Epigenetic modification of the gene for the vitamin B12 chaperone MMACHC can result in increased tumorigenicity and methionine dependence

Loewy, Amanda D.; Niles, Kirsten M.; Anastasio, Natascia; Watkins, David; Lavoie, Josée; Lerner‐Ellis, Jordan; Pastinen, Tomi; Trasler, Jacquetta M.; Rosenblatt, David S.

doi:10.1016/j.ymgme.2008.12.011

Cited by 26 publications

(18 citation statements)

References 23 publications

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“…The results of the analysis of pathways correlates with the clinical features of the cbl C disorder: The cbl C complementation group is a genetic and metabolic disease, which presents with neurological, hematological, cardiovascular, skeletal and muscular abnormalities as the principal clinical manifestations. Statistically significant associations with other functions (hepatic system disease, behavioral problems) were also found, some of which have been described less commonly in patients with the cbl C disease [11, 22–30]. This confirms that the cblC patient cell lines chosen for this study provide global insights into the general biochemical and functional hallmarks of the cblC disease, rather than focusing in the case-specific metabolic changes.…”

Section: Resultssupporting

confidence: 67%

The MMACHC proteome: Hallmarks of functional cobalamin deficiency in humans

Hannibal

DiBello

et al. 2011

Molecular Genetics and Metabolism

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Cobalamin (Cbl, B12) is an essential micronutrient required to fulfill the enzymatic reactions of cytosolic methylcobalamin-dependent methionine synthase and mitochondrial adenosylcobalamin-dependent methylmalonyl-CoA mutase. Mutations in the MMACHC gene (cblC complementation group) disrupt processing of the upper-axial ligand of newly internalized cobalamins, leading to functional deficiency of the vitamin. Patients with cblC disease present with both hyperhomocysteinemia and methylmalonic acidemia, cognitive dysfunction, and megaloblastic anemia. In the present study we show that cultured skin fibroblasts from cblC patients export increased levels of both homocysteine and methylmalonic acid compared to control skin fibroblasts, and that they also have decreased levels of total intracellular folates. This is consistent with the clinical phenotype of functional cobalamin deficiency in vivo. The protein changes that accompany human functional Cbl deficiency are unknown. The proteome of control and cblC fibroblasts was quantitatively examined by two dimensional in-gel electrophoresis (2D-DIGE) and liquid chromatography-electrospray ionization-mass spectrometry (LC/ESI/MS). Major changes were observed in the expression levels of proteins involved in cytoskeleton organization and assembly, the neurological system and cell signaling. Pathway analysis of the differentially expressed proteins demonstrated strong associations with neurological disorders, muscular and skeletal disorders, and cardiovascular diseases in the cblC mutant cell lines. Supplementation of the cell cultures with hydroxocobalamin did not restore the cblC proteome to the patterns of expression observed in control cells. These results concur with the observed phenotype of patients with the cblC disorder and their sometimes poor response to treatment with hydroxocobalamin. Our findings could be valuable for designing alternative therapies to alleviate the clinical manifestation of the cblC disorder, as some of the protein changes detected in our study are common hallmarks of known pathologies such as Alzheimer’s and Parkinson's diseases as well as muscular dystrophies.

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Section: Resultssupporting

confidence: 67%

The MMACHC proteome: Hallmarks of functional cobalamin deficiency in humans

Hannibal

DiBello

et al. 2011

Molecular Genetics and Metabolism

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“…Although the direct effect of inadequate dietary supplement on the neurodevelopment of the fetus is not well investigated, there are sufficient reports demonstrating their pivotal role in epigenetic regulation. In our daily diet there are macronutrient derivatives (choline, methionine, betaine) [106,107], micronutrient elements (Vitamin A, D and B) [108,109,110], microminerals (iron, selenium, zinc) [111,112], and bioactive compounds (polyphenols) [113] that have been found to play a significant role in embryonic development through different epigenetic processes.…”

Section: Maternal Lifestylementioning

confidence: 99%

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

Banik

Kandilya

Ramya

et al. 2017

Genes

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It is well established that the regulation of epigenetic factors, including chromatic reorganization, histone modifications, DNA methylation, and miRNA regulation, is critical for the normal development and functioning of the human brain. There are a number of maternal factors influencing epigenetic pathways such as lifestyle, including diet, alcohol consumption, and smoking, as well as age and infections (viral or bacterial). Genetic and metabolic alterations such as obesity, gestational diabetes mellitus (GDM), and thyroidism alter epigenetic mechanisms, thereby contributing to neurodevelopmental disorders (NDs) such as embryonic neural tube defects (NTDs), autism, Down’s syndrome, Rett syndrome, and later onset of neuropsychological deficits. This review comprehensively describes the recent findings in the epigenetic landscape contributing to altered molecular profiles resulting in NDs. Furthermore, we will discuss potential avenues for future research to identify diagnostic markers and therapeutic epi-drugs to reverse these abnormalities in the brain as epigenetic marks are plastic and reversible in nature.

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“…In 2009, Watkins et al reported the significant finding that a methionine-dependent human melanoma cell line (MeWoLC1) had a defect in the cblC locus [ 34 , 35 ]. This gene codes for the chaperone protein MMACHC which is responsible for assembling the cobalamin coenzymes in situ.…”

Section: Methionine Synthesismentioning

confidence: 99%

Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer

Toohey¹

2017

Molecules

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Evidence from several fields of investigation lead to the hypothesis that the sulfur atom is involved in vitamin B12-dependent methyl group transfer. To compile the evidence, it is necessary to briefly review the following fields: methylation, the new field of sulfane sulfur/hydrogen sulfide (S°/H2S), hydrosulfide derivatives of cobalamins, autoxidation of hydrosulfide radical, radical S-adenosylmethionine methyl transfer (RSMT), and methionine synthase (MS). Then, new reaction mechanisms for B12-dependent methyl group transfer are proposed; the mechanisms are facile and overcome difficulties that existed in previously-accepted mechanisms. Finally, the theory is applied to the effect of S°/H2S in nerve tissue involving the “hypomethylation theory” that was proposed 50 years ago to explain the neuropathology resulting from deficiency of vitamin B12 or folic acid. The conclusions are consistent with emerging evidence that sulfane sulfur/hydrogen sulfide may be beneficial in treating Alzheimer’s disease.

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Epigenetic modification of the gene for the vitamin B12 chaperone MMACHC can result in increased tumorigenicity and methionine dependence

Cited by 26 publications

References 23 publications

The MMACHC proteome: Hallmarks of functional cobalamin deficiency in humans

The MMACHC proteome: Hallmarks of functional cobalamin deficiency in humans

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

Possible Involvement of Hydrosulfide in B12-Dependent Methyl Group Transfer

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