| 1. |
- Baumeier, Christian, et al.
(författare)
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Hepatic DPP4 DNA methylation associates with fatty liver
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:1, s. 25-35
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Tidskriftsartikel (refereegranskat)abstract
- Hepatic DPP4 expression is elevated in subjects with ectopic fat accumulation in the liver. However, whether increased dipeptidyl peptidase 4 (DPP4) is involved in the pathogenesis or is rather a consequence ofmetabolic disease is not known. We therefore studied the transcriptional regulation of hepatic Dpp4 in young mice prone to diet-induced obesity. Already at 6 weeks of age, expression of hepatic Dpp4 was increased in mice with high weight gain, independent of liver fat content. In the same animals, methylation of four intronic CpG sites was decreased, amplifying glucose-induced transcription of hepatic Dpp4. In older mice, hepatic triglyceride content was increased only in animals with elevated Dpp4 expression. Expression and release of DPP4 were markedly higher in the liver compared with adipose depots. Analysis of human liver biopsy specimens revealed a correlation of DPP4 expression and DNA methylation to stages of hepatosteatosis and nonalcoholic steatohepatitis. In summary, our results indicate a crucial role of the liver in participation to systemic DPP4 levels. Furthermore, the data show that glucoseinduced expression of Dpp4 in the liver is facilitated by demethylation of the Dpp4 gene early in life. This might contribute to early deteriorations in hepatic function, which in turn result in metabolic disease such as hepatosteatosis later in life.
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| 2. |
- Cardona, Alexia, et al.
(författare)
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Epigenome-wide association study of incident type 2 diabetes in a British population : EPIC-Norfolk study
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:12, s. 2315-2326
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the populationbased European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesityrelated pathways acting before the collection of baseline samples.We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.
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| 3. |
- Hall, Elin, et al.
(författare)
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Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:10, s. 1965-1974
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is characterized by insufficient insulin secretion and elevated glucose levels, often in combination with high levels of circulating fatty acids. Long-term exposure to high levels of glucose or fatty acids impair insulin secretion in pancreatic islets, which could partly be due to epigenetic alterations. We studied the effects of high concentrations of glucose and palmitate combined for 48 h (glucolipotoxicity) on the transcriptome, the epigenome, and cell function in human islets. Glucolipotoxicity impaired insulin secretion, increased apoptosis, and significantly (false discovery rate <5%) altered the expression of 1,855 genes, including 35 genes previously implicated in T2D by genomewide association studies (e.g., TCF7L2 and CDKN2B). Additionally, metabolic pathways were enriched for downregulated genes. Of the differentially expressed genes, 1,469 also exhibited altered DNA methylation (e.g., CDK1, FICD, TPX2, and TYMS). A luciferase assay showed that increased methylation of CDK1 directly reduces its transcription in pancreatic β-cells, supporting the idea that DNA methylation underlies altered expression after glucolipotoxicity. Follow-up experiments in clonal β-cells showed that knockdown of FICD and TPX2 alters insulin secretion. Together, our novel data demonstrate that glucolipotoxicity changes the epigenome in human islets, thereby altering gene expression and possibly exacerbating the secretory defect in T2D.
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| 4. |
- Volkov, Petr, et al.
(författare)
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Whole-genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:4, s. 1074-1085
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Tidskriftsartikel (refereegranskat)abstract
- Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology.Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome on a single nucleotide resolution, in pancreatic islets from donors with T2D and non-diabetic controls. We identified 25,820 DMRs in islets from individuals with T2D. These DMRs cover loci with known islet function e.g. PDX1, TCF7L2 and ADCY5 Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions and different histone marks were enriched in the T2D associated DMRs. We also identified 457 genes, including NR4A3, PARK2, PID1, SLC2A2 and SOCS2 that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e. protein-coding, non-coding and pseudogenes) was associated with islet expression levels.Our study provides a comprehensive picture of the islet DNA methylome in both non-diabetic and diabetic individuals and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.
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