Metaboloepigenetics: Interrelationships between energy metabolism and epigenetic control of gene expression

It is generally accepted that diet and energy metabolism affect gene expression, which, in turn, influences human health and disease. Although our knowledge of how this occurs is still rather limited, there is strong evidence to support the role of epigenetic mechanisms. This is not surprising because many gene-environment interactions converge at the level of the epigenome to regulate gene expression profiles and phenotypic outcomes (Figure 1). And in this context, bioactive food components and nutrients are environmental factors that we are exposed to on a regular basis. In this review, we discuss “metaboloepigenetic” mechanisms that link energy metabolism and epigenetic control of gene expression. Figure 1 A simple model of metaboloepigenetics Epigenetics refers to how transcription, DNA replication, and other aspects of genome function are regulated in a manner that is independent of DNA sequence. Individuals who are genetically identical but have different traits such as certain cloned animals (including Cc the cat and her calico coat-color patterns due to X chromosome inactivation) and monozygotic twins (who can be afflicted by different diseases) exemplify the concept of epigenetics. Epigenetics also explains why every cell in our body has the same genome sequence (with the exception of lymphocytes due to VDJ recombination), yet each cell type (e.g., neurons, adipocytes, fibroblasts, intestinal epithelial cells) exhibits distinct expression profiles and morphological/functional characteristics. Mechanistically, epigenetics involves changes in either DNA methylation [which occurs almost exclusively at CG dinucleotides (or CpG) in mammals] or how the DNA is packaged as chromatin (Figure 2). At the most fundamental level, chromatin consists of 147-bp segments of DNA wrapped around histone octamers to form nucleosomes. Separated by short DNA linkers, nucleosomes are ubiquitous (>107 per nucleus) and have both structural and regulatory roles in genome function. Chromatin-modifying factors can alter the position/density of nucleosomes on the chromosome as well as catalyze posttranslational modifications of histones or the incorporation of histone variants within nucleosomes (Figure 2). DNA methylation and nucleosomes are usually an impediment to transcription, whereas histone modifications and variants are more nuanced or context dependent and can have opposing effects. For example, histone 3 lysine 4 trimethylation (H3K4me3) usually stimulates transcription while the same modification at certain adjacent lysine residues such as H3K9me3 or H3K27me3 has an inhibitory effect. This adds complexity to what is referred to as the histone code, which is written by enzymes that add posttranslational modifications and read by proteins that bind to modified residues as docking sites. Proteins with bromodomains bind to acetylated lysines (Figure 2), while proteins with chromodomains, tudor domains, and PHD fingers bind to various lysine or arginine residues when they are methylated. The histone code can also be erased, as most reactions are reversible. For example, histone acetyltransferases (HATs) are counteracted by histone deacetylases (HDACs), while histone methyltransferases are counteracted by LSD1 or jumonji C (JmjC) domain demethylases (Figure 2). Both small and large non-coding RNAs also participate in epigenetic mechanisms by guiding chromatin-modifying factors to specific sites in the genome. For instance, the long ncRNA XIST physically associates with and coats one X chromosome in female cells. XIST recruits enzymes that posttranslationally modify histones [e.g. HDACs to deacetylate and a Polycomb repressive complex (PRC2) with catalytic subunit EZH2 to induce H3K27me3] followed by the incorporation of the histone variant macroH2A and CpG methylation to stably inactivate one of two X chromosomes to achieve dosage compensation relative to XY male cells (Figure 2). Figure 2 Epigenetic marks are catalyzed by chromatin-modifying factors