Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. We have engineered the first mouse model of ATC by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion and distant metastases.
Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors.
Sex, Age, Specimen part
View SamplesHuman Polynucleotide Phosphorylase (hPNPaseold-35) is an evolutionarily conserved 35 exoribonuclease implicated in the regulation of numerous physiological processes like maintenance of mitochondrial homeostasis, mtRNA import and aging-associated inflammation.
Identification of genes potentially regulated by human polynucleotide phosphorylase (hPNPase old-35) using melanoma as a model.
Cell line, Treatment
View SamplesPlant Homeo Domain (PHD) is a versatile chromatin reader/effector module which recognizes methylated, acetylated or unmodified histone substrates and regulates cellular gene expression programs. Although PHD domains shows selective epigenetic recognition of methylated, acetylated and unmodified histone substrates, there has been no previous report on its catalytic function regulating malignant transformation of cells. Here we report that PHD finger of UBR7 (Ubiquitin Protein Ligase E3 Component N-Recognin 7 (Putative)), in isolation or in context of full length protein, harbors E3 ubiquitin ligase activity towards monoubiquitination of histone H2B at lysine 120 . Knockdown of UBR7 in MCF10a and breast cancer cells decreased H2BK120ub both at the global levels and on specific genes. Conversely, overexpression of wild type, but not catalytic mutant, rescued H2BK120ub levels. Low UBR7 expression was associated with basal-like and triple negative breast cancers as well as showed poor expression in metastatic tumors. Consistently, UBR7 loss resulted in invasion properties, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 reduced cell growth, invasion and tumor growth in mouse fat pad. Mechanistically, UBR7 reduced H2BK120ub gene body of cell-adhesion related genes as well as gene expression including on CDH4 gene. Importantly, rebuilding CDH4 levels rescued invasion phenotypes seen in UBR7-low cells. Collectively, our results establish that UBR7 PHD has novel H2B ubiquitin ligase activity and it suppresses tumor growth in basal-like breast cancers. Overall design: Triplicate total RNA profiles in Wild Type and UBR7-shRNA MCF10A Cell Line
Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor.
Specimen part, Cell line, Subject
View SamplesPurpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare GBM transcriptome profiling (RNA-seq) after shRNA based knockdown of PRKAB1 and to compare gene expression by optimal high-throughput data analysis Overall design: Methods: Total RNA profiles of two GBM cells (scramble and PRKAB1 sh RNA treated) were generated by deep sequencing, in triplicate, using Illumina Hiseq 2000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. qRT–PCR validation was performed using SYBR Green assays
AMP kinase promotes glioblastoma bioenergetics and tumour growth.
Specimen part, Race, Subject
View SamplesBackground: African Americans (AA) have more pronounced insulin resistance and higher insulin secretion than European Americans (Caucasians or CA) when matched for age, gender, and body mass index (BMI). We hypothesize that physiological differences (including insulin sensitivity [SI]) between CAs and AAs can be explained by co-regulated gene networks in tissues involved in glucose homeostasis. Methods: We performed integrative gene network analyses of transcriptomic data in subcutaneous adipose tissue of 99 CA and 37 AA subjects metabolically characterized as non-diabetic, with a range of SI and BMI values. Results: Transcripts negatively correlated with SI in only the CA or AA subjects were enriched for inflammatory response genes and integrin-signaling genes, respectively. A sub-network (module) with TYROBP as a hub enriched for genes involved in inflammatory response (corrected p= 1.7E-26) was negatively correlated with SI (r= -0.426, p= 4.95E-04) in CA subjects. SI was positively correlated with transcript modules enriched for mitochondrial metabolism in both groups. Several SI-associated co-expressed modules were enriched for genes differentially expressed between groups. Two modules involved in immune response to viral infections and function of adherens junction, are significantly correlated with SI only in CAs. Five modules involved in drug/intracellular transport and oxidoreductase activity, among other activities, are correlated with SI only in AAs. Furthermore, we identified driver genes of these race-specific SI-associated modules. Conclusions: SI-associated transcriptional networks that were deranged predominantly in one ethnic group may explain the distinctive physiological features of glucose homeostasis among AA subjects.
Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans.
Sex, Specimen part, Race
View SamplesMembers of the CUG-BP, Elav-like family (CELF) regulate alternative splicing in the heart. In MHC-CELFdelta transgenic mice, CELF splicing activity is inhibited postnatally in heart muscle via expression of a nuclear dominant negative CELF protein under an a-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy characterized by alternative splicing defects, enlarged hearts, and severe contractile dysfunction. In this study, gene expression profiles in the hearts of wild type, high- and low-expressing lines of MHC-CELFdelta mice were compared using microarrays. Gene ontology and pathway analyses identified contraction and calcium signaling as the most affected processes. Network analysis revealed that the serum response factor (SRF) network is highly affected. Downstream targets of SRF were up-regulated in MHC-CELFdelta mice compared to the wild type, suggesting an increase in SRF activity. Although SRF levels remained unchanged, known inhibitors of SRF activity were down-regulated. These results suggest a role for CELF-mediated alternative splicing in the regulation of contractile gene expression, achieved in part through modulating the activity of SRF, a key cardiac transcription factor.
Gene expression analyses implicate an alternative splicing program in regulating contractile gene expression and serum response factor activity in mice.
Sex, Age, Specimen part
View SamplesExpression profile of MDSC isolated from Bone marrow of lysosomal acid Lipase mice compared to the WT counterpart
Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice.
Age, Specimen part
View SamplesWe report on the regulation of transcripts following siRNA-mediated depletion of an RNA binding protein, CELF1, in primary chicken embryonic cardiomyocytes in culture. Overall design: Cultured chicken primary embryonic cardiomyocytes (isolated from embryonic day 8 hearts) were transfected with siRNA against CELF1 (n=3) or mock transfected (n=3) at 24 hours in culture.
Identification of Targets of CUG-BP, Elav-Like Family Member 1 (CELF1) Regulation in Embryonic Heart Muscle.
Specimen part, Treatment, Subject
View SamplesIn the present study, to identify potential paracrine factor for the stromal regulation of E2-induced epithelial cell proliferation, we treated epithelial and stromal cell populations of mouse uterine primary co-culture with either oil or E2. Three independent RNA pools prepared for each population were then subjected to the Affymetrix gene chip analysis for the whole mouse genome transcripts. Our data revealed up-regulation of 119 genes and down-regulation of 28 genes in epithelial cell populations and up-regulation of 144 genes and down-regulation of 192 genes in stromal cell population.
Estrogen mediated epithelial proliferation in the uterus is directed by stromal Fgf10 and Bmp8a.
Specimen part, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Gaucher disease: transcriptome analyses using microarray or mRNA sequencing in a Gba1 mutant mouse model treated with velaglucerase alfa or imiglucerase.
Age, Specimen part, Treatment
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