The evolving metabolic landscape of chromatin biology and epigenetics

Abstract

Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs - which include both nutrient availability as a result of diet and growth factor signalling - are implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions.

Figure 1. Overview of the mechanisms involved in the metabolic regulation of epigenetics.

The abundance of chromatin-modifying metabolites is intracellularly regulated by several mechanisms. Metabolites that are taken up by cells can passively or actively diffuse through the plasma and nuclear membrane in order to modify chromatin. Alternatively, metabolites can be processed internally by the activity of metabolic enzymes that convert them into substrates or co-factors for chromatin-remodelling enzymes. These enzymes can also translocate to the nucleus where they can locally produce substrates for chromatin modification. The resultant consequence of metabolite abundance on the rate of chromatin modification is dependent upon the kinetic and thermodynamic parameters of the enzyme. Enzymes with initial [S]/Km ratios on the highlighted linear part of the displayed curve are more susceptible to perturbations to substrate concentrations — these include methyltransferases and acetyltransferases, among others. Finally, once the modifications have been deposited, effector proteins can recognize and bind them using specific protein-binding modules, upon which they determine a variety of intracellular fates including the regulation of homeostasis, development, immune regulation and tumorigenesis.

Figure 2. Metabolic pathways producing chromatin-modifying metabolites.

Nutrients such as glucose, fatty acids, amino acids and vitamins are utilized by cellular metabolic pathways to produce metabolites that are used as substrates or activity modulators of chromatin-modifying enzymes. These molecules are included in regulation of the abundance of a plethora of ‘canonical’ modifications, including histone acetylation, histone methylation and DNA methylation, and ‘emerging’ modifications including acylations, homocysteinylation, serotonylation etc. Central-carbon, one-carbon and methionine metabolism, acetate metabolism, ketogenesis and redox-related pathways feed the pools of several of these metabolites, and thus help regulate the epigenomic landscape in concert with chromatin modifiers, remodellers and transcription factors. 2-HG, 2-hydroxyglutarate; αKG, α-ketoglutarate; GlcNAc, β-N-acetylglucosamine; hCys, homocysteine (hcy when a histone modification); MGO, methylglyoxal; PAR, poly(ADP–ribose); SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SucCoA, succinyl-CoA; TCA, tricarboxylic acid.

Figure 3. Physiological contexts of the metabolism–epigenetics axis.

The intersection between metabolism and epigenetics is implicated in a variety of physiological contexts including lineage specification at the embryonic level, immune regulation and the oncogenic transformation of cells. The maintenance of stemness and pluripotency and the process of differentiation are characterized by changes to metabolism and subsequent dynamic changes to epigenetic modifications. This reprogramming is also implicated in the activation or retroactive suppression of a variety of immune cell types including T cells, B cells and macrophages, and the ability to mount an immune response in response to invading pathogens. Finally, the oncogenic transformation of cells can be driven by mutations in metabolic enzymes, or by genomic drivers that reprogram metabolism. These molecular networks offer therapeutic targets in the fields of developmental biology, immunotherapy and oncology. αKG, α-ketoglutarate; FH, fumarate hydratase; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; m⁶A, N⁶- methyladenosine; SDH, succinate dehydrogenase.

Figure 4. Influences of environmental factors on histone acetylation and methylation.

Environmental factors including nutrition, exercise and gut microbiome regulate histone methylation and acetylation by modulating the intracellular pools of metabolites, including S-adenosylmethionine (SAM) and acetyl-CoA that are used by histone methyltransferases (HMTs) and histone acetyltransferases (HATs), respectively. The activity of histone demethylases (HDMs) is supported by α-ketoglutarate (αKG) which can be derived from dietary glutamine, and inhibited by the limited oxygen availability in hypoxia. Ketone bodies and short-chain fatty acids (SCFAs) can provide acyl-CoA precursors for histone acylation, while also directly inhibiting the activity of histone deacetylases (HDACs).