Gene fusions arising from chromosomal translocations are key oncogenic drivers in soft tissue sarcomas but little is known about how they exert their oncogenic effects. Our study explores the molecular mechanisms by which the SS18-SSX fusion oncoprotein subverts epigenetic mechanisms of gene regulation to drive synovial sarcoma. Using functional genomics, we identify KDM2B – a histone demethylase and core component of a non-canonical Polycomb Repressive Complex 1 (PRC1.1) – as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands genome-wide. Via KDM2B, SS18-SSX binds and aberrantly activates expression of a series of developmentally regulated transcription factors that would otherwise be targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation. Thus, SS18-SSX de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression. Overall design: RNA-Seq of human synovial sarcoma cells (HS-SY-II) in control cells (Ren.173) and upon knockdown of SS18-SSX1 (SS18.273 and SSX.1274) or of KDM2B (KDM2B. 4395 and KDM2B.4835) in duplicates.
The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma.
Subject
View SamplesGiven the heterogeneity of disease evident from study of the presentation, histomorphology, disease course, and molecular lesions of bladder cancer, a cohort of 8 non-muscle invasive and 11 muscle invasive bladder cancers were profiled for gene expression using the Affymetrix HG-U133A platform.
Transcriptional signatures of Ral GTPase are associated with aggressive clinicopathologic characteristics in human cancer.
No sample metadata fields
View SamplesWe used Arabidopsis full-genome microarrays to characterize plant transcript accumulations at different stages of infection with the biotrophic oomycete downy mildew pathogen, Hyaloperonospora arabidopsidis : initiation (< 1 dpi) and maintenance of infection (> 4 dpi).
An Arabidopsis (malectin-like) leucine-rich repeat receptor-like kinase contributes to downy mildew disease.
Specimen part
View SamplesB16F1 cells are a good model to study cell motility and cytoskeletal organization. In our lab, a combination of microscopy and gene silencing was used to approach the problem. Having gene expression profiles for B16F1 would facilitate and support subsequent gene silencing by RNAi as well as potentially identify new molecular players.
Role of fascin in filopodial protrusion.
No sample metadata fields
View SamplesTo test whether vitamin D has a functionally important effect upon primary alveolar epithelial type II cells we used gene expression microarray to identify genes that are regulated by 25-dihydroxyvitamin D in adult alveolar type II cells.
Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).
Specimen part, Treatment, Subject
View SamplesEpigenetic events, including covalent post-translational modification of histones, have frequently been demonstrated to play critical roles in tumor development and progression. The transcriptional coactivator, p300/CBP, possesses both histone acetyltransferase (HAT) activity as well as scaffolding properties that directly influence transcriptional activation of targeted genes. We have used a recently reported small molecule inhibitor of p300 HAT activity, C646, to explore the specific contribution of p300/CBP HAT activity to tumor development and progression. We find that C646 inhibits the growth of lineage-specific tumor cell lines including human melanomas through direct transcriptional regulation of cell cycle regulatory proteins. Further evaluation of the p300 HAT transcriptome in human melanoma cells using comprehensive gene expression profiling reveals that p300 HAT activity globally promotes cell cycle progression, nucleosome assembly, and the DNA damage checkpoint through direct transcriptional regulatory mechanisms. Additionally, C646 promotes sensitivity to DNA damaging agents leading to enhanced apoptosis of melanoma cells following combination treatment with cisplatin. Together our data suggest that p300 HAT activity regulates critical growth regulatory pathways in tumors and may serve as a novel therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents.
Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells.
Cell line, Treatment, Time
View SamplesGene transcription in a set of 49 human primary lung adenocarcinomas and 9 normal lung tissue samples was examined using Affymetrix GeneChip technology. We aimed to investigate differential gene expression between the two tissue types. A total of 3,442 genes, called the set MAD, were found to be either up- or down-regulated by at least two fold between the two phenotypes. Genes assigned to a particular gene ontology term were found, in many cases, to be significantly unevenly distributed between the genes in and outside MAD. Terms that were overrepresented in MAD included functions directly implicated in cancer cell metabolism. Based on their functional roles and expression profiles, genes in MAD were grouped into likely co-regulated gene sets.
Conserved transcription factor binding sites of cancer markers derived from primary lung adenocarcinoma microarrays.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesClinical heterogeneity of esrtrogen receptor-negative, progesterone receptor-negative [ER(-)/PR(-)] breast cancer (BC) suggests biological heterogeneity. We performed gene expression analysis of primary BCs and BC cell lines to identify the underlying biology of ER(-)/PR(-) disease, define subsets, and identify potential therapeutic targets.
An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen.
Specimen part, Disease, Disease stage, Treatment
View SamplesDNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells with a live pathogenic bacteria is associated with rapid changes in methylation levels at thousands of loci. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced changes in methylation rarely occur at promoter regions and instead localize to distal enhancer elements. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and the induction of enhancer RNAs, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response of immune cells to infection. Overall design: Transcriptional profiles (polyA+) of 6 non-infected and 6 MTB-infected dendritic cell samples.
Bacterial infection remodels the DNA methylation landscape of human dendritic cells.
No sample metadata fields
View SamplesThe mucosa that lines the respiratory and gastrointestinal (GI) tracts is an important portal of entry for pathogens and provides the frontline of immune defense against HIV infection. Using the simian immunodeficiency virus (SIV) rhesus macaque model, we have performed a comparative analysis of host gene expression in the lung and GI mucosa in response to SIV infection and antiretroviral therapy.
Enhanced innate antiviral gene expression, IFN-α, and cytolytic responses are predictive of mucosal immune recovery during simian immunodeficiency virus infection.
Specimen part
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