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Cited by 926Epigenetics and DNA MethylationCancer, Hypoxia, and MetabolismGenomics and Chromatin Dynamics

Influence of Metabolism on Epigenetics and Disease

Open access
Kaelin, William G., McKnight, Steven L.·2013·Cell
DOI 10.1016/j.cell.2013.03.004PMC PMC3775362
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Abstract

Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer and, more broadly, for how alterations in metabolism and nutrition might contribute to disease. Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells.

Verified 2026-10-06 · 1 reference not checked yet

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Crossref · 10.1016/j.cell.2013.03.004

Cites

134 of 135 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 142 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Chemical inhibition of threonine dehydrogenase in undifferentiated mouse embryonic stem cells causes intracellular acetyl-CoA to fall sharply.

    “When undifferentiated ESCs are exposed to a specific chemical inhibitor of the TDH enzyme, intracellular levels of acetyl-CoA drop precipitously”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Alexander et al., 2011 source

      Not checked in the free run.

  • Findingcitation

    In yeast, many acetylation marks on histone H3 and H4 appear only during a 30-45 min window at the oxidative-to-reductive building boundary, coinciding with peak acetyl-CoA.

    “numerous acetylation marks on the K9, K14, K23, and K27 residues of histone H3 and the K5, K8, and K12 residues on histone H4 only appear over a 30–45 min window corresponding exactly with the Ox/RB boundary that is coincident with the peak abundance of intracellular acetyl-CoA.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cai et al., 2011

      Not checked in the free run.

    • cites Cai and Tu, 2011

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    • cites Cai and Tu, 2012 source

      Not checked in the free run.

  • Findingcitation

    Undifferentiated mouse embryonic stem cells contain significantly more acetyl-CoA than embryoid body cells induced to differentiate by leukemia-inhibitory factor withdrawal and retinoic acid.

    “Undifferentiated ESCs contain significantly higher levels of acetyl-CoA than the embryoid body (EB) cells induced to differentiate by the combined withdrawal of leukemia-inhibitory factor (LIF) and application of retinoic acid (RA)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wang et al., 2009a

      Not checked in the free run.

    • cites Wang et al., 2011 source

      Not checked in the free run.

  • Findingcitation

    Intracellular acetyl-CoA levels fluctuate substantially in biological settings, as shown in yeast and mouse embryonic stem cells.

    “Studies of two different eukaryotic cells have indeed given evidence of significant fluctuation in acetyl-CoA.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Klevecz et al., 2004 source

      Not checked in the free run.

    • cites Tu et al., 2005

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    • cites Tu and McKnight, 2006

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  • Findingcitation

    The off-rate of acetyl-CoA binding to yeast GCN5 is more than tenfold faster than that of human p300/CBP HAT, human GCN5, or Tetrahymena GCN5.

    “the off-rate of acetyl-CoA binding to the yeast GCN5 enzyme is more than an order of magnitude more rapid than that of human p300/CBP HAT enzyme, human GCN5, or Tetrahymena GCN5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Langer et al., 2002 source

      Not checked in the free run.

  • May combine two claims. 28
  • Classified as probably not a substantial claim. 9
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    Undifferentiated mouse embryonic stem cells express threonine dehydrogenase at levels more than 1,000-fold higher than other mouse cells or tissues, and the encoding gene is repressed immediately upon differentiation.

    “Undifferentiated mouse ESCs express levels of TDH upward of 1,000-fold higher relative to any other source of mouse cells or tissues, and the gene encoding TDH is stringently repressed immediately upon induction of ESC differentiation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In wild-type mouse liver, NAD+ abundance shows two ultradian peaks and troughs per 24 hr cycle, with peak-to-trough fluctuation of 20-30%.

    “When NAD+ levels were measured in liver tissue of wild-type mice, two ultradian sets of peaks and troughs of NAD+ abundance were observed per 24 hr cycle (Ramsey et al., 2009). The peak-to-trough fluctuation in NAD+ abundance varied by 20%–30%, as reported in the latter study.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ramsey et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Administering β-hydroxybutyrate to mice via an intraperitoneal pump enhanced H3K9 and H3K14 acetylation, induced FOXO3A-regulated genes, and increased resistance to oxidative stress.

    “By administering β-hydroxybutyrate to laboratory mice via an intraperitoneal pump, Shimazu and colleagues were able to demonstrate enhancement of H3K9 and H3K14 acetylation, induced expression of FOXO3A–regulated genes, and resistance to oxidative stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shimazu et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Threonine can be converted catabolically into acetyl-CoA by a mitochondrial threonine dehydrogenase that is expressed uniquely in mouse embryonic stem cells.

    “Acetyl-CoA can also be produced catabolically from threonine via a mitochondrial threonine dehydrogenase enzyme uniquely expressed in mouse embryonic stem cells”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Acetyl-CoA can be generated through multiple catabolic and anabolic routes.

    “Acetyl-CoA can be produced through a variety of metabolic pathways, both catabolic and anabolic”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The yeast growth gene battery closely matches genes induced by c-Myc in mammalian cells, which are reported to depend on both c-Myc and GCN5/SAGA.

    “This yeast growth gene battery matches closely with the genes induced by the c-Myc oncoprotein in mammalian cells”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ji et al., 2011

      Not checked in the free run.

    • cites McMahon et al., 1998 source

      Not checked in the free run.

    • cites McMahon et al., 2000 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    In metazoan cells, mitochondrial citrate is exported to the cytoplasm by the malate-citrate antiporter and converted by ATP citrate lyase into acetyl-CoA and oxaloacetate, supplying cytoplasmic acetyl-CoA for lipid synthesis.

    “metazoan cells have evolved the malate-citrate antiporter system to move mitochondrial citrate to the cytoplasm, where it can combine with ATP and CoA to be converted to acetyl-CoA and oxaloacetate via the ATP citrate lyase enzyme, thereby affording a cytoplasmic pool of acetyl-CoA for lipid biosynthesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SIRT3 and SIRT6 are encoded by genes with tumor-suppressor activity.

    “the genes encoding SIRT3 and SIRT6 are tumor suppressors”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kim et al., 2010 source

      Not checked in the free run.

    • cites Sebastián et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    SAM contains the active methyl donor group used by most methyltransferase enzymes.

    “S-adenosylmethionine (SAM) contains the active methyl donor group utilized by most methyltransferase enzymes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NAD+ levels fluctuate with the circadian cycle, instructing nuclear sirtuins to control chromatin epigenetic state.

    “NAD+ levels fluctuate as a function of the circadian cycle, thereby instructing nuclear sirtuin enzymes to control the epigenetic state of chromatin in an NAD+-regulated manner.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Nakahata et al., 2009 source

      Not checked in the free run.

    • cites Ramsey et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Sirtuin enzymes oppose protein acetylation, and protein acetylation can be influenced by intracellular acetyl-CoA levels.

    “sirtuin enzymes sit in diametric opposition to protein acetylating and that protein acetylation can be influenced by intracellular levels of acetyl-CoA.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Histone and DNA chemical modifications are central to epigenetic control of gene expression.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    The activated methyl cycle regenerates methionine by transferring a methyl group from N5-MTHF to homocysteine.

    “The activated methyl cycle can then be looped back via the transfer of a methyl group from N5-MTHF to homocysteine, regenerating methionine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sirtuin deacetylases require NAD+ and produce O-acetyl-ADP-ribose, the deacetylated substrate, and nicotinamide.

    “those that are NAD+-dependent, yielding O-acetyl-ADP-ribose, the deacetylated substrate, and nicotinamide as products”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Denu, 2005 source

      Not checked in the free run.

    • cites Feldman et al., 2012 source

      Not checked in the free run.

    • cites Sauve et al., 2006 source

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  • May combine two claims.

    Interpretationcitation

    β-hydroxybutyrate can fuel metabolic adaptation to starvation and help sustain a protective epigenetic state by inhibiting NAD+-independent histone deacetylases.

    “These data provide evidence that a distinct metabolite, β-hydroxybutyrate, is able not only to fuel metabolic adaptation to starvation but also to help sustain a protective epigenetic state by inhibiting the activities of NAD+-independent histone deacetylase enzymes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shimazu et al., 2013 source

      Not checked in the free run.

    • Rests on an assumption: Histone and DNA chemical modifications are central to epigenetic control of gene expression.

  • May combine two claims.

    Premisecitation

    Acetylation of AceCS2 on a specific lysine inhibits its ability to convert acetate into acetyl-CoA, and this regulatory scheme is conserved from Salmonella to mammals.

    “AceCS2 is acetylated on a specific lysine residue that inhibits the ability of the enzyme to convert acetate into acetyl-CoA, a regulatory scheme conserved from Salmonella to mammals”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hirschey et al., 2011 source

      Not checked in the free run.

    • cites Starai et al., 2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    SAM is produced by condensation of methionine and ATP during the first of nine steps converting methionine to succinyl-CoA.

    “SAM is produced by the condensation of methionine and ATP during the first of nine steps required for the conversion of methionine to succinyl-CoA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    For AceCS2 and PGC1α, ample nutrients inhibit their activities through acetyl-CoA-mediated acetylation, which is counterbalanced by SIRT3 and SIRT1.

    “access to ample nutrients can simplistically be understood to inhibit the activities of the two proteins via acetyl-CoA-mediated acetylation. This inhibition, in turn, can be respectively counterbalanced by the mitochondrial SIRT3 and nuclear SIRT1 enzymes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Enzyme-catalyzed donation of SAM's methyl group to an acceptor yields SAH, which is hydrolyzed to homocysteine and adenosine.

    “Enzyme-catalyzed donation of the methyl group of SAM to an acceptor macromolecule yields S-adenosylhomocysteine (SAH), which, in turn, is hydrolyzed to homocysteine and adenosine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TDH inhibition in ESCs increases intracellular threonine and AICAR.

    “Simultaneous increases in the intracellular abundance of threonine and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were observed upon TDH inhibition in ESCs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Alexander et al., 2011 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Threonine deprivation selectively affects H3K4me2 and H3K4me3 but not H3K4me1, H3K9me3, H3K27me3, H3K36me3, or H3K79me3 marks.

    “These impediments were selective; threonine deprivation had no effect on the deposition of H3K4me1, H3K9me3, H3K27me3, H3K36me3, or H3K79me3 marks on histone tails.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shyh-Chang et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LSD1 is a nuclear FAD-dependent enzyme that demethylates methylated H3K4 in vitro and in vivo, establishing histone methylation as dynamic and reversible.

    “In a landmark paper, Yang Shi and coworkers showed that LSD1 (also called KDM1A or AOF2) is a nuclear FAD-dependent enzyme capable of demethylating methylated H3K4 both in vitro and in vivo, thereby establishing that histone methylation is a dynamic, reversible process (Shi et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shi et al., 2004 source

      Not checked in the free run.

    • Rests on an assumption: FAD is derived from riboflavin and functions as a prosthetic group for certain oxidation-reduction enzymes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MafK can either repress or activate gene expression depending on its heterodimeric partner.

    “The latter protein is a small bZip transcription factor that, depending upon its heterodimeric partner, can either repress or activate gene expression (Hintze et al., 2007; Igarashi and Sun, 2006; Muto et al., 1998; Ochiai et al., 2006; Zhang et al., 2006).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hintze et al., 2007 source

      Not checked in the free run.

    • cites Igarashi and Sun, 2006

      Not checked in the free run.

    • cites Muto et al., 1998 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LSD1 regulates mitochondrial respiration and energy expenditure.

    “LSD1, in turn, regulates mitochondrial respiration and energy expenditure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hino et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intracellular fumarate and succinate concentrations are estimated to be in the high micromolar and low millimolar range, respectively.

    “In this regard, intracellular fumarate and succinate concentrations are estimated to be in the high micromolar and low millimolar range, respectively (Johnson et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Johnson et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    This presumably allows such enzymes to respond to changes in concentrations of available agonists and antagonists.

    “This presumably allows such enzymes to respond to changes in the concentrations of available agonists and antagonists.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Collagen prolyl hydroxylases have very low O2 Km, presumably to function in poorly vascularized wounds.

    “By contrast, the collagen prolyl hydroxylases have very low O2 Km, presumably so that they can function in environments such as poorly vascularized wounds (Hirsilä et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hirsilä et al., 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5hmC in the nervous system is associated with actively transcribed genes and recognized by MeCP2, which is inactivated in Rett syndrome.

    “5hmC in the nervous system is associated with actively transcribed genes and is recognized by the histone-reader protein MeCP2, which is mutationally inactivated in the neurological disorder of Rett syndrome (Mellén et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mellén et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The rapid reversal of R-2HG effects suggests either that these phenotypes are not due to epigenetic targets of R-2HG or that R-2HG-induced epigenetic changes are surprisingly dynamic.

    “This suggests either that these phenotypes are not due to epigenetic targets of R-2HG or that R-2HG-induced epigenetic changes are surprisingly dynamic.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These metabolites appear to cause cancer by affecting various 2-oxoglutarate-dependent dioxygenases, including those linked to DNA and histone methylation, and therefore have potential to alter the epigenome.

    “These metabolites appear to cause cancer by affecting the behavior of various 2-oxoglutarate-dependent dioxygenases, including dioxygenases linked to DNA and histone methylation, and therefore have the potential to alter the epigenome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TET2 inactivation is sufficient to promote hematopoietic stem cell self-renewal and block differentiation.

    “In addition, TET2 inactivation is sufficient to promote hematopoietic stem cell self-renewal and to block differentiation (Figueroa et al., 2010; Li et al., 2011; Moran-Crusio et al., 2011; Noushmehr et al., 2010; Turcan et al., 2012; Losman et al., 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Figueroa et al., 2010 source

      Not checked in the free run.

    • cites Li et al., 2011

      Not checked in the free run.

    • cites Moran-Crusio et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    SDH, FH, and IDH mutations cause accumulation of succinate, fumarate, and R-2HG, respectively.

    “In summary, SDH, FH, and IDH mutations cause the accumulation of succinate, fumarate, and R-2HG, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Deletion of HIF1α worsens pathological changes in mice lacking FH, suggesting HIF1α normally constrains rather than promotes FH-defective tumors.

    “Deletion of HIF1α, however, worsened the pathological changes observed in mice engineered to lack FH, suggesting that it normally constrains, rather than promotes, the emergence of FH-defective tumors (Adam et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Adam et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TET2 and IDH mutations are both found in AML and are mutually exclusive, consistent with R-2HG from mutant IDH providing an alternative way to inactivate TET2.

    “In this regard, TET2 and IDH mutations are both found in acute myelogenous leukemia and are mutually exclusive, consistent with the idea that R-2HG produced by mutant IDH provides an alterative means of inactivating TET2 (Figueroa et al., 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Figueroa et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The failure of folic acid trials might suggest that folate deficiency correlates with but does not cause cancer, or that folate is important only during an early time window before or during tumor initiation.

    “This might suggest that folate deficiency correlates with, but does not cause, cancer or that folate is important during an early time window, perhaps occurring at an early age and prior to or during tumor initiation, but not thereafter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Increasing evidence indicates that early exposures, including intrauterine exposures, can lead to lasting epigenetic changes and that epigenetic differences can influence many phenotypes, including disease risk.

    “There is increasing evidence that early exposures, including intrauterine exposures, can lead to lasting epigenetic changes and that epigenetic differences can influence many phenotypes, including the risk of disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    R-2HG is sufficient to promote cytokine independence and block differentiation of hematopoietic cells in vitro, and these effects are rapidly reversed upon R-2HG withdrawal.

    “Interestingly, R-2HG is sufficient to promote cytokine independence and block differentiation of hematopoietic cells in vitro and these effects are fairly rapidly reversed upon R-2HG withdrawal (Losman et al., 2013; K. Yen, personal communication).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Losman et al., 2013 source

      Not checked in the free run.

    • cites K. Yen, personal communication

      Not checked in the free run.

36 of 36

  • The paper relies on this without support.

    Histone and DNA chemical modifications are central to epigenetic control of gene expression.

    “Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation.”

  • The paper relies on this without support.

    Cancer can arise from mutations in the metabolic enzymes SDH, FH, and IDH.

    “This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer”

  • The paper relies on this without support.

    Both histone and DNA methylation require SAM as the high-energy methyl donor.

    “Both histone and DNA methylation require SAM as the high-energy methyl donor (Figure 3).”

  • The paper relies on this without support.

    FAD is derived from riboflavin and functions as a prosthetic group for certain oxidation-reduction enzymes.

    “Flavin adenine dinucleotide (FAD) is derived from the vitamin riboflavin (vitamin B2) and functions as the prosthetic group for certain oxidation-reduction enzymes.”

  • The paper relies on this without support.

    Riboflavin is phosphorylated by riboflavin kinase to FMN, which is converted to FAD by FAD synthetase.

    “Riboflavin is phosphorylated by riboflavin kinase to generate riboflavin 5′-phosphate (sometimes called flavin monucleotide or FMN), which is then converted to FAD by FAD synthetase (also called FMN adenyl-transferase).”

  • The paper relies on this without support.

    Riboflavin kinase appears rate limiting for FAD production.

    “The former enzyme appears to be rate limiting for FAD production.”

  • The paper relies on this without support.

    FAD is produced in mitochondria.

    “FAD is produced in mitochondria.”

  • The paper relies on this without support.

    2-oxoglutarate-dependent dioxygenases require oxygen and Fe(II) in addition to 2-oxoglutarate.

    “2-oxoglutarate-dependent dioxygenases require oxygen and Fe (II) in addition to 2-oxoglutarate (also called α-ketoglutarate).”

  • The paper relies on this without support.

    2-oxoglutarate is decarboxylated to succinate during the oxidation reaction.

    “The latter metabolite is decarboxylated to succinate during the oxidation reaction (Figure 5).”

  • The paper relies on this without support.

    These enzymes are sensitive to reactive oxygen species and their activity is enhanced by ascorbic acid.

    “These enzymes are also sensitive to reactive oxygen species and their activity is enhanced in the presence of ascorbic acid.”

  • The paper relies on this without support.

    HIF synthesis is influenced by the PI3K-AKT-mTOR pathway sensing nutrients, while its degradation is controlled by EglN prolyl hydroxylases responding to oxygen and Krebs cycle intermediates.

    “HIF synthesis is influenced by the PI3K-AKT-mTOR pathway, which senses nutrients such as glucose and amino acids, while its degradation is under the control of the EglN prolyl hydroxylases, which respond to changes in oxygen and different Krebs cycle intermediates (Figure 6A).”

  • The paper relies on this without support.

    2-oxoglutarate is produced from isocitrate in mitochondria by IDH2 and IDH3 in the TCA cycle and can also be generated from several amino acids including arginine, proline, histidine, and glutamine.

    “2-oxoglutarate is produced from isocitrate in the mitochondria by the action of isocitrate dehydrogenases 2 and 3 (IDH2 and IDH3) in the TCA cycle and can also be generated from several amino acids including arginine, proline, histidine, and glutamine, which can be converted to glutamic acid and transaminated to produce 2-oxoglutarate.”

  • The paper relies on this without support.

    2-oxoglutarate generated in the TCA cycle is converted to succinyl CoA by the 2-oxoglutarate dehydrogenase complex and is consumed during conversion of cysteine and lysine to pyruvate and acetyl-CoA.

    “2-oxoglutarate generated in the course of the TCA cycle is converted to succinyl CoA by the action of the 2-oxoglutarate dehydrogenase complex and is also consumed during the conversion of cysteine and lysine to pyruvate and acetyl-CoA, respectively.”

  • The paper relies on this without support.

    2-oxoglutarate generated in mitochondria can enter the cytosol via specific transporters such as the malate-2-oxoglutarate antiporter.

    “2-oxoglutarate generated in the mitochondria can enter the cytosol, either as 2-oxoglutarate or after transamination to produce glutamic acid, via specific transporter proteins such as the malate-2-oxoglutarate antiporter, which participates in the malate-aspartate shuttle.”

  • The paper relies on this without support.

    IDH1 resides in the cytosol and peroxisomes and provides an alternative source for nonmitochondrial 2-oxoglutarate.

    “A third IDH paralog, IDH1, resides in the cytosol and peroxisomes and provides an alternative source for nonmitochondrial 2-oxoglutarate.”

  • The paper relies on this without support.

    Altered epigenetics is believed to play a part in diseases including diabetes, obesity, dyslipidemia, hypertension, and neurodegeneration.

    “Altered epigenetics is believed to play a part in a variety of diseases in addition to cancer, including diabetes, obesity, dyslipidemia, hypertension, and neurodegeneration.”

  • The paper relies on this without support.

    Diet influences one-carbon metabolism, which plays an important role in DNA and histone methylation and in disease risk.

    “In this regard, particular attention has been paid to the influence of diet on one-carbon metabolism, which plays an important role in DNA and histone methylation and in risk of disease.”
17 of 17

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Metabolic intermediates of the TCA cycle affect epigenetic control of gene expression by regulating histone and DNA modifications.

    “metabolic intermediates of the TCA cycle affect epigenetic-mediated control of gene expression through regulating the modification of histones and DNA 137,138”

    From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [137]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Threonine-sensitive histone mark changes from H3K4me3 to H3K3me3

    Minor

    One passage identifies H3K4me3 as a mark whose deposition is impaired by threonine restriction, but the next identifies H3K3me3 as the mark that disappears alongside H3K4me2. The two passages give different identities for the affected mark.

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Authors
Kaelin, W. G., & McKnight, S. L.
Affiliations
  • Brigham and Women's Hospital (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
  • Kaelin, William G.
  • McKnight, Steven L.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2013-03
Volume
153
Issue
1
Pages
56-69
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2013.03.004
PMC
PMC3775362
OpenAlex
W2035010201
Semantic Scholar
732b8265382027a841509c4b7ef3185231cba71c
Cited by
920
References
136
Citations by year
2026: 89 · 2025: 41 · 2024: 52 · 2023: 49 · 2022: 57 · 2021: 85 · 2020: 74 · 2019: 84 · 2018: 58 · 2017: 70 · 2016: 73 · 2015: 82 · 2014: 71 · 2013: 32
FWCI
8.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute (R01CA068490, R01CA076120)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
metabolism, epigenetics, histone methylation, histone acetylation, DNA methylation, epigenetic regulation, succinate dehydrogenase, fumarase, isocitrate dehydrogenase, cancer, nutrition and disease
MeSH terms
Acetylation, Animals, Disease, Histones, Humans, Metabolism, Methylation, DNA Methylation, Epigenesis, Genetic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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