Metabolic regulation of epigenetics

Abstract

How cells sense and respond to environmental cues remains a central question of biological research. Recent evidence suggests that DNA transcription is regulated by chromatin organization. However, the mechanism for relaying the cytoplasmic signaling to chromatin remodeling remains incompletely understood. Although much emphasis has been put on delineating transcriptional output of growth factor/hormonal signaling pathways, accumulated evidence from yeast and mammalian systems suggest that metabolic signals also play critical roles in determining chromatin structure. Here we summarize recent progress in understanding the molecular connection between metabolism and epigenetic modifications of chromatin implicated in a variety of diseases including cancer.

Figure 1. Signaling and metabolic inputs into epigenetics

Growth factors, hormones and cytokines activate the classical signaling pathways and downstream transcriptional factors which will recruit chromatin-modifying enzymes to local chromatin. On the other hand, nutrient levels and cell metabolism will affect levels of the metabolites which are required substrates of chromatin-modifying enzymes that use these metabolites to post-translationally modify both histones and DNA. Variations in these two inputs will determine the epigenome remodeling and transcription.

Figure 2. Metabolic feedback loop of the circadian clock

As master regulators of the circadian clock, CLOCK and BMAL1 control the expression of CRY and PER. CRY and PER proteins in turn regulate CLOCK-BMAL1 complex activity. Recently SIRT1 was found to bind to CLOCK-BMAL1 complex and negatively regulate its target gene transcription by deacetylating histones. SIRT1 activity depends on NAD⁺. Increased glucose metabolism converts nuclear/cytoplasmic NAD⁺ to NADH and suppresses SIRT1. Another NAD⁺-dependent enzyme is PARP1 which catalyzes the polymerization of ADP-ribose units on proteins and generates nicotinamide. The generation of additional cytosolic NAD⁺ requires the rate-limiting enzyme NAMPT. The cyclic expression of NAMPT is under the control of CLOCK-BMAL1, therefore contributing to a metabolic feedback loop. The energy-responsive kinase AMPK can also affect molecular clock machinery by phosphorylating CRY1 and facilitating its degradation. AMPK also phosphorylates histones, though its implication on the circadian system remains unclear.

Figure 3. Crosstalk between metabolism and epigenetics

As glucose enters the glycolytic pathway, a minor portion is branched to hexosamine biosynthetic pathway to produce GlcNAc which can be used as substrate for histone GlcNAcylation by OGT. Flux through glycolysis determines the NAD⁺/NADH ratio which is important for the activities of sirtuin histone deacetylases. Several TCA cycle intermediate can be exported out of mitochondria including citrate and αKG. Cytosolic citrate is converted to acetyl-CoA which is used as a donor for HAT-mediated histone acetylation. αKG is used as co-factors for histone and DNA demethylation reactions by JHDM and TET, respectively. The substrate for HMT and DNMT is SAM which is synthesized from essential amino acid methionine. Finally, a low ATP/AMP ratio can activate AMPK, a kinase that phosphorylates histones.

Figure 4. Proposed model for the role of 2HG in epigenetic regulation and cell differentiation

When progenitor cells differentiate, JHDM removes repressive histone methylation marks (H3K9me3 and H3K27me3) and activates the expression of differentiation-related genes. In addition, TET acts as a failsafe mechanism to protect promoters from aberrant DNA methylation. 2HG produced by mutant IDH inhibits JHDM and TET, which leads to histone and DNA hypermethylation and permanently “locks” differentiation-related genes in a silent state. This results in a differentiation arrest and expansion of progenitor cells, thus facilitating tumor development.