Epigenetics and Cellular Metabolism

Abstract

Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.

Keywords: DNA methylation; cellular metabolism; epigenetics; histone modifications; metabolites; microRNA.

Figure 1

Mechanisms of epigenetic modifications. Cell transduces the environmental changes (eg, nutrients, toxins, etc.) into epigenetic modifications including DNA methylation, histone PTMs, and noncoding RNAs (especially the microRNAs), which eventually turn certain genes on or off and regulate the transcription process without changing DNA sequence.

Figure 2

Crosstalk between cell metabolism and epigenetics. As glucose comes into glycolytic reactions, a minor portion involves in hexosamine biosynthetic pathway to produce GlcNAc, which can act as the substrate for histone GlcNAcylation by O-GlcNAc transferase. The majority of glucose is converted to acetyl-CoA and passed into TCA cycle with the alteration of NAD⁺/NADH pair. NAD⁺ is a key cofactor for reactions catalyzed by sirtuins. Acetyl-CoA is used as an acetyl group donor for histone acetylation catalyzed by HATs. Other intermediates from TCA cycle, such as α-KG, can function as cofactors for DNA and histone demethylation reactions by TET proteins and JHDM, respectively. Lysine-specific demethylase 1 (LSD1) is proposed to catalyze demethylation using FAD.

Figure 3

Involvement of dietary nutrients in epigenetics. Dietary intake of folate, vitamin B (2, 6, and 12), choline, and methionine (green color) regulate epigenetic modifications through involving one-carbon metabolism where the intermediate SAM is produced (red color) and subsequently be provided as the universal methyl group donor for DNA and histone methylations. One-carbon metabolism is described briefly as follows: folate is first converted to dihydrofolate, then to tetrahydrofolate (THF), which enters the cycle. Vitamin B6 is a cofactor in the conversion of THF to 5,10-methylene THF. The process of 5,10-methylene THF to 5-methyl THF is vitamin B2 dependent. 5-methyl THF serves as a methyl donor in a reaction converting homocysteine to methionine, in which vitamin B12 serves as a precursor to methionine synthase. In turn, methionine generated SAM. S-adenosylhomocysteine (SAH) that is converted from SAM participates in the generation of homocysteine. Choline is also involved in the production of methionine by converting it to betaine. The alteration of dietary methionine can also modulate the histone methylations through regulating SAM and SAH levels; the methionine restriction decreases histone modification, and this phenomenon can be sustained by diet.