Influence of Metabolism on Epigenetics and Disease

In the paper

“When undifferentiated ESCs are exposed to a specific chemical inhibitor of the TDH enzyme, intracellular levels of acetyl-CoA drop precipitously”

What the sources say

• Not checked yetcites Alexander et al., 2011 source

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.”

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

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)”

What the sources say

• Not checked yetcites Wang et al., 2009a
• Not checked yetcites Wang et al., 2011 source

In the paper

“Studies of two different eukaryotic cells have indeed given evidence of significant fluctuation in acetyl-CoA.”

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

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”

What the sources say

• Not checked yetcites Langer et al., 2002 source

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”

What the sources say

• Not checked yetcites Cai et al., 2011
• Not checked yetcites Tu et al., 2007

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”

What the sources say

• Not checked yetcites Cai et al., 2011

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”

What the sources say

• Not checked yetcites Cai et al., 2011
• Not checked yetcites Tu et al., 2005

In the paper

“catalytically active GCN5 is critically required for YMC oscillation”

What the sources say

• Not checked yetcites Cai et al., 2011

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”

What the sources say

• Not checked yetcites Tu et al., 2007

In the paper

“extensive studies of yeast cells exposed to a variety of nutritional states, including caloric restriction, have shown no alteration in NAD+ or nicotinamide levels that could be interpreted to increase the activity of sirtuin enzymes upon glucose restriction”

What the sources say

• Not checked yetcites Evans et al., 2010 source

In the paper

“Mouse embryo fibroblast (MEF) cells deficient in the CLOCK transcription factor were reported to contain only 4%–5% as much NAD+ as wild-type MEF cells”

What the sources say

• Not checked yetcites Nakahata et al., 2009 source

In the paper

“Acetyl-CoA is also the substrate used by histone acetyl transferase (HAT) enzymes to modify histone tails as an integral determinant of the epigenetic state of chromatin in eukaryotic cells”

What the sources say

• Not checked yetcites Lee and Workman, 2007
• Not checked yetcites Shahbazian and Grunstein, 2007 source

In the paper

“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.”

In the paper

“Over a 4–5 hr cycle the cells rhythmically oscillate between oxidative and reductive growth”

What the sources say

• Not checked yetcites Tu et al., 2005
• Not checked yetcites Tu and McKnight, 2006
• Not checked yetcites Tu et al., 2007

In the paper

“prototrophic (wild-type) strains of yeast grown in the nutrient-limiting environment of a chemostat spontaneously enter a synchronous and highly robust metabolic cycle”

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

In the paper

“for how alterations in metabolism and nutrition might contribute to disease.”

In the paper

“SIRT3-mediated deacetylation of AceCS2 reactivates the enzyme.”

What the sources say

• Not checked yetcites Hallows et al., 2006 source
• Not checked yetcites Schwer et al., 2006 source

In the paper

“When heavily acetylated, PGC1α is inactive”

What the sources say

• Not checked yetcites Lerin et al., 2006 source
• Not checked yetcites Rodgers et al., 2005 source

In the paper

“the GCN5 histone acetyltransferase enzyme of the SAGA complex is of critical importance for histone acetylation in response to the combined provision of glucose and growth factors to otherwise quiescent cells.”

What the sources say

• Not checked yetcites Wellen et al., 2009 source

In the paper

“the battery of SIRT6 target genes (Sebastián et al., 2012) has been reported to overlap significantly with genes codependent on the c-Myc oncoprotein and the SAGA/GCN5 histone acetylase complex”

What the sources say

• Not checked yetcites Sebastián et al., 2012 source
• Not checked yetcites Cai et al., 2011
• Not checked yetcites Ji et al., 2011

In the paper

“both yeast and human cancer cells may employ similar strategies to couple nutrient availability to the control of gene expression.”

In the paper

“β-hydroxybutyrate, which is one of the three ketone bodies, is produced at mM quantities after prolonged exercise or starvation”

What the sources say

• Not checked yetcites Candido et al., 1978 source

In the paper

“NAD+/NADH levels do not change as a function of starvation, irrespective of whether one measures bound or free fractions of the cofactors”

What the sources say

• Not checked yetcites Krebs and Veech, 1969
• Not checked yetcites Veech et al., 1969 source

In the paper

“The methyl group of SAM is chemically activated via the positive charge on the adjacent sulfur atom, which causes the SAM methyl group to be considerably more reactive than the methyl group on N5-MTHF.”

In the paper

“Like sodium butyrate, β-hydroxybutyrate inhibits the activities of many NAD+-independent histone deacetylase enzymes”

What the sources say

• Not checked yetcites Shimazu et al., 2013 source

In the paper

“cancer cells make acetyl-CoA via a fundamentally different pathway than prototrophic yeast”

What the sources say

• Not checked yetcites Wellen et al., 2009 source

In the paper

“the production of acetyl-CoA in HeLa cells necessary to drive histone acetylation has been attributed to the enzymatic conversion of citrate into oxaloacetate and acetyl-CoA via the ATP citrate lyase enzyme”

What the sources say

• Not checked yetcites Wellen et al., 2009 source

In the paper

“This precisely orchestrated pattern of yeast growth gene induction in response to ambient levels of intracellular acetyl-CoA probably represents an evolutionarily ancient regulatory pathway allowing cells to properly link the commitment of cell growth and division to nutritional state.”

In the paper

“SIRT1-mediated deacetylation reactivates PGC1α”

What the sources say

• Not checked yetcites Lerin et al., 2006 source
• Not checked yetcites Rodgers et al., 2005 source

In the paper

“Thus it remains unclear whether sirtuin activity is operatively linked to metabolic state via fluctuations in the intracellular levels of NAD+.”

In the paper

“Histone methylation represents a covalent modification that is of equal importance to histone acetylation in defining the epigenetic state of chromatin (Kouzarides, 2002; Zhang and Reinberg, 2001).”

What the sources say

• Not checked yetcites Kouzarides, 2002 source
• Not checked yetcites Zhang and Reinberg, 2001

In the paper

“The H3K4me2 and H3K3me3 marks that disappear when mouse ESCs are deprived of threonine (Shyh-Chang et al., 2013) are part of a “bivalent” epigenetic state believed to be uniquely important for keeping the chromatin structure of genes encoding developmentally important transcription factors in a properly repressed/poised state for subsequent induction as a function of embryogenesis (Bernstein et al”

What the sources say

• Not checked yetcites Bernstein et al., 2006 source
• Not checked yetcites Shyh-Chang et al., 2013 source

In the paper

“Cytological experiments revealed the nuclear localization of the MATIIα enzyme,”

What the sources say

• Not checked yetcites Katoh et al., 2011 source

In the paper

“Not surprisingly, chemical inhibition of the TDH enzyme in mouse ESCs causes a precipitous drop in the level of intracellular N5-MTHF (Alexander et al., 2011).”

What the sources say

• Not checked yetcites Alexander et al., 2011 source

In the paper

“When ESCs are exposed to a selective chemical inhibitor of the TDH enzyme, intracellular levels of acetyl-CoA drop significantly (Alexander et al., 2011).”

What the sources say

• Not checked yetcites Alexander et al., 2011 source

In the paper

“the results of a variety of molecular biological experiments were interpreted to indicate that the association of the MATIIα methyltransferase enzyme with MafK target genes may be required for transcriptional repression.”

What the sources say

• Not checked yetcites Katoh et al., 2011 source

In the paper

“Increases in AICAR, a biosynthetic intermediate that awaits N5-MTHF-mediated one-carbon donation to continue along the pathway of purine biosynthesis, could likewise be attributed to attenuation in the production of mitochondrial glycine.”

In the paper

“As such, the unique metabolic properties engendered by copious expression of the TDH enzyme in mouse ESCs cannot apply to human stem cells.”

In the paper

“As mentioned earlier in this review, mouse ESCs express exceptionally high levels of the TDH enzyme, which catabolizes threonine into glycine and acetyl-CoA (Figure 4).”

In the paper

“Intriguingly, threonine restriction was observed to dramatically impede deposition of the H3K4me2 and H3K4me3 marks on chromatin.”

What the sources say

• Not checked yetcites Shyh-Chang et al., 2013 source

In the paper

“More recent work on mouse ESCs has led to the conclusion that TDH-mediated catabolism of threonine might also be important for maintaining high levels of SAM (Shyh-Chang et al., 2013).”

What the sources say

• Not checked yetcites Shyh-Chang et al., 2013 source

In the paper

“LSD1 and its paralog LSD2 (also called KDM1B or AOF1) can also influence H3K9 methylation and DNA methylation, either due to their participation in multiprotein complexes that contain additional chromatin-modifying enzymes, including deacetylases and methyltransferases, or due to indirect effects of H3K4 methylation on recruitment of such enzymes (Ciccone et al., 2009; Lan et al., 2008; Wang et al”

What the sources say

• Not checked yetcites Ciccone et al., 2009 source
• Not checked yetcites Lan et al., 2008 source
• Not checked yetcites Wang et al., 2009b

In the paper

“The chemical reaction catalyzed by LSD1 requires a protonated lysine epsilon amino group, thereby limiting its activity to monomethylated and dimethylated H3K4 (Figure 5).”

In the paper

“Specifically, LSD1 binds directly to genes such as PPARg coactivator-1α (PGC1α), PDK4, FATP1, and ATGL and represses their transcription associated with loss of H3K4 methylation (Hino et al., 2012).”

What the sources say

• Not checked yetcites Hino et al., 2012 source

In the paper

“it may reasonably be concluded that these cells require the specialized features of the TDH catabolic pathway to convert threonine into both acetyl-CoA and the glycine-dependent methylation capacity essential for the biosynthesis of nucleotides.”

In the paper

“The conversion of methionine to SAM is catalyzed in an ATP-dependent manner by methionine adenosyltransferase (MAT) enzymes (Sakata et al., 1993).”

What the sources say

• Not checked yetcites Sakata et al., 1993 source

In the paper

“The latter catabolite of TDH-mediated degradation of threonine is known to feed the mitochondrial glycine cleavage enzyme complex responsible for converting tetrahydrofolate to N5-MTHF (Figure 4).”

In the paper

“Affinity chromatography experiments employing a tagged version of the MafK protein led to the discovery of its interaction with MATIIα,”

What the sources say

• Not checked yetcites Katoh et al., 2011 source

In the paper

“it was straightforward to predict that catabolism of threonine is vitally important for ESCs to biosynthesize the required building blocks for DNA synthesis.”

In the paper

“Perplexingly, unique among all primates, mammals, and— perhaps—all metazoan species, humans do not encode a functional TDH enzyme (Edgar, 2002).”

What the sources say

• Not checked yetcites Edgar, 2002 source

In the paper

“DNA itself is also subject to methylation on the C5 atom of cytosine (Bird, 2002).”

What the sources say

• Not checked yetcites Bird, 2002 source

In the paper

“The increase in threonine can logically be attributed to diminution in the activity of the enzyme that degrades it.”

In the paper

“A recent study has given evidence that one of the MAT isoforms, MATIIα, associates with a gene-specific transcription factor designated MafK.”

What the sources say

• Not checked yetcites Katoh et al., 2011 source

In the paper

“Moreover, increased H3K4 and H3K9 histone methylation has been documented in cells treated with hypoxia in vitro (Johnson et al., 2008; Tausendschön et al., 2011; Zhou et al., 2010).”

What the sources say

• Not checked yetcites Johnson et al., 2008 source
• Not checked yetcites Tausendschön et al., 2011 source
• Not checked yetcites Zhou et al., 2010 source

In the paper

“Therefore, HIF provides another link between metabolism and epigenetics through its transcriptional regulation of JmjC histone demethylases and other modifiers of epigenetic state.”

In the paper

“Tumor-associated IDH mutations unmask a latent ability of these enzymes to produce the R enantiomer of 2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors (Dang et al., 2009; Gross et al., 2010; Ward et al., 2010).”

What the sources say

• Not checked yetcites Dang et al., 2009 source
• Not checked yetcites Gross et al., 2010 source
• Not checked yetcites Ward et al., 2010 source

In the paper

“TET-catalyzed oxidation of 5mC followed by decarboxylation or base excision is strongly suspected of contributing to DNA demethylation (Cortellino et al., 2011; He et al., 2011; Ito et al., 2011), yet there are currently conflicting reports regarding the effect of TET inactivation on global DNA methylation patterns in somatic cells (Figueroa et al., 2010; Ko et al., 2010; Yamazaki et al., 2012).”

What the sources say

• Not checked yetcites Cortellino et al., 2011 source
• Not checked yetcites He et al., 2011
• Not checked yetcites Ito et al., 2011 source

In the paper

“The JmjC histone demethylases, in contrast to LSD proteins, are capable of demethylating trimethylated lysines and arginines.”

In the paper

“Somatic mutations affecting cytosolic IDH1 and mitochondrial IDH2 have been identified in gliomas, acute myelogenous leukemia, chondrosarcomas, and cholangiosarcomas.”

In the paper

“Specifically, the messenger RNAs (mRNAs) for multiple JmjC histone demethylase genes, including JMJD1A (an H3K9 demethylase), JMJD2B (an H3K9 demethylase), and JARIDC (an H3K4 demethylase), are induced by hypoxia and HIF, conceivably to compensate for their diminished catalytic activity under low-oxygen conditions (Chervona and Costa, 2012; Xia et al., 2009) (Figure 6A).”

What the sources say

• Not checked yetcites Chervona and Costa, 2012
• Not checked yetcites Xia et al., 2009 source

In the paper

“A caveat, however, is that such Km values are typically determined under idealized in vitro conditions using purified enzymes in the absence of endogenous inhibitory molecules such as fumarate, succinate, and reactive oxygen species.”

In the paper

“Intracellular 2-oxoglutarate levels are estimated to be in the low millimolar range, well above the 2-oxoglutarate Km values of the JmjC histone demethylases and TET proteins determined to date (Chowdhury et al., 2011; Pritchard, 1995).”

What the sources say

• Not checked yetcites Chowdhury et al., 2011 source
• Not checked yetcites Pritchard, 1995 source

In the paper

“Different JmjC histone demethylases exhibit preferences for different histone methylation marks.”

In the paper

“Certain 2-oxoglutarate-dependent dioxygenases, such as the EglN prolyl hydroxylases that mark the HIF transcription factor for destruction, have O2 Km values at or near atmospheric oxygen levels and hence their activity is sensitive to changes in oxygen availability within a physiologically relevant range (Hirsilä et al., 2003).”

What the sources say

• Not checked yetcites Hirsilä et al., 2003 source

In the paper

“Inactivating mutations affecting the mitochondrial succinate dehydrogenase (SDH) complex subunits and fumarate hydratase (FH) have been identified in cancers, particularly in familial paragangliomas and papillary renal cancers, respectively (Kaelin, 2009).”

What the sources say

• Not checked yetcites Kaelin, 2009 source

In the paper

“A number of chromatin-modifying enzymes, including the approximately 30 JmjC domain-containing histone demethylases and the three TET (ten-eleven translocation) proteins, are 2-oxoglutarate-dependent dioxygenases (Loenarz and Schofield, 2011) (Figure 5).”

What the sources say

• Not checked yetcites Loenarz and Schofield, 2011

In the paper

“Somatic mosaicism for such mutations causes Ollier Disease syndrome and Maffucci syndrome, which are characterized by the development of endochondromas and spindle cell hemangiomas (Amary et al., 2011; Pansuriya et al., 2011).”

What the sources say

• Not checked yetcites Amary et al., 2011 source
• Not checked yetcites Pansuriya et al., 2011 source

In the paper

“TET proteins can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formyl cytosine (5fC), and 5-carboxylcytosine (5caC) (He et al., 2011; Ito et al., 2011; Tahiliani et al., 2009).”

What the sources say

• Not checked yetcites He et al., 2011
• Not checked yetcites Ito et al., 2011 source
• Not checked yetcites Tahiliani et al., 2009 source

In the paper

“The O2 Km values for the JmjC histone demethylases and TET proteins are not known, although indirect evidence suggests that at least some of the former could be oxygen sensitive.”

What the sources say

• Not checked yetcites Chervona and Costa, 2012
• Not checked yetcites Xia et al., 2009 source

In the paper

“In model systems, many metabolic enzymes display Km values in vivo that are higher than their corresponding in vitro values and certainly closer to the concentrations of their cosubstrates (Bennett et al., 2009; Yuan et al., 2009).”

What the sources say

• Not checked yetcites Bennett et al., 2009 source
• Not checked yetcites Yuan et al., 2009 source

In the paper

“These biochemical attributes render these enzymes potentially susceptible to carcinogenic metals such as nickel, arsenic, and chromium, which displace iron, contribute to oxidative stress, or do both (Chervona and Costa, 2012).”

What the sources say

• Not checked yetcites Chervona and Costa, 2012

In the paper

“These mutations lead to the marked accumulation of succinate and fumarate, respectively (Figure 6B).”

In the paper

“The functions of these proteins do, however, appear to be deregulated as a result of altered metabolism under the pathological conditions found in the specific cancers described below.”

In the paper

“Many epigenetic enzymes are potentially susceptible to changes in the levels of cosubstrates and cofactors such as oxygen, ATP, acetyl-CoA, MTHF, S-adenosylmethionine, NAD, FAD, and 2-oxoglutarate and are hence poised to respond to changes in nutrient intake and metabolism.”

In the paper

“Moreover, IDH mutant tumors have been reported to display DNA hypermethylation changes consistent with TET2 inactivation.”

In the paper

“In this regard, animal studies suggest that folate might actually increase cancer progression if given to nascent tumors in the colon (Kim, 2004).”

What the sources say

• Not checked yetcites Kim, 2004 source

In the paper

“For example, the HIF1α transcription factor accumulates in SDH and FH mutant tumors, presumably due to inhibition of the EglN prolyl hydroxylases (Dahia et al., 2005; Isaacs et al., 2005; Pollard et al., 2005, 2007; Selak et al., 2005).”

What the sources say

• Not checked yetcites Dahia et al., 2005 source
• Not checked yetcites Isaacs et al., 2005 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Pollard et al., 2005, 2007

In the paper

“Disappointingly, however, intervention trials have failed to demonstrate a reduction of cancer risk in individuals randomized to receive folic acid supplements compared to controls (Andreeva et al., 2012; Cole et al., 2007; Song et al., 2012; Zhang et al., 2008).”

What the sources say

• Not checked yetcites Andreeva et al., 2012 source
• Not checked yetcites Cole et al., 2007 source
• Not checked yetcites Song et al., 2012 source

In the paper

“Observational studies in humans are also consistent with a possible role of nutrition in epigenetics and disease.”

In the paper

“There is also evidence that changes in glucose and glucose metabolism can leave lasting epigenetic marks (Park et al., 2012; Pirola et al., 2010).”

What the sources say

• Not checked yetcites Park et al., 2012 source
• Not checked yetcites Pirola et al., 2010 source

In the paper

“Therefore, inactivation of TET2 probably contributes to leukemic transformation at the hands of mutant IDH and the R-2HG “oncometabolite” it produces.”

In the paper

“Among the relevant exposures are exposures related to nutrition.”

In the paper

“R-2HG, succinate, and fumarate are all capable of inhibiting multiple 2-oxoglutarate-dependent dioxygenases, including the JmjC histone demethylases and TET proteins, when present at sufficiently high concentrations (Figure 6B) (Cervera et al., 2009; Chowdhury et al., 2011; Figueroa et al., 2010; Koivunen et al., 2012; Lu et al., 2012; Smith et al., 2007; Turcan et al., 2012; Xiao et al., 2012; Xu”

What the sources say

• Not checked yetcites Cervera et al., 2009 source
• Not checked yetcites Chowdhury et al., 2011 source
• Not checked yetcites Figueroa et al., 2010 source

In the paper

“There are many bioactive molecules present in food and herbs, in addition to folate, that are capable of influencing epigenetics and that have been touted as potential chemopreventative agents. Examples include various B vitamins, retinoic acid, vitamin D3, reservatrol, genistein and daidzein, epigallocatechin-3-gallate (EGCG), and curcumin (Gerhauser, 2013; Stefanska et al., 2012).”

What the sources say

• Not checked yetcites Gerhauser, 2013 source
• Not checked yetcites Stefanska et al., 2012 source

In the paper

“A number of 2-oxoglutarate-dependent enzymes that act on chromatin are themselves targets of inactivating mutations in cancer, including the UTX H3K27 demethylase (also called KDM6A), JARID1C H3K4 demethylase (KDM5C), and TET2, making them attractive candidates for pathogenically relevant inhibition by succinate, fumarate, and R-2HG (Abdel-Wahab et al., 2009; Dalgliesh et al., 2010; Tefferi et al”

What the sources say

• Not checked yetcites Abdel-Wahab et al., 2009 source
• Not checked yetcites Dalgliesh et al., 2010 source
• Not checked yetcites Tefferi et al., 2009 source

In the paper

“Genetic variation in a number of genes linked to one-carbon metabolism, including methylenetetrahydrofolate dehydrogenase 1, FTHF dehydrogenase, 5–10 methylene-THF reductase, methionine synthase, and glycine-N-methyltransferase, has been linked to a variety of disease phenotypes including cancer and developmental defects (Stover, 2011).”

What the sources say

• Not checked yetcites Stover, 2011 source

In the paper

“For example, studies of individuals conceived during famine conditions have revealed decreased DNA methylation of specific loci, such as the IGF2 gene, associated with an increased risk of obesity, dyslipidemia, and insulin resistance later in life (Dominguez-Salas et al., 2012).”

What the sources say

• Not checked yetcites Dominguez-Salas et al., 2012 source

In the paper

“Biomarkers or dietary histories indicative of nutritional deficiencies associated with defects in one-carbon metabolism (for example, folate deficiency) have frequently been associated with an increased risk of cancer in epidemiological studies.”

In the paper

“Studies in rodents and sheep have confirmed that the availability of nutrients required for one-carbon metabolism (for example, folate, choline, methionine, and betaine, as well as selected B vitamins) at the time of conception and during pregnancy can induce epigenetically driven phenotypes in their offspring (Dolinoy et al., 2007; Sinclair et al., 2007; Waterland et al., 2006; Wolff et al., 1998”

What the sources say

• Not checked yetcites Dolinoy et al., 2007 source
• Not checked yetcites Sinclair et al., 2007 source
• Not checked yetcites Waterland et al., 2006 source