DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients

Volkmar, Michael; Dedeurwaerder, Sarah; Cunha, Daniel Andrade Da; Ndlovu, Matladi N.; Defrance, Matthieu; Deplus, Rachel; Calonne, Emilie; Volkmar, Ute; Igoillo-Esteve, Mariana; Naamane, Najib; Guerra, S Del; Masini, Matilde; Bugliani, Marco; Marchetti, Piero; Cnop, Miriam; Eizirik, Décio L.; Fuks, François

doi:10.1038/emboj.2011.503

Cited by 370 publications

(314 citation statements)

References 156 publications

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“…Although modest in absolute magnitude, the widespread DNA methylation changes induced by HFO in this study are quantitatively similar to those previously reported to be influenced by HFO in selected candidate genes implicated in growth and metabolic disease, including type 2 diabetes [14,16,18,22,23]. However, the extent to which general epigenetic changes play a role in the short-term regulation of metabolic functions in muscle by HFO, including IR, remains to be established.…”

Section: Discussionsupporting

confidence: 85%

“…However, the extent to which general epigenetic changes play a role in the short-term regulation of metabolic functions in muscle by HFO, including IR, remains to be established. The functional read-out of altered DNA methylation has traditionally been thought to involve altered mRNA expression, and significant correlations between DNA promoter methylation and distinct gene expression has previously been reported in some [13,15] but not all human studies, including the Human Epigenome Project, supporting the notion that the relationship between DNA methylation and gene expression is not always straightforward [14,16,24]. Few significant correlations were observed between DNA The top three common diseases and disorders are presented according to hypomethylated, hypermethylated and both hypo-and hypermethylated CpG sites/genes methylation and gene expression levels for a number of candidate genes in the present study.…”

Section: Discussionmentioning

confidence: 98%

“…Studies have indicated that DNA methylation may play a role in metabolic diseases such as diabetes. Differential methylation has been identified in the promoter region of the key metabolic regulator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) gene and in 1.8% of 14,475 genes examined in recent methylation profiling in pancreatic islets from type 2 diabetic patients [13,14]. Furthermore, increased methylation of PPARGC1A has been found in the skeletal muscle of patients with glucose intolerance and type 2 diabetes [15], as well as in muscle from low-birthweight individuals with an increased risk of type 2 diabetes [16].…”

Section: Introductionmentioning

confidence: 99%

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Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

et al. 2012

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Aims/hypothesis Energy-dense diets that are high in fat are associated with a risk of metabolic diseases. The underlying molecular mechanisms could involve epigenetics, as recent data show altered DNA methylation of putative type 2 diabetes candidate genes in response to high-fat diets. We examined the effect of a short-term high-fat overfeeding (HFO) diet on genome-wide DNA methylation patterns in human skeletal muscle. Methods Skeletal muscle biopsies were obtained from 21 healthy young men after ingestion of a short-term HFO diet and a control diet, in a randomised crossover setting. DNA methylation was measured in 27,578 CpG sites/14,475 genes using Illumina's Infinium Bead Array. Candidate gene expression was determined by quantitative real-time PCR. Results HFO introduced widespread DNA methylation changes affecting 6,508 genes (45%), with a maximum methylation change of 13.0 percentage points. The HFO-induced methylation changes were only partly and non-significantly reversed after 6-8 weeks. Alterations in DNA methylation levels primarily affected genes involved in inflammation, the reproductive system and cancer. Few gene expression changes were observed and these had poor correlation to DNA methylation. Conclusions/interpretation The genome-wide DNA methylation changes induced by the short-term HFO diet could have implications for our understanding of transient epigenetic regulation in humans and its contribution to the development of metabolic diseases. The slow reversibility suggests a methylation build-up with HFO, which over time may influence gene expression levels.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

et al. 2012

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“…For example, the Paired box 4 (PAX4) gene, which is necessary for the formation of mature b-cells, is hypermethylated and silenced in islets from patients with T2DM. 19,20 Vice versa, Arista-less-related homeobox (ARX), a master gene for a-cells, is normally methylated and repressed in pancreatic b-cells by DNMT1 with concomitant preservation of b-cell identity. 21 Therefore, it has been proposed that b-cell identity depends on the epigenetically controlled antagonistic activities of PAX4 and ARX, but the fine tuning mechanisms are still unclear.…”

Section: B-cell Development and Functionmentioning

confidence: 99%

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

et al. 2017

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Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling b-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on b-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease.

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“…CpG loci affiliated to 254 gene promoters displaying significant differential DNA methylation in diabetic pancreatic islets (Volkmar et al, 2012).…”

Section: Hyperglycemiamentioning

confidence: 99%

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

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Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding of the importance of the inheritance of these epigenetic marks.

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DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients

Cited by 370 publications

References 156 publications

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

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