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Review
, 19 (11), 1298-1306

The Impact of Cellular Metabolism on Chromatin Dynamics and Epigenetics

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Review

The Impact of Cellular Metabolism on Chromatin Dynamics and Epigenetics

Michael A Reid et al. Nat Cell Biol.

Abstract

The substrates used to modify nucleic acids and chromatin are affected by nutrient availability and the activity of metabolic pathways. Thus, cellular metabolism constitutes a fundamental component of chromatin status and thereby of genome regulation. Here we describe the biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics, discuss the functional roles of this interplay in developmental and cancer biology, and present future directions in this rapidly emerging area.

Conflict of interest statement

Competing Financial Interests

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Biochemical basis of metabolite interaction with chromatin and metabolic pathways that contribute
a) In contrast to kinases and E3 ligases, the physiological concentrations of substrates of chromatin modifying enzymes such as DNA methyltransferase (DNMTs), histone methyltransferase (HMTs), and histone acetyltransferases (HATs) are much lower thus limiting enzymatic activities. Thus, the reaction rates of these enzymes are highly responsive to local changes in substrate availability. x axis: ratio of substrate concentration to Km value; y axis: relative reaction rate. Ranges of [S]/Km for all five types of enzymes were estimated from Km values in the BRENDA database (www.brenda-enzymes.org). b) Uptake and catabolism of macronutrients such as glucose and amino acids generate substrates such as acetyl-CoA and S-adenosylmethionine (SAM), and activity modulators such as alpha-ketoglutarate (αKG), (R)-2-hydroxyglutarate (2-HG), succinate, fumarate, lactate, S-adenosylhomocysteine (SAH), oxidized and reduced nicotinamide adenine dinucleotide (NAD+, NADH), and oxidized and reduced flavin adenine dinucleotide (FAD, FADH2) used by enzymes that modify chromatin. SAM is the major methyl donor for methylation of cytosine bases in DNA and histone residues by DNA methyltransferase (DNMTs) and histone methyltransferases (HMTs), respectively. Acetyl-CoA is an essential substrate for acetylation of histone residues carried out by histone acetyltransferases (HATs). Other metabolites such as αKG, NAD+, and FAD are critical co-factors for the activity of chromatin modifying enzymes. αKG is used by TET-family DNA demethylases (TET) and JmjC-family histone demethylases (JmjC) to facilitate removal of methyl groups from cytosine bases and histone residues, respectively. LSD-family histone demethylases (LSD) require FAD to demethylate histone residues. Sirtuins and other histone deacetylaces (HDACs) require NAD+ to deacetylate histone residues. Additionally, metabolites such as 2-HG, succinate, fumarate, lactate and SAH can inhibit the activity of chromatin modifying enzymes.
Figure 2
Figure 2. Metabolic reprograming and Waddington’s epigenomic landscape
a) Schematic representation of Waddington’s Landscape depicting cell states existing in valleys maintained by epigenotypes and the phenotypic barrier between two cell states such as pluripotent and differentiated, epithelial and mesenchymal, somatic and induced pluripotent (iPSC), and primary and metastatic cancer cells. b) Model of how metabolism could facilitate cell state transitions without affecting the shape of the epigenomic landscape such as a change in metabolite level allowing for reorganization of specific chromatin marks. c) Model of how metabolic reprograming could reshape the entire epigenomic landscape leading to new cell states in a case where a cell type has different metabolic requirements. Balls represent cells transitioning from one state to another after changes in metabolism-dependent chromatin remodeling alters the phenotypic barrier.
Figure 3
Figure 3. Analogy of cancer-associated mutations found in growth signaling with those in metabolism-dependent chromatin modifying processes
a) During oncogenesis, cells gain growth factor independence by frequently acquiring mutations that co-opt normal growth signaling. RAS and RAF are commonly mutated in cancer and drive downstream signaling through MEK and ERK, which can lead to gene regulation by c-Myc. RAS and growth factor signaling can activate the PI3K/AKT/mTOR signaling axis to promote cell growth and survival through downstream transcription factors such as HIF1α. Mutations to PI3K, AKT, PTEN, TSC, and LKB1 are also common in cancer. Purple indicates oncogenes; blue indicates tumor suppressors; yellow star indicates common lesions in cancer; solid lines represent direct biochemical interactions; dotted lines represent indirect regulation. b) Metabolism regulates normal physiological activity of chromatin modifying enzymes, which are commonly mutated in cancer. Glucose (Glc.) and amino acids (AAs) feed into the TCA cycle, which generates regulators of chromatin modifying enzymes such as αKG. Methionine (Met.) produces the methyl donor SAM in the methionine cycle. With exception of Isocitrate dehydrogenase (IDH1/2), mutations in metabolic enzymes are uncommon in cancer, yet cancer-associated mutations in chromatin modifiers such as DNA methyltransferases (DNMTs), TET-family DNA demethylases (TET), histone methyltransferases (HMTs), histone lysine demethylases (KDMs), and histones (H3K27 and H3K36) are prevalent suggesting cells may subvert the normal regulation of these enzymes by metabolism during transformation. Blue indicates enzymes that perform methylation reactions; green indicates enzymes that perform demethylation reactions; yellow star indicates common lesions in cancer.

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