Tissue-specific Changes in H19 Methylation and Expression inMice withHyperhomocysteinemia

Devlin, Angela M.; Bottiglieri, Teodoro; Domann, Frederick E.; Lentz, Steven R.

doi:10.1074/jbc.m504815200

Cited by 84 publications

(87 citation statements)

References 32 publications

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“…[9][10][11]15,26 We surprisingly observed no effect of the HH diet on AdoMet and AdoHcy concentrations in brain. This is in contrast to our previous report that dietinduced HHcy in Cbs +/-mice is associated with higher AdoHcy concentrations and lower AdoMet/AdoHcy ratios in brain.…”

Section: Discussionmentioning

confidence: 80%

“…Biallelic expression of H19 has been observed in renal disease patients with HHcy, 22 which suggests that changes in cellular methylation capacity during HHcy may be accompanied by hypomethylation of the H19 DMD and consequent changes in H19 expression and loss of H19 imprinting. Furthermore, we previously showed tissue-specific differences in expression and methylation of H19 in C57BL/6J mice with diet-induced HHcy, 11 but were unable to assess parental allele-specific methylation and expression in this study.…”

Section: Diet-induced Hhcy and Tissue Methylation Capacity In Micementioning

confidence: 92%

“…9 In the current study we assessed diet-induced HHcy in mice that are a hybrid of two different mouse strains (Cast and C57BL/6J) and the degree of plasma total homocysteine elevation was 2-5-fold lower than what we and others have reported previously for Cbs +/-mice on a C57BL/6J background. 9,11 The effect of diet on plasma tHcy concentrations in Cast mice has not been reported but it is well known that mouse strain can influence the effect of diet on plasma tHcy concentrations. 27 As such, the extent of the elevation in plasma total homocysteine that we observed in F1 Cast × Cbs +/-mice may not be large enough to…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11][12] Earlier in vitro studies demonstrated that elevated AdoHcy concentrations and a reduced AdoMet/AdoHcy ratio inhibits DNA methyltransferase reactions in liver 24 and in cultured human fibroblasts. 25 This led to the concept that a lower AdoMet/AdoHcy ratio is an indicator of reduced DNA methylation capacity.…”

Section: Discussionmentioning

confidence: 99%

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Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

et al. 2013

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osteoporosis3,4 and depression. 5 The molecular mechanisms contributing to HHcy-related pathologies are not fully known but may involve several pathways including gene-specific changes in DNA methylation. Homocysteine is metabolically-linked to cellular methylation reactions through the methionine cycle. Within the cycle, methionine is converted to S-adenosylmethionine (AdoMet), which serves as a methyl donor for numerous methyl acceptors, including phospholipids, DNA, RNA and proteins. S-adenosylhomocysteine (AdoHcy) is produced as a byproduct of methyl donation, and homocysteine is formed through the DNa methylation is linked to homocysteine metabolism through the generation of S-adenosylmethionine (adoMet) and S-adenosylhomocysteine (adohcy). The ratio of adoMet/adohcy is often considered an indicator of tissue methylation capacity. The goal of this study is to determine the relationship of tissue adoMet and adohcy concentrations to allele-specific methylation and expression of genomically imprinted H19/Igf2. Expression of H19/Igf2 is regulated by a differentially methylated domain (DMD), with H19 paternally imprinted and Igf2 maternally imprinted. F1 hybrid c57BL/6J x Castaneous/EiJ (Cast) mice with (+/-), and without (+/+), heterozygous disruption of cystathionine-β-synthase (Cbs) were fed a control diet or a diet (called hh) to induce hyperhomocysteinemia and changes in tissue adoMet and adohcy. F1 Cast x Cbs +/-mice fed the hh diet had significantly higher plasma total homocysteine concentrations, higher liver adohcy, and lower adoMet/adohcy ratios and this was accompanied by lower liver maternal H19 DMD allele methylation, lower liver Igf2 mRNa levels, and loss of Igf2 maternal imprinting. In contrast, we found no significant differences in adoMet and adohcy in brain between the diet groups but F1 Cast x Cbs +/-mice fed the hh diet had higher maternal H19 DMD methylation and lower H19 mRNa levels in brain. a significant negative relationship between adohcy and maternal H19 DMD allele methylation was found in liver but not in brain. These findings suggest the relationship of adoMet and adohcy to gene-specific DNa methylation is tissue-specific and that changes in DNa methylation can occur without changes in adoMet and adohcy.

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Section: Discussionmentioning

confidence: 80%

Section: Diet-induced Hhcy and Tissue Methylation Capacity In Micementioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

et al. 2013

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“…In this model exposure to a diet that is artificially high in methyl donors as a result of an approximately 9-fold increase in choline and folic acid, approximately three times more methionine and approximately sixty times more vitamin B 12 compared with control diets (62,64) results in a shift in the methylation pattern and thus a comparable change in the coat colour distribution (55) . This magnitude of change for each of these nutrients is extreme, especially when compared with the approximately doubling of folic acid that has accompanied dietary fortification in America (65) , although re-cycling of these nutrients is very different in rodents because they exhibit croprophagia (66) . However, as the majority of these mice (i.e.…”

Section: Nutritional Programming and Epigenetic Adaptations: Responsementioning

confidence: 99%

Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention?

Symonds

2008

Proc. Nutr. Soc.

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Whilst previously type 2 diabetes occurred in older adults, its incidence, together with obesity, has increased rapidly in children. An improved understanding of this disease pathway from a developmental view point is critical. It is likely that subtle changes in dietary patterns over an extended period of time contribute to diabetes, although this type of rationale is largely ignored in animal studies aimed at determining the mechanisms involved. Small-animal studies in which large, and often extreme, changes in the diet are imposed at different stages of the life cycle can have substantial effects on fat mass and/or pancreatic functions. These responses are not representative of the much more gradual changes seen in the human population. An increasing number of studies indicate that it is growth rate per se, rather than the type of dietary intervention that determines pancreatic function during development. Epigenetic mechanisms that regulate insulin secretion by the pancreas can be re-set by more extreme changes in dietary supply in early life. The extent to which these changes may contribute to more subtle modulations in glucose homeostasis that can accompany excess fat growth in childhood remains to be established. For human subjects there is much less information as to whether specific dietary components determine disease onset. Indeed, it is highly likely that genotype has a major influence, although recent data relating early diet to physical activity and the FTO gene indicate the difficulty of establishing the relative contribution of diet and changes in body mass to diabetes. Adipose tissue: Carbohydrates: Epigenetics: GrowthA major and dramatic change in the health of children in the UK and many other developed countries has occurred over the past 10-20 years. As a consequence, primarily because of excess weight gain during early life, type 2 diabetes is now being seen in an alarming number of children (1) . This situation is not only of concern in its own right but will substantially add to the health burden of these individuals as they approach adulthood. As a result of the increased concern relating to early disease in children it has even been proposed that they are routinely placed on, for example, statins (2) . These individuals should then remain on prescription for the majority of their lives in order to ensure they do not have raised cholesterol (3) . This approach has been suggested without knowing the adverse developmental consequences statins could cause on growing children and adolescents. The present review will focus on some of the more recent findings that suggest potential pathways responsible for excess adiposity in early life and how this information may lead ultimately to sustainable strategies aimed at overcoming this health challenge. Adiposity in early lifeThe recent finding that obese individuals possess approximately 30 % more fat cells than lean counterparts indicates that it is not only the accumulation of excess lipid within existing adipocytes that contributes to obesity (...

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Homocysteine Metabolism and Pathological Implications: The Homocysteine Thiolactone Hypothesis of Vascular Disease

Jakubowski

2008

Glutathione and Sulfur Amino Acids in Human Health and Disease

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Tissue-specific Changes in H19 Methylation and Expression inMice withHyperhomocysteinemia

Cited by 84 publications

References 32 publications

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

Tissue-specific relationship of S-adenosylhomocysteine with allele-specificH19/Igf2methylation and imprinting in mice with hyperhomocysteinemia

Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention?

Homocysteine Metabolism and Pathological Implications: The Homocysteine Thiolactone Hypothesis of Vascular Disease

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