Tatjana Degenhardt
University of Luxembourg
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Featured researches published by Tatjana Degenhardt.
Circulation Research | 2010
Anastasia Georgiadi; Laeticia Lichtenstein; Tatjana Degenhardt; Mark V. Boekschoten; Marc van Bilsen; Béatrice Desvergne; Michael Müller; Sander Kersten
Rationale: Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart. Objective: To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences. Methods and Results: Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)&bgr;/&dgr;−/− and not PPAR&agr;−/− mice and was blunted on siRNA-mediated PPAR&bgr;/&dgr; knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPAR&bgr;/&dgr; but not PPAR&agr; to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding. Conclusions: Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPAR&bgr;/&dgr; is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid–induced oxidative stress.
Genome Biology | 2007
Merja Heinäniemi; J Oskari Uski; Tatjana Degenhardt; Carsten Carlberg
BackgroundPeroxisome proliferator-activated receptors (PPARs) are known for their critical role in the development of diseases, such as obesity, cardiovascular disease, type 2 diabetes and cancer. Here, an in silico screening method is presented, which incorporates experiment- and informatics-derived evidence, such as DNA-binding data of PPAR subtypes to a panel of PPAR response elements (PPREs), PPRE location relative to the transcription start site (TSS) and PPRE conservation across multiple species, for more reliable prediction of PPREs.ResultsIn vitro binding and in vivo functionality evidence agrees with in silico predictions, validating the approach. The experimental analysis of 30 putative PPREs in eight validated PPAR target genes indicates that each gene contains at least one functional, strong PPRE that occurs without positional bias relative to the TSS. An extended analysis of the cross-species conservation of PPREs reveals limited conservation of PPRE patterns, although PPAR target genes typically contain strong or multiple medium strength PPREs. Human chromosome 19 was screened using this method, with validation of six novel PPAR target genes.ConclusionAn in silico screening approach is presented, which allows increased sensitivity of PPAR binding site and target gene detection.
Journal of Biological Chemistry | 2006
Tatjana Degenhardt; Merja Matilainen; Karl-Heinz Herzig; Thomas W. Dunlop; Carsten Carlberg
Insulin-like growth factor-binding protein 1 (IGFBP-1) is a biomarker for metabolic and hyperproliferative diseases. At the same time, the nuclear receptors peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the development of both the metabolic syndrome and various cancers. Here we demonstrate, in human hepatocellular carcinoma cells and in normal mouse liver, that IGFBP-1 mRNA expression is under the primary control of PPAR ligands. We applied an improved in silico screening approach for PPAR response elements (PPREs) and identified five candidate PPREs located within 10 kb of the transcription start site (TSS) of the IGFBP-1 gene. Chromatin immunoprecipitation assays showed that, in living cells, the genomic region containing the most proximal PPRE, at position -1200 (relative to the TSS), preferentially associates with multiple PPAR subtypes and various other components of the transcriptional apparatus, which include their heterodimerizing partner, retinoid X receptor, as well as phosphorylated RNA polymerase II, co-repressor, co-activator, and mediator proteins. Moreover, further chromatin immunoprecipitation assays demonstrated that the TSS regions of the IGFBP-1 gene and those of the related IGFBP-2, -5, and -6, but not of IGFBP-3 and -4 genes, bind PPARs as well. We also show that these additional PPAR binding genes contain a number of candidate PPREs and that their mRNA levels respond quickly to the presence of PPAR ligands, indicating that they are also primary PPAR target genes.
Nucleic Acids Research | 2008
Marjo Malinen; Anna Saramäki; Antti Ropponen; Tatjana Degenhardt; Sami Väisänen; Carsten Carlberg
The anti-proliferative effects of histone deacetylase (HDAC) inhibitors and 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] converge via the interaction of un-liganded vitamin D receptor (VDR) with co-repressors recruiting multiprotein complexes containing HDACs and via the induction of cyclin-dependent kinase inhibitor (CDKI) genes of the INK4 and Cip/Kip family. We investigated the effects of the HDAC inhibitor Trichostatin A (TSA) and 1α,25(OH)2D3 on the proliferation and CDKI gene expression in malignant and non-malignant mammary epithelial cell lines. TSA induced the INK4-family genes p18 and p19, whereas the Cip/Kip family gene p21 was stimulated by 1α,25(OH)2D3. Chromatin immunoprecipitation and RNA inhibition assays showed that the co-repressor NCoR1 and some HDAC family members complexed un-liganded VDR and repressed the basal level of CDKI genes, but their role in regulating CDKI gene expression by TSA and 1α,25(OH)2D3 were contrary. HDAC3 and HDAC7 attenuated 1α,25(OH)2D3-dependent induction of the p21 gene, for which NCoR1 is essential. In contrast, TSA-mediated induction of the p18 gene was dependent on HDAC3 and HDAC4, but was opposed by NCoR1 and un-liganded VDR. This suggests that the attenuation of the response to TSA by NCoR1 or that to 1α,25(OH)2D3 by HDACs can be overcome by their combined application achieving maximal induction of anti-proliferative target genes.
Cell | 2009
Tatjana Degenhardt; Katja N. Rybakova; Aleksandra Tomaszewska; Martijn J. Moné; Hans V. Westerhoff; Frank J. Bruggeman; Carsten Carlberg
Eukaryotic transcription is a dynamic process relying on a large number of proteins. By measuring the cycling expression of the pyruvate dehydrogenase kinase 4 gene in human cells, we constructed a detailed stochastic model for single-gene transcription at the molecular level using realistic kinetics for diffusion and protein complex dynamics. We observed that gene induction caused an approximate 60 min periodicity of several transcription related processes: first, the covalent histone modifications and presence of many regulatory proteins at the transcription start site; second, RNA polymerase II activity; third, chromatin loop formation; and fourth, mRNA accumulation. Our model can predict the precise timing of single-gene activity leading to transcriptional cycling on the cell population level when we take into account the sequential and irreversible multistep nature of transcriptional initiation. We propose that the cyclic nature of population gene expression is primarily based on the intrinsic periodicity of the transcription process itself.
PLOS ONE | 2008
Ursula Mager; Tatjana Degenhardt; Leena Pulkkinen; Marjukka Kolehmainen; Anna-Maija Tolppanen; Jaana Lindström; Johan G. Eriksson; Carsten Carlberg; Jaakko Tuomilehto; Matti Uusitupa
Background Ghrelin may influence the development of obesity through its role in the control of energy balance, food intake, and regulation of body weight. The effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). Methodology/Principal Findings We genotyped 7 single nucleotide polymorphisms (SNPs) in the GHSR gene and assessed the association between those SNPs and obesity and type 2 diabetes-related phenotypes from 507 middle-aged overweight persons with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study (DPS). Additionally, we performed in silico screening of the 5′-regulatory region of GHSR and evaluated SNPs disrupting putative transcription factor (TF) binding sites in vitro with gelshift assays to determine differences in protein binding between different alleles of SNPs. Rs9819506 in the promoter region of GHSR was associated with body weight (p = 0.036); persons with rs9819506-AA genotype having the lowest body weight. Individuals with rs490683-CC genotype displayed highest weight loss in the whole study population (p = 0.032). The false discovery rate for these results was <10%. Rs490683 and rs509035 were associated with several measures of glucose and insulin metabolism during the follow-up. Rs490683 may be a functional SNP, since gelshift experiments showed differential protein binding between the alleles, with higher binding to the G-allele. Rs490683-C may disrupt a putative binding site for the TF nuclear factor 1 (NF-1), thus rs4906863-GG genotype where the NF-1 site is intact may lead to a higher GHSR gene expression. Conclusion/Significance Polymorphisms in the GHSR promoter may modify changes in body weight during long-term lifestyle intervention and affect ghrelin receptor signalling through modulation of GHSR gene expression.
Journal of Molecular Biology | 2009
Tatjana Degenhardt; Sami Väisänen; Maryam Rakhshandehroo; Sander Kersten; Carsten Carlberg
Heme is an essential prosthetic group of proteins involved in oxygen transport, energy metabolism and nitric oxide production. ALAS1 (5-aminolevulinate synthase) is the rate-limiting enzyme in heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). In primary human hepatocytes and in HepG2 cells, PPARalpha agonists induced an increase in ALAS1 mRNA levels, which was abolished by PPARalpha silencing. These effects are mediated by two functional PPAR binding sites at positions -9 and -2.3 kb relative to the ALAS1 transcription start site. PPARalpha ligand treatment also up-regulated the mRNA levels of the genes ALAD (5-aminolevulinate dehydratase), UROS (uroporphyrinogen III synthase), UROD (uroporphyrinogen decarboxylase), CPOX (coproporphyrinogen oxidase) and PPOX (protoporphyrinogen oxidase) encoding for enzymes controlling further steps in heme biosynthesis. In HepG2 cells treated with PPARalpha agonists and in mouse liver upon fasting, the association of PPARalpha, its partner retinoid X receptor, PPARgamma co-activator 1alpha and activated RNA polymerase II with the transcription start site region of all six genes was increased, leading to higher levels of the metabolite heme. In conclusion, these data strongly support a role of PPARalpha in the regulation of human ALAS1 and of five additional genes of the pathway, consequently leading to increased heme synthesis.
Journal of Molecular Biology | 2007
Tatjana Degenhardt; Anna Saramäki; Marjo Malinen; Markus Rieck; Sami Väisänen; Anne Huotari; Karl-Heinz Herzig; Rolf Müller; Carsten Carlberg
Cell | 2010
Tatjana Degenhardt; Katja N. Rybakova; Aleksandra Tomaszewska; Martijn J. Moné; Hans V. Westerhoff; Frank J. Bruggeman; Carsten Carlberg
Archive | 2010
Linda M. Sanderson; Tatjana Degenhardt; Arjen Koppen; Eric Kalkhoven; Béatrice Desvergne; Sander Kersten