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Homocysteine and gene hypomethylation

V K Chaithanya Ponnaluri, Pierre-Olivier Estève, Cristian I Ruse, Sriharsa Pradhan
DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-L-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-L-homocysteine binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity in vitro, and its overexpression in mammalian cells led to hypermethylation of the genome, whereas its inhibition by adenosine periodate or siRNA mediated knock down resulted in hypomethylation of the genome...
May 11, 2018: Journal of Molecular Biology
Ruiping Zhang, Lirong Cao, Yizheng Wang, Yulian Fang, Linsheng Zhao, Weidong Li, Ou-Yan Shi, Chun-Quan Cai
Neural tube defects (NTDs) are a complex trait associated with gene-environment interactions. Folic acid deficiency and planar cell polarity gene mutations account for some NTD cases; however, the etiology of NTDs is still little understood. In this study, in three Han Chinese NTD pedigrees (two with multiple affected children), with no information on folic acid deficiency or supplement, we examined genome-wide methylation profiles of each individual in these families. We further compared methylation status among cases and normal individuals within the pedigrees...
December 2017: Neurological Sciences
Sheng-Chao Ma, Jian-Cheng Cao, Hui-Ping Zhang, Yun Jiao, Hui Zhang, Yang-Yang He, Yan-Hua Wang, Xiao-Ling Yang, An-Ning Yang, Jue Tian, Ming-Hao Zhang, Xiao-Ming Yang, Guan-Jun Lu, Shao-Ju Jin, Yue-Xia Jia, Yi-Deng Jiang
Vascular smooth muscle cell (VSMC) proliferation is a primary pathological event in atherosclerosis (AS), and homocysteine (Hcy) is an independent risk factor for AS. However, the underlying mechanisms are still lagging. Studies have used the combination of methylation of promoters of multiple genes to diagnose tumors, thus the aim of the current study was to investigate the role of methylation status of several genes in VSMCs treated with Hcy. CpG islands were identified in the promoters of platelet‑derived growth factor (PDGF), p53, phosphatase and tensin homologue on chromosome 10 (PTEN) and mitofusin 2 (MFN2)...
November 2017: Molecular Medicine Reports
Zaizhong Zhang, Yang He, Xiaohuang Tu, Sheng Huang, Zhuo Chen, Lie Wang, Jingxiang Song
BACKGROUND: Aberrant DNA methylation patterns play a major role in tumorigenesis and the effects of nutrients, especially folate in the diet, on methylation changes is of great importance in colorectal cancer (CRC). Folate deficiency would disrupt methylation patterns; however, its exact effects on DNA methylation patterns in CRC are unclear. This study was performed to gain insight into the methylation changes induced by folate deficiency and the putative role of methylation pattern diversities of related genes in the clinical outcome of CRC...
April 1, 2017: Clinical Laboratory
Jian-Guo Li, Carlos Barrero, Salim Merali, Domenico Praticò
Environmental and genetic risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). However, how they interact and influence its pathogenesis remains to be investigated. High level of homocysteine (Hcy) is an AD risk factor and associates with an up-regulation of the ALOX5 gene. In the current paper we investigated whether this activation is responsible for the Hcy effect on the AD phenotype and the mechanisms involved. Triple transgenic mice were randomized to receive regular chow diet, a diet deficient in folate and B vitamins (Diet), which results in high Hcy, or the Diet plus zileuton, a specific ALOX5 inhibitor, for 7 months...
April 6, 2017: Scientific Reports
James Auta, Huaibo Zhang, Subhash C Pandey, Alessandro Guidotti
BACKGROUND: Epigenetic mechanisms such as DNA methylation play an important role in regulating the pathophysiology of alcoholism. Chronic alcohol exposure leads to behavioral changes as well as decreased expression of genes associated with synaptic plasticity. In the liver, it has been documented that chronic alcohol exposure impairs methionine synthase (Ms) activity leading to a decrease in S-adenosyl methionine/S-adenosyl homocysteine (SAM/SAH) ratio which results in DNA hypomethylation; however, it is not known whether similar alterations of SAM and SAH levels are also produced in brain...
June 2017: Alcoholism, Clinical and Experimental Research
Nannan Zhao, Shu Yang, Yun Hu, Haibo Dong, Ruqian Zhao
SCOPE: Betaine is widely used in animal nutrition to promote growth. Here, we aimed to investigate whether maternal betaine supplementation during pregnancy can exert multigenerational effects on growth across two generations and the possible epigenetic modifications associated to such effects. METHODS AND RESULTS: In this study, 3-month-old female Sprague-Dawley rats were fed diet supplemented with 1% betaine throughout the pregnancy and lactation. Betaine-supplemented dams produced bigger litter but smaller F1 pups at birth and weaning...
August 2017: Molecular Nutrition & Food Research
Daniel S Lupu, Luz D Orozco, Ying Wang, John M Cullen, Matteo Pellegrini, Steven H Zeisel
Folate B12 -dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway-catalyzed by betaine-homocysteine methyltransferase (BHMT)-for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J Bhmt (betaine-homocysteine methyltransferase)-null mice at age 4, 12, 24, and 52 wk ( N = 8) and observed elevation of S -adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathione S -transferase and cytokeratin 8-18 activity; starting at 12 wk)...
May 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jiyeon Yang, Pu Fang, Daohai Yu, Lixiao Zhang, Daqing Zhang, Xiaohua Jiang, William Y Yang, Teodoro Bottiglieri, Satya P Kunapuli, Jun Yu, Eric T Choi, Yong Ji, Xiaofeng Yang, Hong Wang
RATIONALE: Patients with chronic kidney disease (CKD) develop hyperhomocysteinemia and have a higher cardiovascular mortality than those without hyperhomocysteinemia by 10-fold. OBJECTIVE: We investigated monocyte differentiation in human CKD and cardiovascular disease (CVD). METHODS AND RESULTS: We identified CD40 as a CKD-related monocyte activation gene using CKD-monocyte -mRNA array analysis and classified CD40 monocyte (CD40+ CD14+ ) as a stronger inflammatory subset than the intermediate monocyte (CD14++ CD16+ ) subset...
November 11, 2016: Circulation Research
Amandeep Kaur, Anupam Kaur
Methylenetetrahydrofolate reductase (MTHFR) is the most important gene that participates in folate metabolism. Presence of valine instead of alanine at position 677 and elevated levels of homocystein causes DNA hypomethylation which in turn favours nondisjunction. In this study, we conducted a meta-analysis to establish link between maternal single-nucleotide polymorphism (SNP) and birth of Down's syndrome (DS) child. A total of 37 case-control studies were selected for analysis including our own, in which we investigated 110 cases and 111 control mothers...
September 2016: Journal of Genetics
Natwadee Poomipark, Janet E Flatley, Marilyn H Hill, Barbara Mangnall, Elnaz Azar, Peter Grabowski, Hilary J Powers
BACKGROUND: Methyl donor status influences DNA stability and DNA methylation although little is known about effects on DNA methyltransferases. The aim of this study was to determine whether methyldonor status influences DNA methyltransferase (Dnmt) gene expression in cervical cancer cells, and if so, whether there are associated effects on global DNA methylation. MATERIALS AND METHODS: The human cervical cancer cell line, C4 II, was grown in complete medium and medium depleted of folate (FM+) and folate and methionine (FM)...
2016: Asian Pacific Journal of Cancer Prevention: APJCP
Yideng Jiang, Shengchao Ma, Huiping Zhang, Xiaoling Yang, Guan Jun Lu, Hui Zhang, Yangyang He, Fanqi Kong, Anning Yang, Hua Xu, Minghao Zhang, Yun Jiao, Guizhong Li, Jun Cao, Yuexia Jia, Shaoju Jin, Jun Wei, Yingkang Shi
Hyperhomocysteinemia (HHcy) is an independent risk factor for the development of atherosclerosis (AS), according to overwhelming number of clinical and epidemiological studies. However, the underlying pathogenic molecular mechanisms by which HHcy promotes AS remain to be fully elucidated. Fatty acid binding protein 4 (FABP4) has been shown to be important in macrophage cholesterol trafficking. The objective of the present study was to determine whether homocysteine (Hcy) accelerates AS through regulating FABP4, and then mediates cholesterol accumulation in macrophages...
July 2016: Molecular Medicine Reports
Huiping Zhang, Zhihong Liu, Shengchao Ma, Hui Zhang, Fanqi Kong, Yangyang He, Xiaoling Yang, Yanhua Wang, Hua Xu, Anning Yang, Jue Tian, Minghao Zhang, Jun Cao, Yideng Jiang, Xiong Guo
The present study aimed to confirm whether the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) is a sensitive indicator, and whether it can be used as a biomarker for the clinical diagnosis of atherosclerosis. Apolipoprotein E (ApoE)-/- mice were randomly divided into four groups and fed with a high methionine diet for 15 weeks. Serum levels of homocysteine (Hcy) were measured using an automatic biochemistry analyzer. The concentrations of SAM and SAH were determined using high‑performance liquid chromatography...
July 2016: Molecular Medicine Reports
Mohammad Taghi Akbari, Asieh Naderi, Leila Saremi, Arezou Sayad, Shiva Irani, Ali Ahani
Association of epigenetic modifications with cancer has been widely studied. Gene-specific hypermethylation and global DNA hypomethylation are the most frequently observed patterns in great number of tumors. The methionine synthase (MTR) gene plays key role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations and, its polymorphism have been associated with the risk of retinoblastoma and other neoplasms. We evaluated the association of MTR A2756G polymorphism with the risk of retinoblastoma in an Iranian population...
December 2015: Cancer Epidemiology
Cui Song, Jingyi He, Jie Chen, Youxue Liu, Feng Xiong, Yutian Wang, Tingyu Li
DNA methylation is a major epigenetic mechanism regulating gene expression. In order to analyze the impact of the one‑carbon unit cycle on the overall level of DNA methylation in children with Down's syndrome (DS), the levels of indicators associated with the one‑carbon unit cycle, including folic acid (FA), vitamin B12 (VB12) and homocysteine (Hcy), and the overall DNA methylation level of DS and healthy controls (HCs) were determined in the present study. A total of 36 DS children and 40 age‑ and gender‑matched HCs were included in the present study to determine the levels of FA, VB12, Hcy and overall DNA methylation...
December 2015: Molecular Medicine Reports
Shan-Shan Xue, Jin-Long He, Xu Zhang, Ya-Jin Liu, Feng-Xia Xue, Chun-Jiong Wang, Ding Ai, Yi Zhu
Arachidonic acid (AA) metabolism plays an important role in vascular homeostasis. We reported that DNA hypomethylation of EPHX2 induced a pro-inflammatory response in vascular endothelial cells (ECs). However, the change in the whole AA metabolism by DNA methylation is still unknown. Using a metabolomic approach, we investigated the effect of DNA methylation on the balance of AA metabolism and the underlying mechanism. ECs were treated with a DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-AZA), and AA metabolic profiles were analyzed...
October 2015: Biochimica et Biophysica Acta
Xiuwei Wang, Zhen Guan, Yan Chen, Yanting Dong, Yuhu Niu, Jianhua Wang, Ting Zhang, Bo Niu
DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR...
2015: PloS One
Antonysunil Adaikalakoteswari, Sarah Finer, Philip D Voyias, Ciara M McCarthy, Manu Vatish, Jonathan Moore, Melissa Smart-Halajko, Nahla Bawazeer, Nasser M Al-Daghri, Philip G McTernan, Sudhesh Kumar, Graham A Hitman, Ponnusamy Saravanan, Gyanendra Tripathi
BACKGROUND: The dietary supply of methyl donors such as folate, vitamin B12, betaine, methionine, and choline is essential for normal growth, development, and physiological functions through the life course. Both human and animal studies have shown that vitamin B12 deficiency is associated with altered lipid profile and play an important role in the prediction of metabolic risk, however, as of yet, no direct mechanism has been investigated to confirm this. RESULTS: Three independent clinical studies of women (i) non-pregnant at child-bearing age, (ii) in early pregnancy, and (iii) at delivery showed that low vitamin B12 status was associated with higher total cholesterol, LDL cholesterol, and cholesterol-to-HDL ratio...
2015: Clinical Epigenetics
Donghong Zhang, Xiaoli Sun, Jianlan Liu, Xina Xie, Wei Cui, Yi Zhu
OBJECTIVE: Homocysteine can accelerate the senescence of endothelial progenitor cells or endothelial cells (ECs) via telomerase inactivation and length shortening. However, the underlying mechanism is unclear. Here, we investigated whether homocysteine promotes endothelial senescence by reducing the expression and activity of human telomerase reverse transcriptase (hTERT) by DNA methylation to reduce ECs telomerase activity. APPROACH AND RESULTS: When compared with primary human umbilical vein endothelial cells grown under standard conditions, ECs with chronic homocysteine treatment showed accelerated upregulation of p16, p21, and p53, markers of cellular senescence, during 6 to 10 passages...
January 2015: Arteriosclerosis, Thrombosis, and Vascular Biology
Jean-Marie Sontag, Brandi Wasek, Goce Taleski, Josephine Smith, Erland Arning, Estelle Sontag, Teodoro Bottiglieri
Common functional polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate and homocysteine metabolism, influence risk for a variety of complex disorders, including developmental, vascular, and neurological diseases. MTHFR deficiency is associated with elevation of homocysteine levels and alterations in the methylation cycle. Here, using young and aged Mthfr knockout mouse models, we show that mild MTHFR deficiency can lead to brain-region specific impairment of the methylation of Ser/Thr protein phosphatase 2A (PP2A)...
2014: Frontiers in Aging Neuroscience
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