Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes

Abstract

The physiological identity of every cell is maintained by highly specific transcriptional networks that establish a coherent molecular program that is in tune with nutritional conditions. The regulation of cell-specific transcriptional networks is accomplished by an epigenetic program via chromatin-modifying enzymes, whose activity is directly dependent on metabolites such as acetyl-coenzyme A, S-adenosylmethionine, and NAD+, among others. Therefore, these nuclear activities are directly influenced by the nutritional status of the cell. In addition to nutritional availability, this highly collaborative program between epigenetic dynamics and metabolism is further interconnected with other environmental cues provided by the day-night cycles imposed by circadian rhythms. Herein, we review molecular pathways and their metabolites associated with epigenetic adaptations modulated by histone- and DNA-modifying enzymes and their responsiveness to the environment in the context of health and disease.

Figure 1. Interplay between intermediary metabolites and epigenetics

A. Acetyl-CoA and histone acetylation. Various metabolic pathways lead to the formation of acetyl-CoA, which is then utilized as an acetyl group donor during histone acetyltransferase-dependent acetylation of nucleosomal histones. B. NAD can be de novo synthesized from amino acids such as tryptophan and also through the salvage pathway. NAD⁺ is an obligatory cofactor for the activity of SIRT1 and SIRT6, which decetylase histone H3K9/14 and H3K9/56, respectively. Decetylation of histone H3 by these sirtuins modulate the expression of metabolic genes, thereby altering metabolic pathways such as glycolysis, gluconeogenesis, mitochondrial respiration, fatty acid oxidation and lipogenesis. C. S-adenosylmethionine (SAM) is generated through methionine byosinthesis pathway and it is the universal donor of methyl groups to both histone methyltransferases (HMTs) and DNA methyltransferases (DNMTs). Within this metabolic pathway, S-adenosyl homocysteine (SAH) functions as a repressor of both DNMTs and histone lysine demethylases (KDMs). Alpha-ketogluterate (a-KG) is generated through the TCA cycle and serves as an obligatory cofactor for the catalytic activity of KDMs and ten-eleven translocation (TETs) enzymes. TETs oxidized DNA by successive catalysis of methylated cytosines into 5-hydroxymethylcytosine (5hmC), 5-carboxylcytosine (5caC) and 5-formylcytosine (5fC).

Figure 2. Metabolic influence on epigenetic and transcriptional regulatory pathways

Metabolic pathways including glucose, glutamine and glucosamine lead to the biosynthesis of UDP-GlcNAc, which serves as a donor for the O-GlcNAcylation of TET enzymes by O-GlcNAcyltransferase (OGT). O-GlcNAcylated TETs promote the O-GlcNAcylation of histone H2B. O-GlcNAcylated OCT4 and SOX2 is required for embryonic stem cell (ESC) self-renewal and reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). O-GlcNAcylation of he C-terminal repeat (CTD) of RNA polymerase II (Pol II) is postulated to serve as a transcriptional regulatory mechanism.

Figure 3. Interplay between metabolism, epigenetic and disease

While a-KG functions as a positive metabolite required for TEt activity, succinate and fumarate are both inhibitors of TET- and KDM-mediated catalysis. Mutated cancer derived SDH and FH enzymes lead to the accumulation of succinate and fumarate, thereby inactivating TET-mediated production of 5hmC and KDM-dependent demethylation of methylated H3K4 and H3K9. Vitamin C, however, activates TET-dependent generation of 5hmC.

Figure 4. At the crossroad between NAD and the circadian clock

NAMPT, the rate-limiting enzyme for the biosynthesis of NAD is under circadian regulation. Therefore, levels of NAD, the essential cofactor for the activity of sirtuins, exhibit 24-hr oscillatory patterns. SIRT1 has a direct participation in the circadian regulation of NAMPT, by modulating CLOCK and BMAL1 heterodimeric-dependent trans-activation of Nampt gene. Along with NAD, the activity of SIRT6 also depends of free fatty acids. Both SIRT1 and SIRT6 regulate different sets of circadian genes and metabolic pathways referred to as circadian partition where SIRT1 regulates peptides and cofactors, while SIRT6 controls lipids and carbohydrate metabolism.

Figure 5. Interplay between circadian clock and metabolism

The circadian clock is composed of interlocking feedback loops consisting of transcription activators (CLOCK, BMAL1, RORa/b) and repressors (CRYs, PERs and Rev-erba/b). Circadian activity of coactivator and corepressor complexes underlies epigenetic dynamics of histone acetylation and methylation, resulting in circadian gene expression. The metabolite heme participates in a circadian feedback loop by promoting transcriptional inhibition of genes associated with adipogenesis, lipid and glucose metabolism via the corepressor complex formed by Rev-erba/b, HDAC3 and NCoR. This corepressor complex regulates the expression of PGC-1a, which activates the expression of ALAS-1, the ratelimiting enzyme required for the biosynthesis of heme. Thus, levels of heme itself are under circadian regulation.