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Review
. 2016 Nov 1;8(11):a019463.
doi: 10.1101/cshperspect.a019463.

Metabolic Signaling to Chromatin

Shelley L Berger  1 , Paolo Sassone-Corsi  2
Affiliations
Review

Metabolic Signaling to Chromatin

Shelley L Berger et al. Cold Spring Harb Perspect Biol. .

Abstract

There is a dynamic interplay between metabolic processes and gene regulation via the remodeling of chromatin. Most chromatin-modifying enzymes use cofactors, which are products of metabolic processes. This article explores the biosynthetic pathways of the cofactors nicotinamide adenine dinucleotide (NAD), acetyl coenzyme A (acetyl-CoA), S-adenosyl methionine (SAM), α-ketoglutarate, and flavin adenine dinucleotide (FAD), and their role in metabolically regulating chromatin processes. A more detailed look at the interaction between chromatin and the metabolic processes of circadian rhythms and aging is described as a paradigm for this emerging interdisciplinary field.

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Figures

Figure 1.
Figure 1.
The major cofactors involved in enzyme-mediated DNA or histone posttranslational modification (PTM). NAD, nicotinamide adenine dinucleotide; acetyl-CoA, acetyl coenzyme A; SAM, S-adenosyl methionine; FAD, flavin adenine dinucleotide; PARP, poly-ADP-ribose polymerase; HAT, histone acetyltransferase; PRMT, protein arginine methyltransferase; DNMT, DNA methyltransferase; KMT, lysine (K) methyltransferase; KDM, lysine demethylase; TET, ten-eleven translocation protein; LSD, lysine-specific demethylase.
Figure 2.
Figure 2.
Biosynthesis pathways of acetyl-CoA and NAD cofactors, and their involvement in chromatin-related processes. Acetyl-CoA is produced via two pathways to metabolize pyruvate, involving the key catalytic action of ACL or AceCS1. Acetyl-CoA is an essential metabolite required for the activity of HATs involved in creating an active chromatin conformation via the acetylation of histones. NAD is produced via the NAD salvage pathway. It is an essential cofactor for the PARP and SIRT enzymes, among other proteins. A link exists between the two pathways, as indicated by the dashed lines, by virtue that the NAD-using enzyme, SIRT1, activates the AceCS1 enzyme via protein deacetylation, which, in turn, produces the metabolite acetyl-CoA.
Figure 3.
Figure 3.
The biosynthesis pathway of S-adenosyl methionine (SAM) and its involvement in chromatin-related processes. SAM is an essential cofactor for PRMT, DNMT, and KMT chromatin-modifying enzymes. This pathway is metabolically influenced by the NAD salvage pathway by virtue that the SAH hydrolase (SAHH) enzyme in its biosynthesis pathway uses NAD. The primary product of SAM metabolism is SAH, which has an inhibitory effect on all the SAM-dependent chromatin-modifying complexes. SAH, S-adenosyl homocysteine; HCy, homocysteine.
Figure 4.
Figure 4.
Metabolism of the α-ketoglutarate cofactor regulates the activity of the TET and KDM enzymes in normal and cancer cells. The α-ketoglutarate metabolite is produced by the enzymatic action of the IDH proteins. Some cancer driving dominant-negative mutants of IDH cause the accumulation of an aberrant metabolite, 2-hydroxy-glutarate, which blocks TET and KDM activity.
Figure 5.
Figure 5.
A simplified scheme of the timing of key regulator activity in the molecular circadian clock machinery. (A) A maximum accumulation of CLOCK:BMAL1 heterodimers is achieved by daybreak following nighttime transcription and translation. CLOCK:BMAL1 binding to E-box elements of clock-controlled genes (CCGs) leads to chromatin remodeling and activation of genes. (B) The daytime expression of the repressors, PER and CRY, partially through the acetylated BMAL1 K537 residue, leads to CCG transcriptional repression at night. (C) The nighttime degradation of PER/CRY repression gradually leads to the derepression of CCGs by daybreak. (D) At nighttime, the predominance of RORα binding to the RORE (retinoic acid–related orphan receptor response element) lends to transcription of BMAL1, CLOCK, and RORα. (E) The predominance of REV-ERBα, as a result of the gene’s daytime transcription, has an inhibitory action on BMAL1, CLOCK, and RORα.
Figure 6.
Figure 6.
Key chromatin-remodeling factors involved in the activation and repression of CCGs and BMAL1. Recruitment of the CLOCK:BMAL1 heterodimer to CCGs during the day is facilitated by binding to the E-box and via the MLL1 enzyme. A transcriptionally active chromatin conformation is achieved through the combined action of H3K4me3, via the MLL1 lysine methyltransferase enzyme, and the histone acetylating activity of CLOCK, CBP, and P300 (cyan shaded proteins). Repressive chromatin conformations at CCGs may be achieved by the SIRT1-mediated deacetylation of histones at H3K9, K14, and H4K16, and possibly the actions of EZH2-catalyzed H3K27me3 or SUV39H-catalyzed H3K9 methylation. SIRT1 also has an inhibitory effect by deacetylating BMAL1 K537-ac. Silencing of RORE-containing genes, such as BMAL1, by day is, in part, achieved by recruitment to the RORE-bound inhibitor, REV-ERBα, of the NCoR1 complex and associated HDAC3 deacetylase. At night, predominance of RORα-bound ROREs promotes active chromatin structure, typified by histone acetylation and H3K4 methylation.
Figure 7.
Figure 7.
Linking the circadian clock with the NAD+ salvage pathway. The NAMPT enzyme is the limiting factor in the NAD+ salvage pathway; thus, because the NAMPT gene is regulated by the circadian CLOCK:BMAL1 machinery, its product, the NAD+ metabolite, oscillates via this NAMPT transcriptional feedback loop. The HDAC, SIRT1, among other functions, acts as a repressor of the clock machinery by effecting deacetylation of the BMAL1 protein and histones at CCGs (see also Fig. 6). Thus, whereas the enzymatic activity of SIRT1 oscillates in a circadian manner via the circadian controlled supply of its metabolite, NAD+, its activity also constitutes an enzymatic feedback loop for the circadian clock via its repressive activity at the NAMPT gene.
Figure 8.
Figure 8.
Features of aging and senescent cells. (Top) Aging is a biological inevitability for all eukaryotes, from budding yeast and C. elegans to mice and humans (depicted). The features of senescence and cellular aging are compared between a normal or “young” cell (left) and a diseased or “old” cell (right) at three levels: chromatin, nuclear organization, and integrity of the genome. (Top images [left to right] from chemistryland.com; from Hazreet Gill, Francis Ghandi, and Arjumand Ghazi, University of Pittsburgh School of Medicine, http://www.chp.edu/CHP/ghazilab; courtesy of Christopher Fisher; from victorymedspa.com.)
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