Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes  Jean-Pierre Etchegaray, Raul Mostoslavsky  Molecular Cell  Volume 62, Issue 5, Pages 695-711 (June 2016) DOI: 10.1016/j.molcel.2016.05.029 Copyright © 2016 Elsevier Inc. Terms and Conditions

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 deacetylate histone H3K9/14 and H3K9/56, respectively. Deacetylation 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 the methionine biosynthesis pathway and 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). α-ketoglutarate (α-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). Molecular Cell 2016 62, 695-711DOI: (10.1016/j.molcel.2016.05.029) Copyright © 2016 Elsevier Inc. Terms and Conditions

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 are required for embryonic stem cell (ESC) self-renewal and reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). O-GlcNAcylation of the C-terminal repeat (CTD) of RNA Polymerase II (Pol II) is postulated to serve as a transcriptional regulatory mechanism. Molecular Cell 2016 62, 695-711DOI: (10.1016/j.molcel.2016.05.029) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 3 Interplay between Metabolism, Epigenetics, and Disease While α-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. Molecular Cell 2016 62, 695-711DOI: (10.1016/j.molcel.2016.05.029) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 4 At the Crossroads 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 on 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. Molecular Cell 2016 62, 695-711DOI: (10.1016/j.molcel.2016.05.029) Copyright © 2016 Elsevier Inc. Terms and Conditions

Figure 5 Interplay between Circadian Clock and Metabolism The circadian clock is composed of interlocking feedback loops consisting of transcription activators (CLOCK, BMAL1, RORα/β) and repressors (CRYs, PERs, and Rev-erbα/β). 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-erbα/β, HDAC3, and NCoR. This corepressor complex regulates the expression of PGC-1α, which activates the expression of ALAS-1, the rate-limiting enzyme required for the biosynthesis of heme. Thus, levels of heme itself are under circadian regulation. Molecular Cell 2016 62, 695-711DOI: (10.1016/j.molcel.2016.05.029) Copyright © 2016 Elsevier Inc. Terms and Conditions