Recurrent somatic hotspot mutations of DICER1 appear to be clustered around each of four critical metal binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3 end of the 5p-miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated hotspot mutations we engineered mouse Dicer1-deficient ES cells to express wild-type and an allelic series of the mutant human DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal binding site mutations were compared to each other and wild-type human DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation carrying cells were distinct from both wild-type and Dicer1-deficient cells. Further, miRNA profiles showed mutant DICER1 results in a dramatic loss in processing of mature 5p-miRNA strands but were still able to create 3p-strand miRNAs. Messenger-RNA profile changes were consistent with the loss of 5p-strand miRNAs and showed enriched expression for predicted targets of the lost 5p derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA-processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p-strand miRNA. We further propose that this resulting 3p-strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations.
Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage.
Specimen part
View SamplesExpression profile of 30 LMP tumours and 60 Serous tumours were compared to identify the biolgical pathways specific to these groups. Genotyping was done to identify the mutations potentially causing these phenotypes
Mutation of ERBB2 provides a novel alternative mechanism for the ubiquitous activation of RAS-MAPK in ovarian serous low malignant potential tumors.
No sample metadata fields
View SamplesS. aureus biofilms are associated with the organism's ability to cause disease. Biofilm associated bacteria must cope with the host's innate immune system.
Global transcriptome analysis of Staphylococcus aureus biofilms in response to innate immune cells.
No sample metadata fields
View SamplesWe used unsupervised hierarchical clustering to analyse expression in primary ovarian tumors and associated abdominal deposits. GeneGo pathway analysis of differentially expressed genes between primary tumors and deposits revealed 4 of the top 10 pathways related to cytoskeleton remodeling and cell adhesion.
LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin.
Sex, Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver.
Disease, Disease stage, Subject
View SamplesLow-grade serous ovarian carcinomas are typically Ras-pathway mutated, TP53 wild-type, have limited chromosomal aberration, and are frequently associated with borderline tumors. By contrast, high-grade serous ovarian carcinoma lack Ras-pathway mutations, are invariably TP53 mutated, show widespread genomic change, and are commonly BRCA-pathway disrupted. We sought to identify differentially expressed genes between co-existing borderline and invasive components of serous carcinoma.
Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver.
Disease, Disease stage, Subject
View SamplesMagnaporthe oryzae causes rice blast, the most devastating foliar fungal disease of cultivated rice. During disease development the fungus simultaneously maintains both biotrophic and necrotrophic growth corresponding to a hemi-biotrophic life style. The ability of M. oryzae to also colonize roots and subsequently develop blast symptoms on aerial tissue has been recognized. The fungal root infection strategy and the respective host responses are currently unknown. Global temporal expression analysis suggested a purely biotrophic infection process reflected by the rapid induction of defense response-associated genes at the early stage of root invasion and subsequent repression coinciding with the onset of intracellular fungal growth. The same group of down-regulated defense genes was increasingly induced upon leaf infection by M. oryzae where symptom development occurs shortly post tissue penetration. Our molecular analysis therefore demonstrates the existence of fundamentally different tissue-specific fungal infection strategies and provides the basis for enhancing our understanding of the pathogen life style.
Tissue-adapted invasion strategies of the rice blast fungus Magnaporthe oryzae.
Specimen part
View SamplesObjective: Physical exercise and vitamin E are considered effective treatments of nonalcoholic fatty liver and other metabolic diseases. However, vitamin E has also been shown to interfere with the adaptation to exercise training, in particular for the skeletal muscle. Here, we studied the hypothesis that vitamin E also interferes with the metabolic adaptation of the liver to acute exercise.
A Vitamin E-Enriched Antioxidant Diet Interferes with the Acute Adaptation of the Liver to Physical Exercise in Mice.
Sex, Specimen part
View SamplesGene expression profiling in dopaminergic brain structures of rats self-administering cocaine. Effect of histone deacetylase inhibition
Inhibition of histone deacetylases in rats self-administering cocaine regulates lissencephaly gene-1 and reelin gene expression, as revealed by microarray technique.
Sex, Specimen part, Treatment
View SamplesEmbryonic mouse brain development involves a sequential differentiation of multipotent progenitor cells into neurons and glia. Using microarrays and large 2-D electrophoresis, we investigated the transcriptome and proteome of mouse brains at embryonic days 9.5, 11.5 and 13.5. During this developmental period, neural progenitor cells shift from proliferation to neuronal differentiation. As expected, we detected numerous expression changes between the time points investigated but interestingly, the rate of alteration was about 10% to 13% of all proteins and mRNAs during every two days of development. Furthermore, up- and downregulation was balanced. This was confirmed for two additional stages of development, embryonic day 16 and 18. We hypothesize that during embryonic development, the rate of protein expression alteration is rather constant due to a limitation of cellular resources such as energy, space and free water. The similar complexity found at the transcriptome and proteome level at all stages suggests, that changes in relative concentration of gene products rather than an increased number of gene products dominate throughout cellular differentiation. We found that metabolism and cell cycle related gene products were downregulated in expression when precursor cells switched from proliferation to neuronal differentiation (day 9.5 to 11.5), whereas neuron specific gene products were upregulated. A detailed analysis revealed their implication in differentiation related processes such as rearrangement of the actin cytoskeleton as well as Notch and Wnt signaling pathways.
Transcriptome and proteome analysis of early embryonic mouse brain development.
No sample metadata fields
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