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      Global and gene-specific DNA methylation in adult type 2 diabetic individuals: a protocol for a systematic review

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          Abstract

          Background

          DNA methylation (global and gene-specific) has been reported as an epigenetic mechanism that could be involved in the pathogenesis of type 2 diabetes mellitus (T2DM). Furthermore, epigenetic therapy has been suggested as a future possibility for T2DM treatment. Epigenetic changes illustrate the environmental link of the disease. Since some of the epigenetic modifications can be reversed, they could be used as potential therapeutic targets. The aim of the systematic review will be to synthesise the available evidence pertaining to the link between DNA methylation and T2DM. The systematic review will evaluate characteristics of reported studies such as the source of DNA used, methods of quantifying DNA methylation and the participants’ demographics (age, gender, race and adiposity). We will conduct a narrative synthesis of data, and if there are an adequate number of sufficiently homogenous studies, we will consider performing a meta-analysis. The review will evaluate if the levels of DNA methylation are a possible risk factor for T2DM. Furthermore, we will assess whether DNA methylation is a plausible biomarker and therapeutic target for the treatment and management of T2DM.

          Methods

          This systematic review protocol will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 statement. An extensive search for original research articles, published since inception, was performed on major databases such as Embase, MEDLINE and Cochrane Library. The search strategy will include a combination of key words and MeSH words. Literature that is available in English and studies in other languages that can be translated into English will be used. Data extraction will be done in duplicate, and two authors will independently screen for eligible studies using pre-defined criteria. The Cochrane Risk of Bias Assessment Tool and Joanna Briggs Institute (JBI) Critical Appraisal tools will be used to assess the risk of bias. The Grading of Recommendations, Assessment, Development and Evaluation assessment tool will be used to assess the overall quality of extracted data.

          Discussion

          This systematic review will evaluate published literature, assessing the link between DNA methylation and T2DM. Our findings could help guide future research evaluating epigenetic changes in T2DM and direct future therapeutic interventions.

          Electronic supplementary material

          The online version of this article (10.1186/s13643-018-0708-7) contains supplementary material, which is available to authorized users.

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          Most cited references21

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          Epigenetics in cancer.

          Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies.
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            DNA methylation: the nuts and bolts of repression.

            DNA methylation is an epigenetic modification which plays an important role in chromatin organization and gene expression. DNA methylation can silence genes and repetitive elements through a process which leads to the alteration of chromatin structure. The mechanisms which target DNA methylation to specific sites in the genome are not fully understood. In this review, we will discuss the mechanisms which lead to the long-term silencing of genes and will survey the progression that has been made in determining the targeted mechanisms for de novo DNA methylation.
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              DNA Methylation as a Biomarker for Cardiovascular Disease Risk

              Background Elevated serum homocysteine is associated with an increased risk of cardiovascular disease (CVD). This may reflect a reduced systemic remethylation capacity, which would be expected to cause decreased genomic DNA methylation in peripheral blood leukocytes (PBL). Methodology/Principal Findings We examined the association between prevalence of CVD (myocardial infarction, stroke) and its predisposing conditions (hypertension, diabetes) and PBL global genomic DNA methylation as represented by ALU and Satellite 2 (AS) repetitive element DNA methylation in 286 participants of the Singapore Chinese Health Study, a population-based prospective investigation of 63,257 men and women aged 45–74 years recruited during 1993–1998. Men exhibited significantly higher global DNA methylation [geometric mean (95% confidence interval (CI)): 159 (143, 178)] than women [133 (121, 147)] (P = 0·01). Global DNA methylation was significantly elevated in men with a history of CVD or its predisposing conditions at baseline (P = 0·03) but not in women (P = 0·53). Fifty-two subjects (22 men, 30 women) who were negative for these CVD/predisposing conditions at baseline acquired one or more of these conditions by the time of their follow-up I interviews, which took place on average about 5·8 years post-enrollment. Global DNA methylation levels of the 22 incident cases in men were intermediate (AS, 177) relative to the 56 male subjects who remained free of CVD/predisposing conditions at follow-up (lowest AS, 132) and the 51 male subjects with a diagnosis of CVD or predisposing conditions reported at baseline (highest AS 184) (P for trend = 0.0008) No such association was observed in women (P = 0.91). Baseline body mass index was positively associated with AS in both men and women (P = 0·007). Conclusions/Significance Our findings indicate that elevated, not decreased, PBL DNA methylation is positively associated with prevalence of CVD/predisposing conditions and obesity in Singapore Chinese.
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                Author and article information

                Contributors
                +27 84 053 2069 , 217063119@stu.ukzn.ac.za
                +27 79 273 1696 , 217063126@stu.ukzn.ac.za
                +27 31 260 8964 , nkambuleb@ukzn.ac.za
                Journal
                Syst Rev
                Syst Rev
                Systematic Reviews
                BioMed Central (London )
                2046-4053
                15 March 2018
                15 March 2018
                2018
                : 7
                : 46
                Affiliations
                ISNI 0000 0001 0723 4123, GRID grid.16463.36, School of Laboratory Medicine and Medical Sciences (SLMMS), College of Health Sciences, , University of KwaZulu-Natal, ; Durban, 4001 South Africa
                Author information
                http://orcid.org/0000-0002-4767-733X
                Article
                708
                10.1186/s13643-018-0708-7
                5856358
                29544537
                b0de5923-5fc4-412e-9c72-df6663d1e292
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 May 2017
                : 28 February 2018
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                Protocol
                Custom metadata
                © The Author(s) 2018

                Public health
                global dna methylation,gene-specific dna methylation,genome-wide dna methylation,epigenetics,type 2 diabetes mellitus

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