Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes

Ling, Charlotte; Groop, Leif

doi:10.2337/db09-1003

Cited by 562 publications

(458 citation statements)

References 117 publications

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“…Epigenetic modifications induced by transient hyperglycemia have been proven to play an important role in diabetic metabolic memory, as has been suggested by epidemiological studies (Ling & Groop 2009). Such regulatory mechanisms have been frequently investigated in diabetic microvascular and macrovascular complications (El-Osta et al 2008, Villeneuve et al 2008, Ling et al 2009.…”

Section: Discussionmentioning

confidence: 96%

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Li¹,

Ren²,

Yang³

et al. 2013

Journal of Molecular Endocrinology

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Inappropriately high expression of matrix metalloproteinase 9 (MMP9) in the late stage of diabetic foot ulcers suppresses wound healing. The underlying mechanisms are not completely understood. Site-specific demethylation was reported to function in the regulation of genes, causing persistent high expression of target genes. Therefore, this study was designed to determine whether site-specific DNA demethylation was a key regulatory component of MMP9 expression in diabetic wound healing, and to further verify the crucial CpG site(s). Human keratinocyte cell line (HaCaT) cells were exposed to tumor necrosis factor a (TNFa), and changes in MMP9 expression and DNA methylation status were detected. We found TNFa treatment increased endogenous MMP9 expression in HaCaT cells and decreased the DNA methylation percentage at the K36 bp promoter site in a timedependent manner. Bisulfite sequencing PCR revealed differentially demethylated CpG sites in the human MMP9 promoter region, but only the change at the K36 bp site was statistically significant. Dual-luciferase reporter assays showed that the promoter with only the K36 bp site demethylated had slightly higher transcriptional activity than the promoter with all other sites except the K36 bp site demethylated. Our results demonstrate that site-specific DNA demethylation plays an important role in MMP9 expression in TNFa-stimulated keratinocytes. The K36 bp site in the MMP9 gene promoter is crucial to this effect, but other CpG sites may exert synergistic effects. Collectively, these data may contribute to the future development of novel therapeutic strategies to treat diabetic foot ulcers and prevent gangrene and amputation. Key Words" keratinocytes " tumor necrosis factor a " matrix metalloproteinase 9" site-specific DNA demethylation " diabetic foot ulcers

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Section: Discussionmentioning

confidence: 96%

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Li¹,

Ren²,

Yang³

et al. 2013

Journal of Molecular Endocrinology

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“…14,20 For example, Ling et al found DNA hypermethylation at the peroxisome proliferator-activated receptor g coactivator 1a (PPARGC1A) promoter and concomitant transcriptional repression in pancreatic islets isolated from patients with T2DM compared to healthy control subjects. 16 Recently, McCarthy et al 30 published a review showing the different DNA methylation candidate genes and epigenome-wide association studies for T2DM.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 Previous studies have suggested that DNA methylation in these types of sequences may play a role in complex diseases other than cancer, such as cardiovascular diseases and diabetes. 9,10,20 It is well known that DNA methylation is a dynamic process and it is affected by environmental factors, both from development in uterus (intrauterine development) and in adult life. Several of these environmental exposures are associated with the risk of complex diseases.…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: A cohort study

et al. 2014

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In the last years, epigenetic processes have emerged as a promising area of complex diseases research. DNA methylation measured in Long Interspersed Nucleotide Element 1 (LINE-1) sequences has been considered a surrogate marker for global genome methylation. New findings have suggested the potential involvement of epigenetic mechanisms in Type 2 diabetes (T2DM) as a crucial interface between the effects of genetic predisposition and environmental influences. Our study evaluated whether global DNA methylation predicted increased risk from T2DM or other carbohydrate metabolism disorders in a cohort study. We used a prospective cohort intervention study and a control group. We collected phenotypic, anthropometric, biochemical, and nutritional information from all subjects. Global LINE-1 DNA methylation was quantified by pyrosequencing technology. Subjects that did not improve their carbohydrate metabolism status showed lower levels of global LINE-1 DNA methylation (63.9 § 1.7 vs. 64.7 § 2.4) and they practiced less intense physical activity (5.8% vs. 21.5%). Logistic regression analyses showed a significant association between LINE-1 DNA methylation and metabolic status after adjustment for sex, age, BMI, and physical activity. Our study showed that lower LINE-1 DNA methylation levels were associated with a higher risk metabolic status worsening, independent of other classic risk factors. This finding highlights the potential role for epigenetic biomarkers as predictors of T2DM risk or other related metabolic disorders.

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“…These are chemical alterations of the DNA that affect gene function and expression without changing the DNA sequence (20 -22). Recent studies by our group and others' demonstrate that epigenetic modifications, including DNA methylation and histone modifications, in human pancreatic islets influence gene expression, islet function, and most likely the pathogenesis of T2D (23)(24)(25)(26)(27). To our knowledge, it has not yet been shown that FAs regulate histone modifications in pancreatic ␤-cells.…”

Section: Type 2 Diabetes (T2d)mentioning

confidence: 99%

Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832/13 β-Cells Accompany Functional Adaptations to Lipotoxicity

Malmgren

Sartipy

Danielsson

et al. 2013

Journal of Biological Chemistry

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Background: Epigenetic regulation may mediate lipotoxic effects on ␤-cells in type 2 diabetes. Results: Lipotoxicity impairs insulin secretion, and alters metabolism, gene expression, and histone marks in INS-1 832/13 ␤-cells. Conclusion: Perturbed insulin secretion results from epigenetic, genetic, and metabolic adaptations to increased fatty acid metabolism in ␤-cells. Significance: Elucidation of the link between lipotoxicity and insulin secretion is crucial for understanding the pathogenesis of type 2 diabetes.

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Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes

Cited by 562 publications

References 117 publications

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Role of site-specific DNA demethylation in TNFα-induced MMP9 expression in keratinocytes

Type 2 diabetes mellitus in relation to global LINE-1 DNA methylation in peripheral blood: A cohort study

Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832/13 β-Cells Accompany Functional Adaptations to Lipotoxicity

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