Regeneration of differentiated tissue in mammals is rare. In an effort to identify genes that affect the healing process, we screened G3 mice containing germline point mutations for closure of an ear punch wound. One particular line was identified with a heritable hole closure phenotype containing differentiated tissue. Mapping and sequencing efforts revealed that the mutant mice harbor a R244Q point mutation coded by the TGFBR1 gene which leads to enhanced signaling activity in a reporter gene assay. Although there was no obvious effect on the immune system, bone marrow stromal cells from the mutant mice revealed accelerated chondrogenesis, mimicking the in vivo development of cartilage islands in the regenerated ears. This genetically well-defined mouse model should help to further dissect the role of TGF-beta signaling in vertebrate healing and regeneration.
Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1).
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View SamplesCilia are ubiquitous cell surface projections that modulate various sensory- and motility based processes and are implicated in a growing number of multi-organ genetic disorders termed ciliopathies. As new components required for cilium biogenesis and function remain unidentified, we sought to further define and validate the transcriptional targets of the ciliogenic C. elegans RFX transcription factor DAF-19. To this end, transcriptional profiling of daf-19 mutants (which do not form cilia) and wild-type animals was performed using selectively staged embryos where ciliogenesis occurs in most ciliated sensory neurons
Transcriptional profiling of C. elegans DAF-19 uncovers a ciliary base-associated protein and a CDK/CCRK/LF2p-related kinase required for intraflagellar transport.
Specimen part
View SamplesIn order to investigate the mechanism for the progressive lens degeneration caused by targeted deletion of Dicer, we compared expression profiles of protein-coding genes in wild type and DicerCN lenses at E13.5, at a time before gross morphological changes had occurred. We identified distinct classes of differentially expressed genes in the conditional knockout lenses.
Targeted deletion of Dicer disrupts lens morphogenesis, corneal epithelium stratification, and whole eye development.
Specimen part
View SamplesGenome-wide gene expression analysis on tibialis anterior muscle from 2-month-old nebulin SH3 domain deleted (NebSH3) mice compared to wildtype.
The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse.
Sex, Age, Specimen part
View SamplesDifferential mRNA expression patterns were seen in GSC272-vector compared to GSC272-POSTN shRNA tumors.
Periostin (POSTN) Regulates Tumor Resistance to Antiangiogenic Therapy in Glioma Models.
Specimen part, Treatment
View SamplesAbstract: Cellular senescence, an integral component of aging and cancer, arises in response to diverse triggers, including telomere attrition, macromolecular damage, and signaling from activated oncogenes. At present, senescent cells are identified by the combined presence of multiple traits, such as senescence-associated protein expression and secretion, DNA damage, and ß-galactosidase activity; unfortunately, these traits are neither exclusively nor universally present in senescent cells. To identify robust shared markers of senescence, we have performed RNA-sequencing analysis across 8 diverse models of senescence triggered in human diploid fibroblasts (WI-38, IMR-90) and endothelial cells (HUVEC, HAEC) by replicative exhaustion, exposure to ionizing radiation or doxorubicin, and expression of the oncogene HRASG12V. The intersection of the altered transcriptomes revealed 47 RNAs consistently elevated and 26 RNAs consistently reduced across all senescence models, including many protein-coding mRNAs and some long noncoding RNAs. We propose that these shared transcriptome profiles will enable the identification of senescent cells in vivo, the investigation of their roles in aging and malignancy, and the development of strategies to target senescent cells therapeutically. Overall design: Transcriptomic analysis of various cell line models of senescence and their respective controls
Transcriptome signature of cellular senescence.
Specimen part, Cell line, Treatment, Subject
View SamplesBevacizumab induces glioblastoma resistance in two in vivo xenograft models. Two cell lines were developed with acquired resistance to bevacizumab. Gene expression difference were analyzed between treated and untreated tumors.
Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition.
Specimen part, Treatment
View SamplesPerivascular adipose tissue (PVAT) is thought to play a role in vascular homeostasis and in the pathogenesis of diseases of large vessels, including abdominal aortic aneurysm (AAA). We tested the hypothesis that locally restricted transcriptional profiles characterize PVAT surrounding AAA. Using a genome-wide approach, we investigated the PVAT transcriptome of AAA in 30 patients with either large (55 mm) or small (<55 mm) aneurysm diameter. We performed a data adjustment step using the DaMiRseq R/Bioconductor package, to remove the effect of confounders as produced by high-throughput gene expression techniques. We compared PVAT of AAA with PVAT of not-dilated abdominal aorta of each patient to limit the effect of inter-individual variability, using the limma R/Bioconductor package. We found highly consistent differences in PVAT gene expression clearly distinguishing PVAT of AAA from PVAT of not-dilated aorta, which increased in number and magnitude with increasing AAA diameter. These changes did not systemically affect other abdominal adipose depots (omental or subcutaneous fat). We dissected putative mechanisms associated with PVAT involvement in AAA through a functional enrichment network analysis: both innate and adaptive immune-response genes along with genes related to cell-death pathways, metabolic processes of collagen, sphingolipids, aminoglycans and extracellular matrix degradation were strongly overrepresented in PVAT of AAA compared with PVAT of not-dilated aorta. Our results provide support to a possible role of PVAT in AAA pathogenesis and suggest that AAA is an immunologic disease with an underlying autoimmune component. These disease-specific expression signatures could help identifying pharmacological targets for preventing AAA progression.
Genome-Wide Expression Profiling Unveils Autoimmune Response Signatures in the Perivascular Adipose Tissue of Abdominal Aortic Aneurysm.
Sex, Age, Specimen part, Subject
View SamplesAminaphtone, a drug used in the treatment of chronic venous insufficiency (CVI), showed a remarkable role in the modulation of several vasoactive factors, like endothelin-1 and adhesion molecules. We analysed in vitro the effects of Aminaphtone on whole-genome gene expression. ECV304 endothelial cells were stimulated with IL-1 100 U/ml in the presence or absence of Aminaphtone 6 g/ml. Gene expression profiles were compared at 1, 3, and 6 h after stimulation by microarray.
Gene expression profiling reveals novel protective effects of Aminaphtone on ECV304 endothelial cells.
Cell line
View SamplesInhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we analyze the transcriptome of a well established model for mitochondrial deficiency, gas-1(fc21) mutant nematodes, which when placed in a genetic context of IIS inhibition, undergo metabolic rewiring leading to a massive lifespan extension Overall design: 5 biological replicates each of wild-type, gas-1(fc21) and age-1(hx546);gas-1(fc21) mutant nematodes (L4 stage) were analyzed by RNA Next Generation Sequencing
Multi-omics identify xanthine as a pro-survival metabolite for nematodes with mitochondrial dysfunction.
Subject
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