Gene expression profiling with microarrays was used to identify genes differentially expressed in the lungs of B6 and BALB CF mice compared to non-CF littermates
Strain-dependent pulmonary gene expression profiles of a cystic fibrosis mouse model.
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Definition of the landscape of promoter DNA hypomethylation in liver cancer.
Specimen part, Cell line, Subject
View SamplesExtensive loss of DNA methylation is a hallmark of cancer. The role of hypomethylation in altering gene expression in cancer cells has been poorly understood. Hepatic cellular carcinoma (HCC) is one of the most common human cancers. We use HCC as a model to investigate hypomethylation in cancer by a combination of methylated DNA immunoprecipitation and hybridization with comprehensive promoter arrays. We identify approximately 2,800 promoters that are hypomethylated in tumor samples. The hypomethylated promoters appear in clusters across the genome suggesting a high-level organization behind the epigenomic changes in cancer. The genes whose promoters are demethylated are mainly involved in cell growth, cell adhesion and communication, signal transduction, mobility and invasion; functions that are essential for cancer progression and metastasis. Previous studies suggested that MBD2 was involved in demethylation of uPA and MMP2 genes in human breast and prostate cancer cell lines. We extend these results here showing that whereas MBD2 depletion in normal liver cells has little or no effect, its depletion in the human hepatocellular carcinoma cell line HepG2 and the adenocarcinoma cell line SkHep1 results in suppression of cell growth, anchorage-independent growth and invasiveness, as well as an increase in promoter methylation and silencing of several of the genes that are hypomethylated in tumors. Our studies establish for the first time the rules governing hypomethylation of promoters in liver cancer and define the potential functional role of hypomethylation in cancer.
Definition of the landscape of promoter DNA hypomethylation in liver cancer.
Specimen part, Subject
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Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.
Sex, Specimen part
View SamplesMetastatic relapse is the major cause of death in neuroblastoma (NB), yet there are no therapies to specifically target metastases. To understand the molecular mechanisms mediating NB metastasis, we developed a mouse model using intracardiac injection and in vivo selection to isolate metastatic subpopulations that exhibited a higher propensity for bone and central nervous system metastases. Gene expression profiling revealed two distinct subtypes, primary and metastatic, with differential regulation of 412 genes and multiple pathways including CADM1, SPHK1, and YAP/TAZ whose expression independently predicted survival. Loss- and gain-of-function experiments with these genes demonstrated a rescue of metastatic phenotypes in multiple NB cell lines in vitro or in vivo. Treatment with the compounds SKI II and Verteporfin that target SPHK1 and YAP/TAZ, respectively, inhibited NB metastasis in vivo. In addition, using gene expression profiling from the metastatic subpopulations, a gene signature (MET-75) was identified that predicts NB survival of patients with metastatic disease. This model therefore identifies genes regulating metastasis and candidate therapeutics for metastatic NB
A Metastatic Mouse Model Identifies Genes That Regulate Neuroblastoma Metastasis.
Disease
View SamplesGene expression profiling of nucleus Accumbens of rats that self administered cocaine and were subjected to 1 or 30 withdrawal days with or without extinction tests.
Role of DNA methylation in the nucleus accumbens in incubation of cocaine craving.
Sex, Specimen part
View SamplesImmunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by anti-tumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor Stat3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathological analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, non-metastatic Stat3-deficient mammary tumors escaped immunosurveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3 inhibitory strategies that may reactivate the immunosurveillance program.
STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis.
Age, Specimen part
View SamplesAlthough early developmental processes involve cell fate decisions that define the body axes and establish progenitor cell pools, development does not cease once cells are specified. Instead, most cells undergo specific maturation events where changes in the cell transcriptome ensure that the proper gene products are expressed to carry out unique physiological functions. Pancreatic acinar cells mature post-natally to handle an extensive protein synthetic load, establsih organized apical-basal polarity for zymogen granule trafficking, and assemble gap-junctions to perimt efficient cell-cell communication. Despite significant progress in defining transcriptional networks that control initial acinar cell specification and differentiation decisions, little is know regarding the role of transcription factors in the specification and maintenance of maturation events. One candidate maturation effector is MIST1, a secretory cell-restricted transcription factor that has been implicated in controlling regulated exocytosis events in a number of cell types. Embryonic knock-out of MIST1 generates acinar cells that fail to establish an apical-basal organization, fail to properly localize zymogen granule and fail to communicate intra-cellularly, making the exocrine organ highly suceptible to pancreatic diseases.
Induced Mist1 expression promotes remodeling of mouse pancreatic acinar cells.
Age, Specimen part
View SamplesE2F1 has been shown to induce both proliferation and apoptosis.
An E2F1-dependent gene expression program that determines the balance between proliferation and cell death.
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Disruption of histone methylation in developing sperm impairs offspring health transgenerationally.
Specimen part
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