The DOI matches its Crossref record; 134 of the 136 references it cites were found in a registry or an index, and 1 are not checked yet; 3 of the 142 sources its claims cite were checked for support.
Influence of Metabolism on Epigenetics and Disease
Open accessAbstract
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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Claims the paper makes
83 Not checked yet · 22 No basis given · 19 Own interpretation · 2 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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)”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Fluctuation
What the sources say
- Not checked yetcites Wang et al., 2009a
- Partly supportedcites Wang et al., 2011 sourceExperimental — accuracy not yet measured
The paper states that acetyl-CoA levels drop as mouse ES cells differentiate, and its metabolite survey compares undifferentiated cells with embryoid bodies produced by LIF withdrawal and retinoic acid (section labeled Abstract; page unavailable). Figure 1’s caption describes triplicate measurements, but the available text does not establish that the acetyl-CoA difference was statistically significant. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“When undifferentiated ESCs are exposed to a specific chemical inhibitor of the TDH enzyme, intracellular levels of acetyl-CoA drop precipitously”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Fluctuation
What the sources say
- Not checked yetcites Alexander et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Control of Gene Expression by Acetyl-CoA
What the sources say
- Not checked yetcites Cai et al., 2011
- Not checked yetcites Cai and Tu, 2011
- Not checked yetcites Cai and Tu, 2012 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Studies of two different eukaryotic cells have indeed given evidence of significant fluctuation in acetyl-CoA.”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Fluctuation
What the sources say
- Not checked yetcites Klevecz et al., 2004 source
- Not checked yetcites Tu et al., 2005
- Not checked yetcites Tu and McKnight, 2006
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA and Histone Acetyltransferase Enzymes
What the sources say
- Not checked yetcites Langer et al., 2002 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Acetyl-CoA levels peak at a 6-fold-higher level at the transition of the oxidative (Ox) phase to the reductive building (RB) phase relative to the metabolically quiescent, reductive charging (RC) phase of the YMC”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Fluctuation
What the sources say
- Not checked yetcites Cai et al., 2011
- Not checked yetcites Tu et al., 2007
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The GCN5 histone acetylase enzyme of the SAGA complex has been identified as the critical enzyme responsible for transient acetylation of growth genes at the Ox/RB boundary”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA and Histone Acetyltransferase Enzymes
What the sources say
- Not checked yetcites Cai et al., 2011
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“Further DNA microarray and ChIP-seq experiments led to the identification of roughly 1,000 growth genes selectively acetylated and activated only when intracellular levels of acetyl-CoA peak”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Control of Gene Expression by Acetyl-CoA
What the sources say
- Not checked yetcites Cai et al., 2011
- Not checked yetcites Tu et al., 2005
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“catalytically active GCN5 is critically required for YMC oscillation”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA and Histone Acetyltransferase Enzymes
What the sources say
- Not checked yetcites Cai et al., 2011
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“when NAD+ levels were measured as a function of the YMC, which is far more robust in amplitude than metabolic fluctuation taking place as a function of the circadian cycle, no changes in NAD+ levels were observed”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
What the sources say
- Not checked yetcites Tu et al., 2007
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 28
- Probably not a substantial claim. 9
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the genes encoding SIRT3 and SIRT6 are tumor suppressors”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
What the sources say
- Partly supportedcites Kim et al., 2010 sourceExperimental — accuracy not yet measured
The Results section identifies SIRT3 as a tumor suppressor, reporting mammary tumors in SIRT3-knockout mice but none in wild-type controls. The Introduction mentions SIRT6 only as a member of the sirtuin family; our copy does not establish tumor-suppressor activity for SIRT6. (LLM, conf=0.90)
- Supportedcites Sebastián et al., 2012 source
The Discussion describes SIRT3 as having tumor-suppressive activity and states that this study shows SIRT6 functions as a tumor suppressor. It distinguishes their contexts—SIRT3’s reported effect is in already transformed cells, whereas SIRT6 can suppress tumor initiation—but supports the claim about both genes. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Fluctuation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
What the sources say
- Not checked yetcites Ramsey et al., 2009 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ Independent Histone Deacetylases
What the sources say
- Not checked yetcites Shimazu et al., 2013 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Acetyl-CoA can also be produced catabolically from threonine via a mitochondrial threonine dehydrogenase enzyme uniquely expressed in mouse embryonic stem cells”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Generation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Acetyl-CoA can be produced through a variety of metabolic pathways, both catabolic and anabolic”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Generation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This yeast growth gene battery matches closely with the genes induced by the c-Myc oncoprotein in mammalian cells”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Cancer Connection
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > Acetyl-CoA: “Activated Acetate” and Histone Acetylation > Acetyl-CoA Generation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“S-adenosylmethionine (SAM) contains the active methyl donor group utilized by most methyltransferase enzymes”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“sirtuin enzymes sit in diametric opposition to protein acetylating and that protein acetylation can be influenced by intracellular levels of acetyl-CoA.”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Histone and DNA chemical modifications are central to epigenetic control of gene expression.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The activated methyl cycle can then be looped back via the transfer of a methyl group from N5-MTHF to homocysteine, regenerating methionine.”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“those that are NAD+-dependent, yielding O-acetyl-ADP-ribose, the deacetylated substrate, and nicotinamide as products”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ Independent Histone Deacetylases
What the sources say
- Not checked yetcites Shimazu et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Histone and DNA chemical modifications are central to epigenetic control of gene expression.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > NAD+ and Deacetylation > NAD+ and Sirtuin Deacetylases
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Simultaneous increases in the intracellular abundance of threonine and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) were observed upon TDH inhibition in ESCs.”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“ > Threonine Dehydrogenase and SAM
What the sources say
- Not checked yetcites Alexander et al., 2011 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These impediments were selective; threonine deprivation had no effect on the deposition of H3K4me1, H3K9me3, H3K27me3, H3K36me3, or H3K79me3 marks on histone tails.”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“ > Threonine Dehydrogenase and SAM
What the sources say
- Not checked yetcites Shyh-Chang et al., 2013 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > FAD and Histone Demethylation
What the sources say
- Not checked yetcites Shi et al., 2004 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: FAD is derived from riboflavin and functions as a prosthetic group for certain oxidation-reduction enzymes.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“ > SAM and Histone/DNA Methylation
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“LSD1, in turn, regulates mitochondrial respiration and energy expenditure.”
§ Influence of Metabolism on Epigenetics and Disease > FAD and Histone Demethylation
What the sources say
- Not checked yetcites Hino et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > 2-Oxoglutarate-Dependent Dioxygenases > 2-Oxoglutarate
What the sources say
- Not checked yetcites Johnson et al., 2008 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This presumably allows such enzymes to respond to changes in the concentrations of available agonists and antagonists.”
§ Influence of Metabolism on Epigenetics and Disease > 2-Oxoglutarate-Dependent Dioxygenases > 2-Oxoglutarate
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > 2-Oxoglutarate-Dependent Dioxygenases > Iron and Oxygen
What the sources say
- Not checked yetcites Hirsilä et al., 2003 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > 2-Oxoglutarate-Dependent Dioxygenases > JmjC and TET Demethylases
What the sources say
- Not checked yetcites Mellén et al., 2012 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In summary, SDH, FH, and IDH mutations cause the accumulation of succinate, fumarate, and R-2HG, respectively.”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
What the sources say
- Not checked yetcites Adam et al., 2011 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
What the sources say
- Not checked yetcites Figueroa et al., 2010 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > Nutrition, Epigenetics, and Disease
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Influence of Metabolism on Epigenetics and Disease > Conclusions and Future Questions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Influence of Metabolism on Epigenetics and Disease > SDH, FH, and IDH Mutations and Cancer
What the sources say
- Not checked yetcites Losman et al., 2013 source
- Not checked yetcites K. Yen, personal communication
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
In the citing paper
“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]
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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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“ > Threonine Dehydrogenase and SAM
“The H3K4me2 and H3K3me3 marks that disappear when mouse ESCs are deprived of threonine”
§ Influence of Metabolism on Epigenetics and Disease > Methylation of DNA and Histones: SAM and the “Activated Methyl Cycle“ > Threonine Dehydrogenase and SAM
“Intriguingly, threonine restriction was observed to dramatically impede deposition of the H3K4me2 and H3K4me3 marks on chromatin.”
Citations
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Metadata
- 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.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 153
- Issue
- 1
- Pages
- 56-69
- ISSN
- 0092-8674 (ISSN-L)
- 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
- bronze
- doi.org
- 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.
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