This SuperSeries is composed of the SubSeries listed below.
Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects.
Specimen part, Treatment
View SamplesHypoxia is known to regulate tumor-initiating cells and to have an effect on miRNA expression. We were interested in studying the role of hypoxia-induced miR-210 in colorectal cancer patient-derived sphere cultures.
Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production.
Specimen part
View SamplesUsing primary cultures of normal human prostate epithelial cells, we developed a novel prostasphere-based, label-retention assay that permits identification and isolation of stem cells at a single cell level. Their bona fide stem cell nature was confirmed using in vitro and in vivo regenerative assays and documentation of symmetric/asymmetric division. Robust WNT10B and KRT13 expression without E-cadherin or KRT14 staining distinguished individual stem cells from daughter progenitors in spheroids. Following FACS to separate stem and progenitor cells, RNA-seq identified unique gene signatures for the separate populations which may serve as biomarkers. Pathways enrichment in stem cells identified ribosome biogenesis and membrane estrogen-receptor signaling with NF?B signaling enriched in progenitors and these were biologically confirmed. Further, bioassays identified heightened autophagy flux and reduced metabolism in stem cells relative to progenitors. These approaches similarly identified cancer stem-like cells from prostate cancer specimens and prostate, breast and colon cancer cell lines suggesting wide applicability. Together, the present studies isolate and identify unique characteristics of normal human prostate stem cells and uncover processes that maintain stem cell homeostasis in the prostate gland. Overall design: Comparing RNA-seq gene profiles in label-retaining prostate stem cells and non-retaining progenitor cells
Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution.
Specimen part, Subject
View SamplesAfrican American men are disproportionately affected by both vitamin D deficiency and increased risk of prostate cancer.
Prostatic compensation of the vitamin D axis in African American men.
Specimen part
View SamplesPhospholamban R14del mutazion (PLN-R14del) has been identified in a large family pedigree in which heterozygous carriers exhibited inherited dilated cardiomyopathy (DCM) and death by middle age. To better understand the causal link between the mutations in PLN and DCM pathology, we derived induced pluripotent stem cells from a DCM patient carrying the PLN R14del mutation. We showed that iPSC-derived cardiomyocytes recapitulated the DCM-specific phenotype and demonstrated that either TALEN-mediated genetic correction or combinatorial gene therapy resulted in phenotypic rescue. Our findings offer novel insights into the pathogenesis caused by mutant PLN and point to the development of potential new therapeutics of pathogenic genetic variants associated with inherited cardiomyopathies. Overall design: iPSCs were derived from a female patient carrying a heterozygous mutation (R14del) in the PLN gene. Tree samples were analyzed: Cardiomyocytes derived from PLN-R41del iPSC cells (R14del-CM); R14del-CMs infected with AAV6-EGFP-miR-PLN and R14del-CMs infected with AAV6-EGFP-miR-luc used as a negative control
Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.
Cell line, Treatment
View SamplesThe branched chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. By performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem cell (LSC) and non-LSC populations, we found the BCAA pathway enriched and BCAT1 overexpressed in LSCs. We show that BCAT1, which transfers -amino groups from BCAAs to -ketoglutarate (KG), is a critical regulator of intracellular KG homeostasis. Next to its role in the tricarboxylic acid (TCA) cycle KG is an essential co-factor for KG-dependent dioxygenases such as EGLN1 and the TET family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of KG leading to HIF1a protein degradation mediated by EGLN1. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. In contrast, overexpression (OE) of BCAT1 in leukaemia cells decreased intracellular KG levels and caused DNA hypermethylation via altered TET activity. BCAT1high AMLs displayed a DNA hypermethylation phenotype similar to cases carrying mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHwtTET2wt, but not IDHmut or TET2mut AMLs. Gene sets characteristic for IDHmut AMLs were enriched in IDHwtTETwtBCAT1high patient samples. BCAT1high AMLs showed robust enrichment for LSC signatures and paired sample analysis revealed a significant increase of BCAT1 levels upon disease relapse. In summary, by limiting intracellular KG, BCAT1 links BCAA catabolism to HIF1a stability and regulation of the epigenomic landscape. Our results suggest the BCAA-BCAT1-KG pathway as a therapeutic target to compromise LSC function in IDHwtTET2wt AML patients.
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.
Treatment
View SamplesWe create catalogues of genes showing significant strain, parent-of-origin, dominance, sex effect in inbreds and reciprocal F1 hybrids of three wild-derived strains (CAST, PWK, WSB) across 4 different tissues (brain, kidney, liver, and lung)
Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.
Age, Specimen part
View SamplesThis series contain mouse and rat lung samples treated with mechanical ventilation and corresponded controls.
Bioinformatic identification of novel early stress response genes in rodent models of lung injury.
No sample metadata fields
View SamplesThe expression profiles were determined using Affymetrix ATH1 arrays. Comparisons among the Col-0, ARF10 and mARF10 sample groups allow the identification of genes regulated by ARF10.
Repression of AUXIN RESPONSE FACTOR10 by microRNA160 is critical for seed germination and post-germination stages.
No sample metadata fields
View Samples