Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

Yamamoto, Masayo; Tanaka, Hiroki; Toki, Yasumichi; Hatayama, Mayumi; Ito, Satoshi; Addo, Lynda; Shindo, Motohiro; Sasaki, Katsunori; Ikuta, Katsuya; Ohtake, Takaaki; Fujiya, Mikihiro; Torimoto, Yoshihiro; Kohgo, Yutaka

doi:10.1007/s12185-016-2054-7

Cited by 8 publications

(5 citation statements)

References 39 publications

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“…Iron-overloaded Tibetans have higher methylation levels Single-base methylation of iron-overloaded Tibetans was deciphered by WGBS. The methylation level of the whole genome in the TH group was about 2.26%, and the proportion of mCG, mCHH and mCHG in the TH group was slightly higher than that in the TL group, which was consistent with the results observed in iron overload mice, where iron overload can enhance genomic DNA methylation (Yamamoto et al, 2016). The ratio and level of CG methylation types in the genome is the highest, which is consistent with previous findings in humans (Rademacher et al, 2014).…”

Section: Discussionsupporting

confidence: 91%

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DNA methylation plays an important role in iron-overloaded Tibetans

Zhao

et al. 2022

Genes Genet. Syst.

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The prevalence of iron overload in Tibetans in Tibet is higher than that in Han. DNA methylation (DNAm) is closely related to iron metabolism and iron level. Nevertheless, the epigenetic status of Tibetans with iron overload is unknown, and we therefore aimed to explore whether the phenomenon observed in the Tibetan population is regulated by epigenetics. The results showed that 2.26% of cytosine was methylated in the whole genome, and that the rate of CG cytosine methylation was higher in individuals in the iron overload (TH) group than in those in the iron normal (TL) group. We analyzed differentially methylated genes (DMGs) in whole-genome bisulfite sequencing data from the TH and TL groups of high-altitude Tibetans. Protein-protein interaction and pathway analyses of candidate DMGs related to iron uptake and transport showed that epigenetic changes in 10 candidate genes (ACO1, CYBRD1, FLVCR1, HFE, HMOX2, IREB2, NEDD8, SLC11A2, SLC40A1 and TFRC) are likely to relate to iron overload. This work reveals, for the first time, changes of DNAm in Tibetan people with iron overload, which suggest that DNAm is a mechanism underlying differences in iron content between individuals in the high-altitude Tibetan population. Our findings should contribute to the study of iron metabolism and the overall health status of Tibetans.

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Section: Discussionsupporting

confidence: 91%

“…In addition, DNAm may change the susceptibility to diseases or phenotypic traits of normal people. Iron metabolism is closely associated with DNAm, and the level and status of iron affect DNAm (Yamamoto et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation plays an important role in iron-overloaded Tibetans

Zhao

et al. 2022

Genes Genet. Syst.

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“…[ 23 ] DNA methylation is increased in bone marrow of male C57BL/6N mice after a 5‐day FeDx injection. [ 24 ] FXR expression is regulated by two DNA methyltransferases (DNMTs; DNMT1 and 3B) in colon cancer cells. [ 21 ] Our data showed that knockdown of DNMT1 , but not DNMT3B , significantly diminished the suppressive effect of FAC on FXR in HepG2 and Huh7 cells (Figure ).…”

Section: Resultsmentioning

confidence: 99%

Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron‐induced hepatotoxicity

et al. 2022

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Background and Aims: Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity. Approach and Results:Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild-type and Fxr −/− mice were fed an iron-rich diet for 1 or 5 weeks. Mice fed an iron-rich diet were coadministered the FXR agonist, GW4064. Forced expression of FXR was carried out with recombinant adeno-associated virus 1 week before iron-rich diet feeding. Serum levels of bile acids and fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with β-thalassemia.The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine.

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“…Although barely nonstatistically significant, this result may deserve further studies because iron has not been previously identified as a potential risk factor for PDAC. Iron is a known carcinogen: it promotes mitosis, interferes with MnSOD functionalism, activates xanthine oxidase causing oxidative damage, inhibits apoptosis, and increases telomerase activity (Toyokuni ; Yamamoto et al ). As with iron, higher concentrations of vanadium were associated with a higher probability of having a PDAC without KRAS mutations.…”

Section: Discussionmentioning

confidence: 99%

Concentrations of trace elements and KRAS mutations in pancreatic ductal adenocarcinoma

Gómez-Tomás

Pumarega

Alguacil

et al. 2019

Environ and Mol Mutagen

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Trace elements are a possible risk factor for pancreatic ductal adenocarcinoma (PDAC). However, their role in the occurrence and persistence of KRAS mutations remains unstudied. There appear to be no studies analyzing biomarkers of trace elements and KRAS mutations in any human cancer. We aimed to determine whether patients with KRAS mutated and nonmutated tumors exhibit differences in concentrations of trace elements. Incident cases of PDAC were prospectively identified in five hospitals in Spain. KRAS mutational status was determined through polymerase chain reaction from tumor tissue. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Concentrations of trace elements were compared in 78 PDAC cases and 416 hospital‐based controls (case–control analyses), and between 17 KRAS wild‐type tumors and 61 KRAS mutated tumors (case–case analyses). Higher levels of iron, arsenic, and vanadium were associated with a statistically nonsignificant increased risk of a KRAS wild‐type PDAC (OR for higher tertile of arsenic = 3.37, 95% CI 0.98–11.57). Lower levels of nickel and manganese were associated with a statistically significant higher risk of a KRAS mutated PDAC (OR for manganese = 0.34, 95% CI 0.14–0.80). Higher levels of selenium appeared protective for both mutated and KRAS wild‐type PDAC. Higher levels of cadmium and lead were clear risk factors for both KRAS mutated and wild‐type cases. This is the first study analyzing biomarkers of trace elements and KRAS mutations in any human cancer. Concentrations of trace elements differed markedly between PDAC cases with and without mutations in codon 12 of the KRAS oncogene, thus suggesting a role for trace elements in pancreatic and perhaps other cancers with such mutations. Environ. Mol. Mutagen., 60:693–703, 2019. © 2019 Wiley Periodicals, Inc.

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Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

Cited by 8 publications

References 39 publications

DNA methylation plays an important role in iron-overloaded Tibetans

DNA methylation plays an important role in iron-overloaded Tibetans

Suppressed farnesoid X receptor by iron overload in mice and humans potentiates iron‐induced hepatotoxicity

Concentrations of trace elements and KRAS mutations in pancreatic ductal adenocarcinoma

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