PMC

Shown is a schematic of the TCA cycle. Several intermediates that are boxed or encircled (acetyl-Co-A, NAD⁺, α-ketoglutarate, and FAD) serve as essential co-factors for epigenetic enzymes (highlighted by colors).

Shown is a transmission electron micrograph of the proximal mouse colon. This image exemplifies the number and diversity of bacteria present in the mammalian GI tract. Bacterial metabolites such as butyrate can influence host epigeneitcs.

The day-night cycle sets an internal pacemaker that regulates circadian rhythms. Daily fluctuations in the NADH/NAD⁺ ratio contribute by regulating SIRT1 and its ability to counteract clock HAT activity. This helps determine histone acetylation and transcriptional activity of downstream target genes such as PER and CRY. See text for more details.

General types of epigenetic/epigenomic marks are listed at the left and a schematic of each reversible reaction is shown to the right. In the top 4 panels, enzymes are highlighted in blue and co-factors are highlighted in yellow. Nucleosome position and incorporation of histone variants are also reversible as indicated. In the bottom panel, XIST recruits enzymes and epigenomic marks in a sequential manner (from left to right) with stimulatory and inhibitory marks shown in green and red, respectively. See text for additional details.

The importance of food is not restricted to its nutritional content (e.g., calories and essential vitamins/minerals), but it is also important because bioactive food components and energy metabolites can function as environmental factors. And many gene-environment interactions converge at the level of the epigenome, which regulates gene expression profiles and determines phenotypic outcomes, referred to collectively as the phenome, at both the cellular and organismal levels. This is particularly true for certain energy metabolites and bioactive food components that activate or inhibit chromatinmodifying factors.

(A) Western blot showing pan-histone 3 acetylation (H3ac) levels in HCT116 cells grown in DMEM formulated without glucose (−Glu, left lane) or formulated with 25mM glucose (+Glu, right lane). β actin serves as the loading control. (B) A model of how glucose increases histone acetylation. First, it contributes carbons that can be incorporated into acetyl-CoA via the following pathway (denoted by thick arrows): glycolysis, PDH (pyruvate dehydrogenase), the TCA cycle and citrate shuttle, and ACL. Second, increased TCA-cycle activity increases the NADH/NAD⁺ ratio to inhibit SIRT1, which inhibits histone acetylation. Enzymes and metabolites that are most relevant are highlighted in blue and yellow, respectively.

(A) Schematic of 1C cycle and synthesis of SAM. (B) Photograph of 5 genetically-identical agouti viable-yellow mice with different coat-color phenotypes ranging from yellow through 3 degrees of mottling to agouti. (C) Schematic of agouti-viable yellow “epialleles”. Agouti exons are shown as boxes with the filled portions corresponding to coding sequence. An IAP retrovirus-like element is immediately upstream of the agouti gene. In the top panel, CpG methylation (red circles labeled CH₃) of the IAP renders it functionally inert. The endogenous promoter of the agouti gene (arrow) drives modest gene activity resulting in a brown (agouti) coat-color appearance in these mice. In the bottom panel, the IAP is not methylated and a strong, cryptic promoter (thicker arrow) drives high-level gene activity resulting in yellow pigmentation. (D) Methyl-donor supplementation provided to pregnant viable-yellow mice changes the coat-color distribution of their progeny after birth. Adapted from and .