ORCID Profile
0000-0002-6055-9709
Current Organisations
IT University of Copenhagen
,
Rigshospitalet
,
Københavns Universitet
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Wiley
Date: 12-06-2007
Publisher: Elsevier BV
Date: 06-2021
Publisher: American Diabetes Association
Date: 16-08-2014
DOI: 10.2337/DB13-1459
Abstract: Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation carbohydrate, amino acid, and lipid metabolism and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
Publisher: American Physiological Society
Date: 06-2010
DOI: 10.1152/JAPPLPHYSIOL.01295.2009
Abstract: A low maximal oxygen consumption (V̇o 2max ) is a strong risk factor for premature mortality. Supervised endurance exercise training increases V̇o 2max with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial s le sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts V̇o 2max training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous V̇o 2max response. Two independent preintervention RNA expression data sets were generated ( n = 41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in V̇o 2max (“predictor” genes). The HERITAGE Family Study ( n = 473) was used for genotyping. We discovered a 29-RNA signature that predicted V̇o 2max training response on a continuous scale these genes contained ∼6 new single-nucleotide polymorphisms associated with gains in V̇o 2max in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., “reciprocal” RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in V̇o 2max , corresponding to ∼50% of the estimated genetic variance for V̇o 2max . In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. V̇o 2max responses to endurance training can be predicted by measuring a ∼30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2007
Abstract: Mutations in the PTEN induced putative kinase 1 ( PINK1 ) are implicated in early-onset Parkinson's disease. PINK1 is expressed abundantly in mitochondria rich tissues, such as skeletal muscle, where it plays a critical role determining mitochondrial structural integrity in Drosophila . Herein we characterize a novel splice variant of PINK1 (svPINK1) that is homologous to the C-terminus regulatory domain of the protein kinase. Naturally occurring non-coding antisense provides sophisticated mechanisms for ersifying genomes and we describe a human specific non-coding antisense expressed at the PINK1 locus (naPINK1). We further demonstrate that PINK1 varies in vivo when human skeletal muscle mitochondrial content is enhanced, supporting the idea that PINK1 has a physiological role in mitochondrion. The observation of concordant regulation of svPINK1 and naPINK1 during in vivo mitochondrial biogenesis was confirmed using RNAi, where selective targeting of naPINK1 results in loss of the PINK1 splice variant in neuronal cell lines. Our data presents the first direct observation that a mammalian non-coding antisense molecule can positively influence the abundance of a cis -transcribed mRNA under physiological abundance conditions. While our analysis implies a possible human specific and dsRNA-mediated mechanism for stabilizing the expression of svPINK1, it also points to a broader genomic strategy for regulating a human disease locus and increases the complexity through which alterations in the regulation of the PINK1 locus could occur.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2021
DOI: 10.1038/S41467-021-22068-5
Abstract: Insulin resistance and lower muscle quality (strength ided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from in iduals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from in iduals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from in iduals with T2D. Furthermore, the muscle of Vps39 +/− mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D.
Publisher: Elsevier BV
Date: 07-2016
Publisher: Springer Science and Business Media LLC
Date: 14-09-2016
DOI: 10.1007/S00125-016-4099-9
Abstract: Low birthweight (LBW) is associated with dysfunctions of adipose tissue and metabolic disease in adult life. We hypothesised that altered epigenetic and transcriptional regulation of adipose-derived stem cells (ADSCs) could play a role in programming adipose tissue dysfunction in LBW in iduals. ADSCs were isolated from the subcutaneous adipose tissue of 13 normal birthweight (NBW) and 13 LBW adult men. The adipocytes were cultured in vitro, and genome-wide differences in RNA expression and DNA methylation profiles were analysed in ADSCs and differentiated adipocytes. We demonstrated that ADSCs from LBW in iduals exhibit multiple expression changes as well as genome-wide alterations in methylation pattern. Reduced expression of the transcription factor cyclin T2 encoded by CCNT2 may play a key role in orchestrating several of the gene expression changes in ADSCs from LBW in iduals. Indeed, silencing of CCNT2 in human adipocytes decreased leptin secretion as well as the mRNA expression of several genes involved in adipogenesis, including MGLL, LIPE, PPARG, LEP and ADIPOQ. Only subtle genome-wide mRNA expression and DNA methylation changes were seen in mature cultured adipocytes from LBW in iduals. Epigenetic and transcriptional changes in LBW in iduals are most pronounced in immature ADSCs that in turn may programme physiological characteristics of the mature adipocytes that influence the risk of metabolic diseases. Reduced expression of CCNT2 may play a key role in the developmental programming of adipose tissue.
Publisher: The Endocrine Society
Date: 13-02-2017
DOI: 10.1210/JC.2016-3907
Abstract: Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood. In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16 age, 31.5 ± 2.7 years) and cultured in vitro. First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration. We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply. Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from in iduals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.
No related grants have been discovered for Camilla Scheele.