| 41. |
|
|
| 42. |
- Rönn, Tina, et al.
(författare)
-
Extensive changes in the transcriptional profile of human adipose tissue including genes involved in oxidative phosphorylation after a six months exercise intervention.
- 2014
-
Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 211:1, s. 188-200
-
Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue has an important function in total energy homeostasis and its dysregulation may contribute to life-style related diseases such as type 2 diabetes, cancer and cardiovascular diseases. The aim of this study was to investigate genome-wide mRNA expression in adipose tissue in healthy men before and after an exercise intervention to identify genes or pathways that mediate the beneficial effect of regular exercise. We also investigated the difference in adipose tissue mRNA expression between individuals with or without a family history of type 2 diabetes.
|
|
| 43. |
- Rönn, Tina, et al.
(författare)
-
Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
- 2023
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.
|
|
| 44. |
|
|
| 45. |
- Rönn, Tina, et al.
(författare)
-
Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins.
- 2009
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:3
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Impaired oxidative capacity of skeletal muscle mitochondria contribute to insulin resistance and type 2 diabetes (T2D). Furthermore, mRNA expression of genes involved in oxidative phosphorylation, including ATP5O, is reduced in skeletal muscle from T2D patients. Our aims were to investigate mechanisms regulating ATP5O expression in skeletal muscle and association with glucose metabolism, and the relationship between ATP5O single nucleotide polymorphisms (SNPs) and risk of T2D. METHODOLOGY/PRINCIPAL FINDINGS: ATP5O mRNA expression was analyzed in skeletal muscle from young (n = 86) and elderly (n = 68) non-diabetic twins before and after a hyperinsulinemic euglycemic clamp. 11 SNPs from the ATP5O locus were genotyped in the twins and a T2D case-control cohort (n = 1466). DNA methylation of the ATP5O promoter was analyzed in twins (n = 22) using bisulfite sequencing. The mRNA level of ATP5O in skeletal muscle was reduced in elderly compared with young twins, both during basal and insulin-stimulated conditions (p<0.0005). The degree of DNA methylation around the transcription start of ATP5O was <1% in both young and elderly twins and not associated with mRNA expression (p = 0.32). The mRNA level of ATP5O in skeletal muscle was positively related to insulin-stimulated glucose uptake (regression coefficient = 6.6; p = 0.02). Furthermore, two SNPs were associated with both ATP5O mRNA expression (rs12482697: T/T versus T/G; p = 0.02 and rs11088262: A/A versus A/G; p = 0.004) and glucose uptake (rs11088262: A/A versus A/G; p = 0.002 and rs12482697: T/T versus T/G; p = 0.005) in the young twins. However, we could not detect any genetic association with T2D. CONCLUSIONS/SIGNIFICANCE: Genetic variation and age are associated with skeletal muscle ATP5O mRNA expression and glucose disposal rate, suggesting that combinations of genetic and non-genetic factors may cause the reduced expression of ATP5O in T2D muscle. These findings propose a role for ATP5O, in cooperation with other OXPHOS genes, in the regulation of in vivo glucose metabolism.
|
|
| 46. |
- Rönn, Tina, et al.
(författare)
-
Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.
- 2015
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:13, s. 3792-3813
-
Tidskriftsartikel (refereegranskat)abstract
- Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed DNA methylation of ∼480,000 sites in human adipose tissue from 96 males and 94 females, and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1,050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of ageing in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2,825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with methylation of 711 sites, annotated to e.g. RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for metabolic diseases and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.
|
|
| 47. |
- Rönn, Tina, et al.
(författare)
-
Predicting type 2 diabetes via machine learning integration of multiple omics from human pancreatic islets
- 2024
-
Ingår i: Scientific Reports. - 2045-2322. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is the fastest growing non-infectious disease worldwide. Impaired insulin secretion from pancreatic beta-cells is a hallmark of T2D, but the mechanisms behind this defect are insufficiently characterized. Integrating multiple layers of biomedical information, such as different Omics, may allow more accurate understanding of complex diseases such as T2D. Our aim was to explore and use Machine Learning to integrate multiple sources of biological/molecular information (multiOmics), in our case RNA-sequening, DNA methylation, SNP and phenotypic data from islet donors with T2D and non-diabetic controls. We exploited Machine Learning to perform multiOmics integration of DNA methylation, expression, SNPs, and phenotypes from pancreatic islets of 110 individuals, with ~ 30% being T2D cases. DNA methylation was analyzed using Infinium MethylationEPIC array, expression was analyzed using RNA-sequencing, and SNPs were analyzed using HumanOmniExpress arrays. Supervised linear multiOmics integration via DIABLO based on Partial Least Squares (PLS) achieved an accuracy of 91 ± 15% of T2D prediction with an area under the curve of 0.96 ± 0.08 on the test dataset after cross-validation. Biomarkers identified by this multiOmics integration, including SACS and TXNIP DNA methylation, OPRD1 and RHOT1 expression and a SNP annotated to ANO1, provide novel insights into the interplay between different biological mechanisms contributing to T2D. This Machine Learning approach of multiOmics cross-sectional data from human pancreatic islets achieved a promising accuracy of T2D prediction, which may potentially find broad applications in clinical diagnostics. In addition, it delivered novel candidate biomarkers for T2D and links between them across the different Omics.
|
|
| 48. |
- Rönn, Tina
(författare)
-
The role of genetic variation and DNA methylation in human glucose metabolism and type 2 diabetes
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The incidence of diabetes is increasing worldwide, with the most prevalent form being type 2 diabetes. Two fundamental processes contribute to the development of type 2 diabetes: insulin resistance in target organs and insufficient insulin secretion from the pancreatic beta-cells. The aim of this thesis was to explore the role of DNA methylation and common genetic variation on glucose metabolism and the pathogenesis of type 2 diabetes. Reduced oxidative capacity of the mitochondria in skeletal muscle has been suggested to play a role in insulin resistance and type 2 diabetes. In studies I and II, we investigated the regulation of COX7A1 and ATP5O, which encode two subunits of the mitochondrial respiratory chain. We found that genetic variation and age were associated with skeletal muscle mRNA expression in both studies. mRNA levels were also positively correlated with the expression of the transcriptional co-activator PPARGC1A and insulin-stimulated glucose uptake, i.e., elderly individuals had reduced mRNA expression levels and reduced in vivo glucose uptake. Additionally, DNA methylation of the COX7A1 promoter was increased in elderly individuals concordant with the decrease in COX7A1 mRNA expression, suggesting a role for genetic, epigenetic and non-genetic factors in gene regulation. In study III, we investigated a common genetic variant in MTNR1B that has previously been found to be associated with increased risk of type 2 diabetes, increased fasting plasma glucose and impaired insulin secretion in populations of European ancestry. We aimed to replicate these findings in a type 2 diabetes case-control cohort of Han Chinese ancestry. We confirmed the association between rs10830963 and both the risk of type 2 diabetes and increased fasting plasma glucose levels, suggesting a relatively ancient origin for this variant. In study IV, common genetic variants that introduce or remove potential DNA methylation sites were selected based on their association with the risk of type 2 diabetes and changes in gene expression in blood. These genetic variants were analysed together with the level of DNA methylation and gene expression in human skeletal muscle, adipose tissue, blood and pancreatic islets. We found that 18 of the 19 sites that we analysed were associated with a difference in DNA methylation related to genotype, and for 11 of these sites this finding was consistent in all four tissues. Additionally, our data suggested a tissue-specific pattern of DNA methylation. Our results confirm an interaction between genetic and epigenetic mechanisms, which introduces a new level of complexity to our knowledge of gene regulation in type 2 diabetes.
|
|
| 49. |
- Volkov, Petr, et al.
(författare)
-
A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits
- 2016
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, highdensity lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys) metabolic traits associated with the development of obesity and diabetes.
|
|
| 50. |
- Volkov, Petr, et al.
(författare)
-
Whole-genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis
- 2017
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:4, s. 1074-1085
-
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.
|
|
