demethylase); HAT (histone acetyltransferase).
Figure 2:
Figure 2:. Reversible histone acetylation/acylation reaction diagrams and acetyl-CoA metabolism schematic.
(A-B) Enzyme reaction diagrams illustrating the reversibility of histone lysine acetylation/acylation for Class I, II, and IV histone deacetylases (HDACs) (A) as well as Class III HDACs (B). (C) Schematic detailing acetyl-CoA metabolism and enzymes implicated in regulating global and/or loci specific histone acetyltransferase (HAT) reactions. Enzyme abbreviations: ACLY (ATP-citrate synthase); ACSS1–3 (acyl-CoA synthetase short-chain family member 1–3); PDC (pyruvate dehydrogenase complex).
Figure 3:
Figure 3:. Lysine acylations are chemically diverse and recognized by unique domains.
(A) Chemical structures for all identified histone lysine acylations. (B) Crystal structure diagram of Kcrotonyl in the YEATs domain binding pocket of H. sapiens AF9 (PDB: 5HJB). π-stacking is facilitated by residues F59 and Y78. (C) Crystal structure diagram of Kcrotonyl in the DPF domain binding pocket of H. sapiens MORF (PDB: 6OIE). S217 and S242 make polar contacts (mediated by a water molecule) with the crotonylated lysine. F218 improves specificity for Kcro over Kacetyl through π-stacking. (D) Crystal structure diagram of Kacetyl in the bromodomain binding pocket of H. sapiens BRPF1 (PDB: 5FFV). N708, a conserved residue in bromodomains, makes the sole polar contact with the acetylated lysine.
Figure 4:
Figure 4:. Reversible chromatin methylation reaction diagrams and SAM metabolism schematic.
(A-B) Enzyme reaction diagrams illustrating reversibility of histone (A) and DNA (B) methylation. (C) Schematic highlighting position of SAM-synthesizing reactions at the crossroads of the folate and methionine cycles. Enzyme abbreviations: HMT (histone methyltransferase); HDM (histone demethylase); DNMT (DNA methyltransferase); TET (DNA demethylase); TDG (thymine DNA glycosylase); base excision repair (BER); MATI/IIα (methionine adenosyltransferase I/IIα).
Figure 5:
Figure 5:. Known and Proposed Effects of NAD+, FAD, and SAM availability on chromatin structure and function.
Circadian rhythm and dietary intake affect cellular availability of key metabolites that act as cofactors for chromatin modifying enzymes such as NAD+, FAD, and SAM. (A) Fluctuations in NAD+ levels enable SIRT1-dependent regulation of CLOCK _target genes (e.g. NAMPT) through 2 independent yet non-exclusive mechanisms: 1) histone/BMAL1 deacetylation and 2) deacetylation of the CLOCK:BMAL1 negative regulator PER2. (B) Changes in SAM and FAD availability have been shown to directly influence chromatin methylation states, although the effect of circadian fluctuations in the abundances of these cofactors is unknown. Interestingly, the literature suggests methyl-modifications at certain loci are more sensitive (highlighted in yellow) to altered SAM and FAD availability than other loci (highlighted in blue). This mechanism may allow for dynamic flexibility in chromatin structure and function by enabling cells to adapt to various perturbations, while still supporting critical chromatin functions.
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