When food meets man: the contribution of epigenetics to health

Abstract

Post-translational modifications of chromatin contribute to the epigenetic control of gene transcription. The response to food intake and individual nutrients also includes epigenetic events. Bile acids are necessary for lipid digestion and absorption, and more recently have emerged as signaling molecules. Their synthesis is transcriptionally regulated also in relation to the fasted-to-fed cycle, and interestingly, the underlying mechanisms include chromatin remodeling at promoters of key genes involved in their metabolism. Several compounds present in nutrients affect gene transcription through epigenetic mechanisms and recent studies demonstrate that, beyond the well known anti-cancer properties, they beneficially affect energy metabolism.

Keywords: bile acid synthesis; cholesterol metabolism; chromatin; fasted-to-fed cycle; gluconeogenesis; histone deacetylases; resveratrol; sirtuins; transcriptional regulation.

Figure 1

The dynamics of DNA packaging. Post translational modifications of histone and non-histone proteins impose changes in the nucleosomal organization and represent the dynamic switch between transcriptional “on-off” states of chromatin.

Figure 2

Model describing the molecular basis for feedback regulation of bile acid synthesis. The scheme is based on the findings reported by Goodwin et al. and Lu et al. [23,24]. It is worth noting that the functions of liver receptor homolog 1 (LRH-1) were revisited more recently and it was concluded that, although this orphan nuclear receptor contributes to bile acid homeostasis, its role in the regulation of CYP7A1 gene is unexpectedly negligible, at least in the mouse [25].

Figure 3

Model describing the mechanism by which bile acids disrupt the formation of a transcriptionally active complex at the promoters of CYP7A1 and PEPCK, the key genes in bile acid synthesis and gluconeogenesis, respectively. Hepatocyte nuclear factor (HNF)-4 bound to a sequence named BARE (bile acid responsive element) interacts with the co-activators PGC-1α and CBP. These protein-protein interactions may promote DNA bending and formation of a multiprotein complex containing general transcription factors (GTFs) and RNA polymerase (RNA pol) II. Bile acids interfere with the interactions between HNF-4 and co-activators and with the association of RNA pol II at the CYP7A1/PEPCK promoters causing reduction of gene transcription.

Figure 4

Metabolic changes occurring in the fasted-to-fed cycle. In the fasted state, plasma levels of glucagon are high while the levels of bile acids are low. These signals contribute to the regulation of gene transcription, and the downstream effects are up-regulation of gluconeogenesis and bile acid synthesis. In the fed state, there is a rise of insulin plasma levels and an increase of bile acids returning to the liver from the intestine. Both signals affect gene transcription and, in particular, bile acids repress both CYP7A1 and PEPCK, thus contributing to the repression of gluconeogenesis and bile acid synthesis.

Figure 5

The scheme depicts the role of chromatin remodeling enzymes in the transcriptional regulation of CYP7A1. In untreated hepatocytes, a transcriptionally active complex is assembled at the bile acid responsive element (BARE) (A). In addition to the factors reported in Figure 4, other proteins contribute to the transactivation, including liver receptor homolog (LRH)-1 and steroid receptor coactivator (SRC)-1. RNA pol II is phosphorylated and becomes more transcriptionally active. HDAC7 is sequestered in the cytoplasm. In these conditions, the arginine residues of histones, in particular histone H3, are acetylated (B). In the presence of bile acids, in a first phase, HDAC7 translocates to the nucleus and associates with the CYP7A1 promoter (A). The recruitment of other factors, HDAC3 and the silencing mediator for retinoid and thyroid-hormone receptors (SMRT), contributes to the formation of a repressive complex. By inhibiting phosphatases with calyculin, the bile acid-induced translocation of HDAC7 is blocked and the bile acid-induced inhibition of CYP7A1 is prevented. On the other hand, bile acids induce the synthesis of SHP that acts as a repressor as depicted in Figure 2. In addition, SHP interacts with HDACs and G9a methyltransferase, which deacetylate and methylate, respectively, arginine residues of histone proteins (B). SHP also promotes the recruitment of the Swi/Snf-Brm complex that drives ATP-dependent chromatin remodeling, which further represses CYP7A1 transcription (B).