Abstract
Molecular inputs to chromatin via cellular metabolism are modifiers of the epigenome. These inputs — which include both nutrient availability as a result of diet and growth factor signalling — are implicated in linking the environment to the maintenance of cellular homeostasis and cell identity. Recent studies have demonstrated that these inputs are much broader than had previously been known, encompassing metabolism from a wide variety of sources, including alcohol and microbiotal metabolism. These factors modify DNA and histones and exert specific effects on cell biology, systemic physiology and pathology. In this Review, we discuss the nature of these molecular networks, highlight their role in mediating cellular responses and explore their modifiability through dietary and pharmacological interventions.
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Change history
25 September 2020
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
References
Alberts, B. Molecular Biology of the Cell 6th ed. (Garland Science, Taylor and Francis Group, 2015).
Hyun, K., Jeon, J., Park, K. & Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 49, e324 (2017).
Schuettengruber, B., Bourbon, H. M., Di Croce, L. & Cavalli, G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell 171, 34–57 (2017).
Stillman, B. Histone modifications: insights into their influence on gene expression. Cell 175, 6–9 (2018).
Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).
Chan, J. C. & Maze, I. Nothing is yet set in (hi)stone: novel post-translational modifications regulating chromatin function. Trends Biochem. Sci. https://doi.org/10.1016/j.tibs.2020.05.009 (2020).
Wu, T. P. et al. DNA methylation on N6-adenine in mammalian embryonic stem cells. Nature 532, 329–333 (2016).
Xiao, C.-L. et al. N6-methyladenine DNA modification in the human genome. Mol. Cell 71, 306–318.e307 (2018).
Galligan, J. J. & Marnett, L. J. Histone adduction and its functional impact on epigenetics. Chem. Res. Toxicol. 30, 376–387 (2017).
Arango, D. et al. Acetylation of cytidine in mRNA promotes translation efficiency. Cell 175, 1872–1886.e1824 (2018).
Yue, Y., Liu, J. & He, C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Gene Dev. 29, 1343–1355 (2015).
Chandel, N. S. Navigating Metabolism (Cold Spring Harbor Laboratory Press, 2015).
Reid, M. A., Dai, Z. W. & Locasale, J. W. The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat. Cell Biol. 19, 1298–1306 (2017).
Cavalli, G. & Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 571, 489–499 (2019).
Tang, S. et al. Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development. EMBO J. 36, 3175–3193 (2017).
Yucel, N. et al. Glucose metabolism drives histone acetylation landscape transitions that dictate muscle stem cell function. Cell Rep. 27, 3939–3955.e3936 (2019). This study shows that glucose metabolism influences differentiation by regulating histone acetylation and chromatin accessibility.
Yu, W. et al. One-carbon metabolism supports S-adenosylmethionine and histone methylation to drive inflammatory macrophages. Mol. Cell 75, 1147–1160.e1145 (2019). This study shows that upregulation of both one-carbon metabolism and H3K36me3 is involved in macrophage activation.
Wang, Z. et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat. Med. 25, 825–837 (2019). This report defines a mechanism for methionine metabolism to drive tumour initiation by modulating epigenetics.
Reina-Campos, M. et al. Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer. Cancer Cell 35, 385–400.e389 (2019).
Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat. Commun. 9, 105 (2018). This study establishes a link between gut microbiota and histone crotonylation.
Kaelin, W. G. Jr. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).
Carrer, A. & Wellen, K. E. Metabolism and epigenetics: a link cancer cells exploit. Curr. Opin. Biotechnol. 34, 23–29 (2015).
Etchegaray, J. P. & Mostoslavsky, R. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell 62, 695–711 (2016).
Haws, S. A. et al. Methyl-metabolite depletion elicits adaptive responses to support heterochromatin stability and epigenetic persistence. Mol. Cell 78, 210–223.e218 (2020).
Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015).
Bulusu, V. et al. Acetate recapturing by nuclear acetyl-CoA synthetase 2 prevents loss of histone acetylation during oxygen and serum limitation. Cell Rep. 18, 647–658 (2017).
Mews, P. et al. Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546, 381–386 (2017).
Nagaraj, R. et al. Nuclear localization of mitochondrial TCA cycle enzymes as a critical step in mammalian zygotic genome activation. Cell 168, 210–223.e211 (2017).
Sivanand, S. et al. Nuclear acetyl-CoA production by ACLY promotes homologous recombination. Mol. Cell 67, 252–265.e6 (2017).
Masui, K. et al. mTORC2 links growth factor signaling with epigenetic regulation of iron metabolism in glioblastoma. J. Biol. Chem. 294, 19740–19751 (2019).
Sdelci, S. et al. MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nat. Genet. 51, 990–998 (2019).
Sun, R. C. et al. Nuclear glycogenolysis modulates histone acetylation in human non-small cell lung cancers. Cell Metab. 30, 903–916.e7 (2019).
Sperber, H. et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat. Cell Biol. 17, 1523–1535 (2015).
Ye, C. Q., Sutter, B. M., Wang, Y., Kuang, Z. & Tu, B. P. A metabolic function for phospholipid and histone methylation. Mol. Cell 66, 180–193.e8 (2017).
Ye, C. Q. et al. Demethylation of the protein phosphatase PP2A promotes demethylation of histones to enable their function as a methyl group sink. Mol. Cell 73, 1115–1126.e6 (2019).
Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).
Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).
Sanulli, S. et al. HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature 575, 390–394 (2019).
Gibson, B. A. et al. Organization of chromatin by intrinsic and regulated phase separation. Cell 179, 470–484 e421 (2019).
Nair, S. J. et al. Phase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly. Nat. Struct. Mol. Biol. 26, 193–203 (2019).
Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).
Ries, R. J. et al. m6A enhances the phase separation potential of mRNA. Nature 571, 424–428 (2019).
Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid–liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).
Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).
Ravanel, S., Gakière, B., Job, D. & Douce, R. The specific features of methionine biosynthesis and metabolism in plants. Proc. Natl Acad. Sci. USA 95, 7805 (1998).
Sanderson, S. M., Gao, X., Dai, Z. W. & Locasale, J. W. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat. Rev. Cancer 19, 625–637 (2019).
Mattocks, D. A. L. et al. Short term methionine restriction increases hepatic global DNA methylation in adult but not young male C57BL/6J mice. Exp. Gerontol. 88, 1–8 (2017).
Zhang, N. Role of methionine on epigenetic modification of DNA methylation and gene expression in animals. Anim. Nutr. 4, 11–16 (2018).
Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).
Shiraki, N. et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab. 19, 780–794 (2014).
Dai, Z., Mentch, S. J., Gao, X., Nichenametla, S. N. & Locasale, J. W. Methionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width. Nat. Commun. 9, 1955 (2018). This study investigates how methionine availability influences quantitative parameters of H3K4me3 in cancer cells and mouse liver.
Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).
Ding, W. et al. Stress-responsive and metabolic gene regulation are altered in low S- adenosylmethionine. PLoS Genet. 14, e1007812 (2018).
Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. eLife 8, e44210 (2019).
Roy, D. G. et al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab. 31, 250–266.e259 (2020). This study highlights the importance of methionine metabolism and methionine-derived histone methylation for supporting T cell function.
Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013).
Shi, Y. Histone lysine demethylases: emerging roles in development, physiology and disease. Nat. Rev. Genet. 8, 829–833 (2007).
Young, J. I., Zuchner, S. & Wang, G. F. Regulation of the epigenome by vitamin C. Annu. Rev. Nutr. 35, 545–564 (2015).
Pan, M. et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 18, 1090–1101 (2016).
Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013 (2019). This study develops a promising strategy for enhancing antitumour immune response by targeting the metabolism–epigenetics axis.
Jiang, Y. et al. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses. Nat. Commun. 10, 2935 (2019).
Schvartzman, J.-M., Reuter, V. P., Koche, R. P. & Thompson, C. B. 2-hydroxyglutarate inhibits MyoD-mediated differentiation by preventing H3K9 demethylation. Proc. Natl Acad. Sci. USA 116, 12851 (2019). This study defines a novel mechanism for 2-HG to regulate differentiation and tumour progression by affecting H3K9 methylation.
Flavahan, W. A. et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature 575, 229–233 (2019).
Sciacovelli, M. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016).
Bazopoulou, D. et al. Developmental ROS individualizes organismal stress resistance and lifespan. Nature 576, 301–305 (2019). This study shows that redox balance affects longevity by changing the epigenomic landscape in worms.
Thienpont, B. et al. Tumour hypoxia causes DNA hyper-methylation by reducing TET activity. Nature 537, 63–68 (2016).
Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019). This study and related work link oxygen availability and hypoxia to histone and DNA methylation.
Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019).
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076 (2009).
Cluntun, A. A. et al. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab. 3, 10 (2015).
Liu, X. et al. Acetate production from glucose and coupling to mitochondrial metabolism in mammals. Cell 175, 502–513.e513 (2018).
Mews, P. et al. Alcohol metabolism contributes to brain histone acetylation. Nature 574, 717–721 (2019). This study shows that alcohol uptake impacts learning, memory and behaviour by increasing brain histone acetylation.
Sebastián, C. & Mostoslavsky, R. The various metabolic sources of histone acetylation. Trends Endocrinol. Metab. 28, 85–87 (2017).
Bose, S., Ramesh, V. & Locasale, J. W. Acetate metabolism in physiology, cancer, and beyond. Trends Cell Biol. 29, 695–703 (2019).
McDonnell, E. et al. Lipids reprogram metabolism to become a major carbon source for histone acetylation. Cell Rep. 17, 1463–1472 (2016).
Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Chalkiadaki, A. & Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol. 8, 287–296 (2012).
Sabari, B. R., Zhang, D., Allis, C. D. & Zhao, Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 18, 90–101 (2017).
Dutta, A., Abmayr, S. M. & Workman, J. L. Diverse activities of histone acylations connect metabolism to chromatin function. Mol. Cell 63, 547–552 (2016).
Hirschey, M. D. & Zhao, Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell. Proteomics 14, 2308–2315 (2015).
Simithy, J. et al. Characterization of histone acylations links chromatin modifications with metabolism. Nat. Commun. 8, 1141 (2017).
Wang, Y. et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277 (2017).
Wagner, G. R. & Hirschey, M. D. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol. Cell 54, 5–16 (2014).
Trefely, S., Lovell, C. D., Snyder, N. W. & Wellen, K. E. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol. Metab. 38, 100941 (2020).
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019). This study identifies histone lactylation as a novel epigenetic modification involved in active transcription.
Huang, H. et al. Lysine benzoylation is a histone mark regulated by SIRT2. Nat. Commun. 9, 3374 (2018).
Goudarzi, A. et al. Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters. Mol. Cell 62, 169–180 (2016).
Xie, Z. et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).
Zhang, X. et al. Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3. Cell Discov. 5, 35 (2019).
Gowans, G. J. et al. Recognition of histone crotonylation by Taf14 links metabolic state to gene expression. Mol. Cell 76, 909–921.e903 (2019).
Zhang, Q. et al. Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects. Nat. Commun. 9, 3436 (2018). This study shows that H3K79 homocysteinylation is related to neural development.
Biskup, C. S. et al. Effects of acute tryptophan depletion on brain serotonin function and concentrations of dopamine and norepinephrine in C57BL/6J and BALB/cJ mice. PLoS ONE 7, e35916 (2012).
Solon-Biet, S. M. et al. Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nat. Metab. 1, 532–545 (2019).
Farrelly, L. A. et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature 567, 535–539 (2019). This study identifies histone serotonylation as a novel epigenetic modification and investigates its roles in regulating gene expression and neuronal differentiation.
Meiser, J., Weindl, D. & Hiller, K. Complexity of dopamine metabolism. Cell Commun. Signal. 11, 34 (2013).
Montgomery, A. J., McTavish, S. F., Cowen, P. J. & Grasby, P. M. Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an 11Craclopride PET study. Am. J. Psychiatry 160, 1887–1889 (2003).
Lepack, A. E. et al. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science 368, 197–201 (2020). This study identifies histone dopaminylation as a novel epigenetic modification involved in addictive behaviours.
Chiaradonna, F., Ricciardiello, F. & Palorini, R. The nutrient-sensing hexosamine biosynthetic pathway as the hub of cancer metabolic rewiring. Cells 7, 53 (2018).
Ryczko, M. C. et al. Metabolic reprogramming by hexosamine biosynthetic and golgi N-glycan branching pathways. Sci. Rep. 6, 23043 (2016).
Zhang, S., Roche, K., Nasheuer, H.-P. & Lowndes, N. F. Modification of histones by sugar β-N-acetylglucosamine (GlcNAc) occurs on multiple residues, including histone H3 serine 10, and is cell cycle-regulated. J. Biol. Chem. 286, 37483–37495 (2011).
Chen, Q., Chen, Y., Bian, C., Fujiki, R. & Yu, X. TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493, 561–564 (2013).
Messner, S. & Hottiger, M. O. Histone ADP-ribosylation in DNA repair, replication and transcription. Trends Cell Biol. 21, 534–542 (2011).
Ciccarone, F., Zampieri, M. & Caiafa, P. PARP1 orchestrates epigenetic events setting up chromatin domains. Semin. Cell Dev. Biol. 63, 123–134 (2017).
Bai, P. & Cantó, C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab. 16, 290–295 (2012).
Harmel, R. & Fiedler, D. Features and regulation of non-enzymatic post-translational modifications. Nat. Chem. Biol. 14, 244–252 (2018).
Kuo, Y. M. & Andrews, A. J. Quantitating the specificity and selectivity of Gcn5-mediated acetylation of histone H3. PLoS ONE 8, e54896 (2013).
Baeza, J., Smallegan, M. J. & Denu, J. M. Site-specific reactivity of nonenzymatic lysine acetylation. ACS Chem. Biol. 10, 122–128 (2015).
Paik, W. K., Lee, H. W. & Kim, S. Non-enzymatic methylation of proteins with S-adenosyl-L-methionine. FEBS Lett. 58, 39–42 (1975).
Rydberg, B. & Lindahl, T. Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-l-methionine is a potentially mutagenic reaction. EMBO J. 1, 211–216 (1982).
Gaschler, M. M. & Stockwell, B. R. Lipid peroxidation in cell death. Biochem. Biophys. Res. Commun. 482, 419–425 (2017).
Chen, D., Fang, L., Li, H., Tang, M. S. & Jin, C. Cigarette smoke component acrolein modulates chromatin assembly by inhibiting histone acetylation. J. Biol. Chem. 288, 21678–21687 (2013).
Carrier, E. J., Zagol-Ikapitte, I., Amarnath, V., Boutaud, O. & Oates, J. A. Levuglandin forms adducts with histone H4 in a cyclooxygenase-2-dependent manner, altering its interaction with DNA. Biochemistry 53, 2436–2441 (2014).
Kold-Christensen, R. & Johannsen, M. Methylglyoxal metabolism and aging-related disease: moving from correlation toward causation. Trends Endocrinol. Metab. 31, 81–92 (2020).
Luengo, A. et al. Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer. Nat. Commun. 10, 5604 (2019).
Galligan, J. J. et al. Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks. Proc. Natl Acad. Sci. USA 115, 9228–9233 (2018).
Wang, Y. et al. Identification of the YEATS domain of GAS41 as a pH-dependent reader of histone succinylation. Proc. Natl Acad. Sci. USA 115, 2365–2370 (2018).
Andreeva, A. et al. The apparent deglycase activity of DJ-1 results from the conversion of free methylglyoxal present in fast equilibrium with hemithioacetals and hemiaminals. J. Biol. Chem. 294, 18863–18872 (2019).
Uribarri, J. et al. Dietary advanced glycation end products and their role in health and disease. Adv. Nutr. 6, 461–473 (2015).
Salomon, T. et al. Ketone body acetoacetate buffers methylglyoxal via a non-enzymatic conversion during diabetic and dietary ketosis. Cell Chem. Biol. 24, 935–943.e7 (2017).
Boccaletto, P. et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 46, D303–D307 (2018).
Shi, H. L., Wei, J. B. & He, C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol. Cell 74, 640–650 (2019).
Zaccara, S., Ries, R. J. & Jaffrey, S. R. Reading, writing and erasing mRNA methylation. Nat. Rev. Mol. Cell Biol. 20, 608–624 (2019).
Pendleton, K. E. et al. The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell 169, 824–835.e14 (2017). This study and related work define a negative feedback mechanism for the maintenance of intracellular SAM levels.
Shima, H. et al. S-adenosylmethionine synthesis is regulated by selective N-6-adenosine methylation and mRNA degradation involving METTL16 and YTHDC1. Cell Rep. 21, 3354–3363 (2017).
Aik, W. et al. Structural basis for inhibition of the fat mass and obesity associated protein (FTO). J. Med. Chem. 56, 3680–3688 (2013).
Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007).
Su, R. et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 172, 90–105.e23 (2018). This study defines a novel antitumour function of 2-HG by modulating RNA methylation.
Mauer, J. et al. FTO controls reversible m6Am RNA methylation during snRNA biogenesis. Nat. Chem. Biol. 15, 340–347 (2019).
Ito, S. et al. Human NAT10 is an ATP-dependent RNA acetyltransferase responsible for N-4-acetylcytidine formation in 18 S ribosomal RNA (rRNA). J. Biol. Chem. 289, 35724–35730 (2014).
Shyh-Chang, N. & Ng, H.-H. The metabolic programming of stem cells. Genes Dev. 31, 336–346 (2017).
Folmes, C. D. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 14, 264–271 (2011).
Panopoulos, A. D. et al. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res. 22, 168–177 (2012).
Tsogtbaatar, E., Landin, C., Minter-Dykhouse, K. & Folmes, C. D. L. Energy metabolism regulates stem cell pluripotency. Front. Cell Dev. Biol. 8, 87 (2020).
Ito, K. et al. Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science 354, 1156–1160 (2016).
Takubo, K. et al. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12, 49–61 (2013).
Ito, K. et al. A PML–PPAR–delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat. Med. 18, 1350–1358 (2012).
Tohyama, S. et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 12, 127–137 (2013).
Boon, R. et al. Amino acid levels determine metabolism and CYP450 function of hepatocytes and hepatoma cell lines. Nat. Commun. 11, 1393 (2020).
Guijas, C., Montenegro-Burke, J. R., Warth, B., Spilker, M. E. & Siuzdak, G. Metabolomics activity screening for identifying metabolites that modulate phenotype. Nat. Biotechnol. 36, 316–320 (2018).
Oburoglu, L. et al. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. Cell Stem Cell 15, 169–184 (2014).
Carey, B. W., Finley, L. W. S., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).
TeSlaa, T. et al. α-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 24, 485–493 (2016).
Moussaieff, A. et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 21, 392–402 (2015).
Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).
Liu, P.-S. et al. α-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).
Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074.e2065 (2019). This study links acetate availability to T cell activation.
Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).
Vander Heiden, M. G. & DeBerardinis, R. J. Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669 (2017).
Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Nacev, B. A. et al. The expanding landscape of ‘oncohistone’ mutations in human cancers. Nature 567, 473–478 (2019).
Gozdecka, M. et al. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nat. Genet. 50, 883–894 (2018).
Donaldson-Collier, M. C. et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat. Genet. 51, 517–528 (2019).
Fujisawa, T. & Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 18, 246–262 (2017).
Deribe, Y. L. et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat. Med. 24, 1047–1057 (2018).
Suva, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. Science 339, 1567–1570 (2013).
Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017).
Feinberg, A. P. The key role of epigenetics in human disease prevention and mitigation. N. Engl. J. Med. 378, 1323–1334 (2018).
Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 5, 3630 (2014).
Schaefer, I. M., Hornick, J. L. & Bovee, J. V. M. G. The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms. Lab. Invest. 98, 414–426 (2018).
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385.e1 (2018).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
Losman, J.-A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016).
Golub, D. et al. Mutant isocitrate dehydrogenase inhibitors as targeted cancer therapeutics. Front. Oncol. 9, 417 (2019).
King, A., Selak, M. A. & Gottlieb, E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682 (2006).
Kaelin, W. G. SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell 16, 180–182 (2009).
Cervera, A. M., Bayley, J.-P., Devilee, P. & McCreath, K. J. Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol. Cancer 8, 89 (2009).
Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).
Sulkowski, P. L. et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 582, 586–591 (2020).
Raffel, S. et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551, 384–388 (2017). This study shows that 2-HG, fumarate and succinate disrupt DNA repair through histone hypermethylation.
Green, N. H. et al. MTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma. Oncogene 38, 6211–6225 (2019).
Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016).
Morris, J. P. et al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature 573, 595–599 (2019). This study unravels a novel mechanism for the metabolism–epigenetic axis to mediate tumour-suppressive effects of p53.
Gao, X. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397–401 (2019). This study shows that dietary modulation of an amino acid results in antitumour effects.
Donohoe, D. R. et al. A gnotobiotic mouse model demonstrates that dietary fiber protects against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner. Cancer Discov. 4, 1387–1397 (2014).
Chalkiadaki, A. & Guarente, L. The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer 15, 608–624 (2015).
Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).
Lee, J. V. et al. Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca(2+)-NFAT signaling. Genes Dev. 32, 497–511 (2018).
Gruber, J. J. et al. HAT1 coordinates histone production and acetylation via H4 promoter binding. Mol. Cell 75, 711–724.e715 (2019).
Afshin, A. et al. Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet 393, 1958–1972 (2019).
Steck, S. E. & Murphy, E. A. Dietary patterns and cancer risk. Nat. Rev. Cancer 20, 125–138 (2020).
Willett, W. et al. Food in the anthropocene: the EAT–Lancet commission on healthy diets from sustainable food systems. Lancet 393, 447–492 (2019).
Barabási, A.-L., Menichetti, G. & Loscalzo, J. The unmapped chemical complexity of our diet. Nat. Food 1, 33–37 (2020).
Taya, Y. et al. Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation. Science 354, 1152–1155 (2016).
Ertl, R. P., Chen, J., Astle, C. M., Duffy, T. M. & Harrison, D. E. Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated. Blood 111, 1709–1716 (2008).
Cerletti, M., Jang, Y. C., Finley, L. W., Haigis, M. C. & Wagers, A. J. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012).
Garcia-Caballero, M. et al. Role and therapeutic potential of dietary ketone bodies in lymph vessel growth. Nat. Metab. 1, 666–675 (2019).
Chang, P. V., Hao, L. M., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 111, 2247–2252 (2014).
Rangan, P. et al. Fasting-mimicking diet modulates microbiota and promotes intestinal regeneration to reduce inflammatory bowel disease pathology. Cell Rep. 26, 2704–2719.e6 (2019).
Waterland, R. A. Assessing the effects of high methionine intake on DNA methylation. J. Nutr. 136, 1706s–1710s (2006).
Mafra, D. et al. Methyl donor nutrients in chronic kidney disease: impact on the epigenetic landscape. J. Nutr. 149, 372–380 (2019).
Halsted, C. H. et al. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc. Natl Acad. Sci. USA 99, 10072–10077 (2002).
Di Francesco, A., Di Germanio, C., Bernier, M. & de Cabo, R. A time to fast. Science 362, 770–775 (2018).
Hahn, O. et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18, 56 (2017).
Wang, T. N. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).
Newman, J. C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Rhoads, T. W. et al. Caloric restriction engages hepatic RNA processing mechanisms in rhesus monkeys. Cell Metab. 27, 677–688.e5 (2018).
Sleiman, S. F. et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife 5, e15092 (2016).
Sato, S. et al. Time of exercise specifies the impact on muscle metabolic pathways and systemic energy homeostasis. Cell Metab. 30, 92–110.e4 (2019).
Guo, X. L. et al. Caloric restriction promotes cell survival in a mouse model of normal tension glaucoma. Sci. Rep. 6, 33950 (2016).
Benjamin, J. S. et al. A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. Proc. Natl Acad. Sci. USA 114, 125–130 (2017).
Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546.e5 (2017).
Tognini, P. et al. Distinct circadian signatures in liver and gut clocks revealed by ketogenic diet. Cell Metab. 26, 523–538.e5 (2017).
Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557.e8 (2017).
Carrer, A. et al. Impact of a high-fat diet on tissue acyl-CoA and histone acetylation levels. J. Biol. Chem. 292, 3312–3322 (2017).
Guan, D. Y. et al. Diet-induced circadian enhancer remodeling synchronizes opposing hepatic lipid metabolic processes. Cell 174, 831–842.e12 (2018).
Gilbert, J. A. et al. Current understanding of the human microbiome. Nat. Med. 24, 392–400 (2018).
Schmidt, T. S. B., Raes, J. & Bork, P. The human gut microbiome: from association to modulation. Cell 172, 1198–1215 (2018).
David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).
Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).
Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).
den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).
Krautkramer, K. A. et al. Diet–microbiota interactions mediate global epigenetic programming in multiple host tissues. Mol. Cell 64, 982–992 (2016). This study links microbiota-derived short-chain fatty acids to histone acetylation dynamics in the host.
Romano, K. A. et al. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption. Cell Host Microbe 22, 279–290.e7 (2017).
Schuckit, M. A. Alcohol-use disorders. Lancet 373, 492–501 (2009).
Kriss, C. L. et al. In vivo metabolic tracing demonstrates the site-specific contribution of hepatic ethanol metabolism to histone acetylation. Alcohol. Clin. Exp. Res. 42, 1909–1923 (2018).
Narlikar, G. J., Sundaramoorthy, R. & Owen-Hughes, T. Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 154, 490–503 (2013).
Bartholomew, B. Regulating the chromatin landscape: structural and mechanistic perspectives. Annu. Rev. Biochem. 83, 671–696 (2014).
Clapier, C. R., Iwasa, J., Cairns, B. R. & Peterson, C. L. Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat. Rev. Mol. Cell Biol. 18, 407–422 (2017).
Qi, Y. F. & Zhang, B. Predicting three-dimensional genome organization with chromatin states. PLoS Comput. Biol. 15, e1007024 (2019).
Buckle, A., Brackley, C. A., Boyle, S., Marenduzzo, D. & Gilbert, N. Polymer simulations of heteromorphic chromatin predict the 3D folding of complex genomic loci. Mol. Cell 72, 786–797.e11 (2018).
MacPherson, Q., Beltran, B. & Spakowitz, A. J. Bottom-up modeling of chromatin segregation due to epigenetic modifications. Proc. Natl Acad. Sci. USA 115, 12739–12744 (2018).
Di Pierro, M., Cheng, R. R., Aiden, E. L., Wolynes, P. G. & Onuchic, J. N. De novo prediction of human chromosome structures: Epigenetic marking patterns encode genome architecture. Proc. Natl Acad. Sci. USA 114, 12126–12131 (2017).
Xiao, Z. T., Dai, Z. W. & Locasale, J. W. Metabolic landscape of the tumor microenvironment at single cell resolution. Nat. Commun. 10, 3763 (2019).
Zhou, F. et al. Reconstituting the transcriptome and DNA methylome landscapes of human implantation. Nature 572, 660–664 (2019).
Bian, S. H. et al. Single-cell multiomics sequencing and analyses of human colorectal cancer. Science 362, 1060–1063 (2018).
Cao, J. Y. et al. Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361, 1380–1385 (2018).
Clark, S. J. et al. scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9, 781 (2018).
Korem, T. et al. Bread affects clinical parameters and induces gut microbiome-associated personal glycemic responses. Cell Metab. 25, 1243–1253.e5 (2017).
Bashiardes, S., Godneva, A., Elinav, E. & Segal, E. Towards utilization of the human genome and microbiome for personalized nutrition. Curr. Opin. Biotech. 51, 57–63 (2018).
Cornish-Bowden, A. Fundamentals of Enzyme Kinetics 4th ed. (Wiley-Blackwell, 2012).
Lau, O. D. et al. p300/CBP-associated factor histone acetyltransferase processing of a peptide substrate. J. Biol. Chem. 275, 21953–21959 (2000).
Tanner, K. G., Langer, M. R. & Denu, J. M. Kinetic mechanism of human histone acetyltransferase P/CAF. Biochemistry 39, 11961–11969 (2000).
Tanner, K. G., Langer, M. R., Kim, Y. J. & Denu, J. M. Kinetic mechanism of the histone acetyltransferase GCN5 from yeast. J. Biol. Chem. 275, 22048–22055 (2000).
Thompson, P. R., Kurooka, H., Nakatani, Y. & Cole, P. A. Transcriptional coactivator protein p300 — kinetic characterization of its histone acetyltransferase activity. J. Biol. Chem. 276, 33721–33729 (2001).
Wapenaar, H. et al. Enzyme kinetics and inhibition of histone acetyltransferase KAT8. Eur. J. Med. Chem. 105, 289–296 (2015).
Albaugh, B. N., Kolonko, E. M. & Denu, J. M. Kinetic mechanism of the Rtt109–Vps75 histone acetyltransferase-chaperone complex. Biochemistry 49, 6375–6385 (2010).
Bintu, L. et al. Dynamics of epigenetic regulation at the single-cell level. Science 351, 720–724 (2016).
Katan-Khaykovich, Y. & Struhl, K. Dynamics of global histone acetylation and deacetylation in vivo: rapid restoration of normal histone acetylation status upon removal of activators and repressors. Genes Dev. 16, 743–752 (2002).
Evertts, A. G. et al. Quantitative dynamics of the link between cellular metabolism and histone acetylation. J. Biol. Chem. 288, 12142–12151 (2013).
Horiuchi, K. Y. et al. Assay development for histone methyltransferases. Assay Drug Dev. Technol. 11, 227–236 (2013).
Duncan, E. M., Chitsazan, A. D., Seidel, C. W. & Alvarado, A. S. Set1 and MLL1/2 target distinct sets of functionally different genomic loci in vivo. Cell Rep. 13, 2741–2755 (2015).
Kerimoglu, C. et al. KMT2A and KMT2B mediate memory function by affecting distinct genomic regions. Cell Rep. 20, 538–548 (2017).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
Becker, J. S., Nicetto, D. & Zaret, K. S. H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet. 32, 29–41 (2016).
Musselman, C. A., Lalonde, M. E., Cote, J. & Kutateladze, T. G. Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol. 19, 1218–1227 (2012).
Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16, 258–264 (2015).
Lauberth, S. M. et al. H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell 152, 1021–1036 (2013).
Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, eaaj2239 (2017).
Andrews, F. H. et al. The Taf14 YEATS domain is a reader of histone crotonylation. Nat. Chem. Biol. 12, 396–398 (2016).
Xiong, X. Z. et al. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat. Chem. Biol. 12, 1111–1118 (2016).
Zhao, S., Yue, Y., Li, Y. Y. & Li, H. T. Identification and characterization of ‘readers’ for novel histone modifications. Curr. Opin. Chem. Biol. 51, 57–65 (2019).
Jaffe, J. D. et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Genet. 45, 1386–1391 (2013).
Ghandi, M. et al. Next-generation characterization of the cancer cell line encyclopedia. Nature 569, 503–508 (2019).
Li, H. X. et al. The landscape of cancer cell line metabolism. Nat. Med. 25, 850–860 (2019).
Skene, P. J., Henikoff, J. G. & Henikoff, S. Targeted in situ genome-wide profiling with high efficiency for low cell numbers. Nat. Protoc. 13, 1006–1019 (2018).
Skene, P. J. & Henikoff, S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. eLife 6, e21856 (2017).
Ku, W. L. et al. Single-cell chromatin immunocleavage sequencing (scChIC-seq) to profile histone modification. Nat. Methods 16, 323–325 (2019).
Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).
Pareek, V., Tian, H., Winograd, N. & Benkovic, S. J. Metabolomics and mass spectrometry imaging reveal channeled de novo purine synthesis in cells. Science 368, 283–290 (2020).
Gilmore, I. S., Heiles, S. & Pieterse, C. L. Metabolic imaging at the single-cell scale: recent advances in mass spectrometry imaging. Annu. Rev. Anal. Chem. 12, 201–224 (2019).
Dai, Z. W. & Locasale, J. W. Understanding metabolism with flux analysis: from theory to application. Metab. Eng. 43, 94–102 (2017).
Kopinski, P. K. et al. Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy. Proc. Natl Acad. Sci. USA 116, 16028–16035 (2019).
Kungulovski, G. & Jeltsch, A. Epigenome editing: state of the art, concepts, and perspectives. Trends Genet. 32, 101–113 (2016).
Stricker, S. H., Koferle, A. & Beck, S. From profiles to function in epigenomics. Nat. Rev. Genet. 18, 51–66 (2017).
Park, M., Patel, N., Keung, A. J. & Khalil, A. S. Engineering epigenetic regulation using synthetic read-write modules. Cell 176, 227–238.e20 (2019).
Acknowledgements
J.W.L. thanks the Marc Lustgarten Foundation and the National Institutes of Health (R01CA193256) for their generous support.
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J.W.L. advises Restoration Foodworks, Nanocare Technologies and Raphael Pharmaceuticals. Z.D. and V.R. declare no competing interests.
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Glossary
- Nucleosome
-
The basic structural unit of chromatin. Each nucleosome consists of two copies apiece of the histones H2A, H2B, H3 and H4.
- Chromatin remodellers
-
Protein complexes that regulate gene expression by changing the organization of nucleosomes.
- Electrophilic moieties
-
Molecules that have the tendency to accept an electron pair by reacting with electron-rich nucleophiles.
- Km and Kd values
-
Quantities that describe the affinity of the substrate (Km) and an inhibitor (Kd) to an enzyme. Smaller values for Km and Kd indicate higher binding affinity.
- Methyl group sinks
-
Molecular pathways that regulate intracellular methyl group availability by consuming S-adenosylmethionine (SAM).
- Liquid–liquid phase separation
-
Demixing of fluid into two or more distinct phases, which can help compartmentalize molecules within a cell by forming membrane-less organelles.
- Enhancers
-
Gene-regulatory elements that can be coding or non-coding sequences and that potentiate the transcription of genes proximal or distal to them.
- Superenhancers
-
Large clusters of enhancers that are bound by multiple master transcription factors in order to activate the transcription of cell-identity-related genes.
- Bromodomain
-
A protein domain that recognizes and binds to acetylated lysine residues.
- One-carbon metabolism
-
A metabolic network for transferring one-carbon units from nutrients to metabolites that support multiple physiological processes, including nucleotide synthesis.
- α-Ketoglutarate
-
(αKG). A metabolic intermediate of the tricarboxylic acid (TCA) cycle, which is derived from isocitrate and is further processed into succinyl-CoA. It can also be derived from glutamine metabolism.
- Redox balance
-
Reaction systems that help maintain healthy levels of reactive oxygen species in intracellular compartments.
- Metabolic fasting
-
An intentional abstinence from food and drink during a period of time.
- Hexosamine biosynthetic pathway
-
A branch of glycolysis that utilizes substrates from amino acid, fatty acid and nucleotide metabolism to generate substrates that participate in N-linked and O-linked protein glycosylation.
- Central-carbon metabolism
-
Metabolic pathways involved in the catabolism of carbohydrates, lipids and amino acids for the production of ATP and biomass precursors, as well as for signalling and redox status maintenance.
- Rate constants
-
Quantities that relate the speed of a chemical reaction to the concentrations of its substrates.
- Lipid peroxidation
-
A process by which lipids are endogenously rendered electrophilic by a degradative chemical reaction with free radicals.
- Nucleophilic functional groups
-
Chemical groups that have the tendency of donating an electron pair in reactions with electron-poor groups.
- Advanced glycation end products
-
(AGEs). Covalent adducts formed through the chemical crosslinking of glycolytic by-products to macromolecules such as DNA and protein.
- Humoral immune response
-
A branch of the immune system that involves the activation and differentiation of B cells into plasma and memory cells, which mount antibody responses to invading pathogens.
- Branched-chain amino acids
-
The amino acids leucine, isoleucine and valine, which each contain a branching aliphatic side chain.
- MTHFD2
-
The enzyme methylenetetrahydrofolate dehydrogenase 2, which couples the folate cycle to the methionine cycle, enabling the transfer of the one-carbon methyl group to homocysteine in order to recycle methionine.
- Warburg effect
-
The phenomenon, first observed by German physiologist Otto Heinrich Warburg, that cancer cells hyperactivate glycolysis, even in the presence of sufficient oxygen.
- Ketogenic diet
-
A diet low in carbohydrate and high in fat, which precipitates the generation of ketone bodies by fatty acid catabolism.
- Fetal alcohol spectrum disorder
-
In utero exposure to alcohol that can give rise to the postnatal acquisition of developmental disorders.
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Dai, Z., Ramesh, V. & Locasale, J.W. The evolving metabolic landscape of chromatin biology and epigenetics. Nat Rev Genet 21, 737–753 (2020). https://doi.org/10.1038/s41576-020-0270-8
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DOI: https://doi.org/10.1038/s41576-020-0270-8
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