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      Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARK-AGE Study

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          Abstract

          Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players. In fact, TETs catalyze the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), driving the DNA demethylation process based on thymine DNA glycosylase (TDG)-mediated DNA repair pathway. The present paper reports the expression of DNA hydroxymethylation components, the levels of 5hmC and of its derivatives in peripheral blood mononuclear cells of age-stratified donors recruited in several European countries in the context of the EU Project ‘MARK-AGE’. The results provide evidence for an age-related decline of TET1, TET3 and TDG gene expression along with a decrease of 5hmC and an accumulation of 5caC. These associations were independent of confounding variables, including recruitment center, gender and leukocyte composition. The observed impairment of 5hmC-mediated DNA demethylation pathway in blood cells may lead to aberrant transcriptional programs in the elderly.

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          Most cited references51

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          5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging.

          DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base that is derived from 5-methylcytosine, accounts for ∼40% of modified cytosine in the brain and has been implicated in DNA methylation-related plasticity. We mapped 5-hmC genome-wide in mouse hippocampus and cerebellum at three different ages, which allowed us to assess its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We found developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions revealed stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum, we found conserved genomic features of 5-hmC. Finally, we found that 5-hmC levels were inversely correlated with methyl-CpG-binding protein 2 dosage, a protein encoded by a gene in which mutations cause Rett syndrome. These data suggest that 5-hmC-mediated epigenetic modification is critical in neurodevelopment and diseases.
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            Methylation of ELOVL2 gene as a new epigenetic marker of age.

            The discovery of biomarkers able to predict biological age of individuals is a crucial goal in aging research. Recently, researchers' attention has turn toward epigenetic markers of aging. Using the Illumina Infinium HumanMethylation450 BeadChip on whole blood DNA from a small cohort of 64 subjects of different ages, we identified 3 regions, the CpG islands of ELOVL2, FHL2, and PENK genes, whose methylation level strongly correlates with age. These results were confirmed by the Sequenom's EpiTYPER assay on a larger cohort of 501 subjects from 9 to 99 years, including 7 cord blood samples. Among the 3 genes, ELOVL2 shows a progressive increase in methylation that begins since the very first stage of life (Spearman's correlation coefficient = 0.92) and appears to be a very promising biomarker of aging. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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              Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine.

              Tet methylcytosine dioxygenase converts 5-mC to 5-hmC in DNA. Ascorbate significantly and specifically enhances Tet-mediated generation of 5-hmC. Our findings suggest that ascorbate enhances 5-hmC generation, most likely by acting as a co-factor for Tet methylcytosine dioxygenase to generate 5-hmC. The availability of ascorbate could have significant consequences for health and diseases by modulating the epigenetic control of genome activity. Ascorbate (vitamin C) is best known for its role in scurvy, in which the hydroxylation of collagen catalyzed by dioxygenases is incomplete due to ascorbate deficiency. Here, we report a novel function of ascorbate in the hydroxylation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) in DNA catalyzed by Tet (ten-eleven translocation) methylcytosine dioxygenase. The content of 5-hmC is extremely low in mouse embryonic fibroblasts cultured in ascorbate-free medium. Additions of ascorbate dose- and time-dependently enhance the generation of 5-hmC, without any effects on the expression of Tet genes. Treatment with another reducer glutathione (GSH) does not change the level of 5-hmC. Further, blocking ascorbate entry into cells by phloretin and knocking down Tet (Tet1, Tet2, and Tet3) expression by short interference RNAs (siRNA) significantly inhibit the effect of ascorbate on 5-hmC. These results suggest that ascorbate enhances 5-hmC generation, most likely by acting as a co-factor for Tet methylcytosine dioxygenase to hydroxylate 5-mC. Thus, we have uncovered a novel role for ascorbate in modulating the epigenetic control of genome activity.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging (Albany NY)
                Aging
                ImpactJ
                Aging (Albany NY)
                Impact Journals LLC
                1945-4589
                September 2016
                29 August 2016
                : 8
                : 9
                : 1896-1915
                Affiliations
                1 Department of Cellular Biotechnologies and Hematology, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome 00161, Italy
                2 Pasteur Institute-Fondazione Cenci Bolognetti, Rome 00161, Italy
                3 National Institute of Health and Science on Aging (INRCA), Nutrition and Ageing Centre, Scientific and Technological Research Area, 60100 Ancona, Italy
                4 Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna 40126, Italy
                5 CIG-Interdepartmental Center “L. Galvani”, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
                6 The School of Medicine, The University of Tampere, 33014 Tampere, Finland
                7 Department for Internal Medicine, University Teaching Hospital Hall in Tirol, Tirol, Austria
                8 BioTeSys GmbH, 73728 Esslingen, Germany
                9 Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
                10 University of Namur, Research Unit on Cellular Biology, Namur B-5000, Belgium
                11 Laboratory of the Molecular Bases of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
                12 National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece
                13 Institute of Nutritional Medicine (180c), University of Hohenheim, 70599 Stuttgart, Germany
                14 German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
                15 Centre for Health Protection, National Institute for Public Health and the Environment, 3720 BA Bilthoven, The Netherlands
                16 Molecular Toxicology Group, Department of Biology, University of Konstanz, 78457 Konstanz, Germany
                17 Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
                Author notes
                Correspondence to: Paola Caiafa; caiafa@ 123456bce.uniroma1.it
                [*]

                Shared senior authorship

                Article
                101022
                10.18632/aging.101022
                5076444
                27587280
                f606a7a8-78ec-4a12-a0c9-1e58bedc7d8d
                Copyright: © 2016 Valentini et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 June 2016
                : 15 August 2016
                Categories
                Research Paper

                Cell biology
                aging,dna hydroxymethylation,tet genes,tdg
                Cell biology
                aging, dna hydroxymethylation, tet genes, tdg

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