Neuromedin U (NMU), which is thought to contribute to putative metastasis processes in various tumor entities, was identified as being up-regulated in breast cancer. Therefore, we aimed to uncover the role of NMU in breast cancer subtypes deciphering for the first time NMU-driven signalling pathways and downstream targets.
Oncogenic features of neuromedin U in breast cancer are associated with NMUR2 expression involving crosstalk with members of the WNT signaling pathway.
Sex, Age, Specimen part, Cell line, Race
View SamplesThe canonical role of eEF1A is to deliver the aminoacyl tRNA to the ribosome, we have used the yeast model system to investigate further roles for this protein.
Inappropriate expression of the translation elongation factor 1A disrupts genome stability and metabolism.
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View SamplesHearts of Myh6-MeCP2 transgenic mice and wildtype littermates were rapidly dissected and flash frozen.
Adrenergic Repression of the Epigenetic Reader MeCP2 Facilitates Cardiac Adaptation in Chronic Heart Failure.
Specimen part
View SamplesDiagnostic samples of peripheral blood form acute myeloid leukemia were analysed for gene expression differences
NFATc1 as a therapeutic target in FLT3-ITD-positive AML.
Sex, Specimen part
View SamplesBackground: Here, the role of a-ketoglutarate (aKG) in the epi-metabolic control of DNA demethylation has been investigated in therapeutically relevant cardiac mesenchymal cells (CMSCs) isolated from controls and type 2 diabetes donors. Methods & results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing and gene specific GC methylation detection revealed an accumulation of 5mC, 5hmC and 5fC in the genomic DNA of human CMSCs isolated from diabetic (D) donors (D-CMSCs). Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high fat diet (HFD), injected with streptozotocin (STZ) or both in combination (STZ-HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of aKG synthesis in D-CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised thymine DNA glycosylase (TDG) and ten eleven translocation protein 1 (TET1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that aKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatched or 5fC. Accordingly, an exogenous source of aKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5fC accumulation thus partially mimicking the diabetic epigenetic landscape in cells of non- diabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of aKG-dehydrogenase, increased the aKG level in D- CMSCs and in the heart of HFD mice eliciting DNA demethylation, glucose uptake and insulin response. Conclusions: In this report we established that diabetes may epigenetically modify and compromise function of therapeutically relevant cardiac mesenchymal cells. Restoring the epi-metabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes. Overall design: Human primary cardiac mesenchymal cells (CMSC) from 7 diabetic (D) and 7 non-diabetic (ND) donors were analyzed after few rounds of ex vivo expansion. RNA was isolated and sequenced.
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes Patients: Rescue by α-Ketoglutarate and TET-TDG Functional Reactivation.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part, Treatment
View SamplesLiver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. Gata4 is described as master regulator of LSEC specification during liver development. Here, we sought to analyze the role of endothelial Gata4 in the adult liver.
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part
View SamplesInsulin degrading enzyme (IDE) is a major enzyme responsible for insulin degradation in the liver. The modulation of insulin degrading enzyme activity is hypothesized to be a link between T2DM and liver cancer. Results provide insight into role of IDE in proliferation and other cell functions.
Modulation of insulin degrading enzyme activity and liver cell proliferation.
Cell line
View SamplesLiver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. LSEC play a pivotal role in liver fibrogenesis in the CDAA dietary model of non-alcoholic steatohepatitis (NASH).
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part, Treatment
View SamplesLiver sinusoidal endothelial cells (LSEC) constitute discontinuous, permeable microvessels, with a characteristic program of gene expression that differs significantly from continuous microvascular endothelial cells e.g. in the lung. Gata4 is described as master regulator of LSEC specification during liver development. Here, we sought to analyze the role of endothelial Gata4 in the adult liver.
Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling.
Specimen part
View Samples