The precise makeup of chromatin remodeling complexes is important for determining cell type and cell function. The SWI/SNF chromatin remodeling complex is made up of multiple subunits that can be filled by mutually exclusive proteins. Inclusion or exclusion of these proteins has profound functional consequences, yet we currently understand little about the direct functional relationship between these biochemically distinct forms of remodeling complexes. Here we combine chromatin immunoprecipitation, transcriptome analysis, and transcription factor binding information from the ENCODE project to determine the functional relationship between three biochemically distinct forms of SWI/SNF. We find widespread overlap in transcriptional regulation and the genomic binding of the three ARID (AT-Rich Interacting Domain) subunits of SWI/SNF. Despite the numerous similarities in their transcriptional regulation and the co-factors bound with each ARID we identify several novel interaction modalities. Previous work has found examples of competition or subunit switching at individual loci, and we find this functional relationship is widespread, and in these cases gene expression changes following loss of one ARID depend on the function of another ARID. We also identify a previously unknown cooperative interaction between ARID1B and ARID2 in the repression of a large number of genes. Together these data help untangle the complicated combinatorial relationships between a highly heterogenous chromatin remodeling family. Overall design: We performed depletion of ARID subunits (ARID1A , n=5; ARID1B, n=3, ARID2, n=5) of SWI/SNF using siRNA or a Non-Targeting control (N=6) and performed expression analysis using polyA+ selected RNA and a strand-specific dUTP incorporation library protocol.
Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes.
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View SamplesUsing gene expression profiling we characterize the global effect of p53 on the TLR5-mediated transcription in MCF7 cells. We found that combined activation of p53 and TLR5 pathways synergistically increases expression of over 200 genes, mostly associated with immunity and inflammation. The synergy was observed in several human cancer cells and primary lymphocytes.
p53 amplifies Toll-like receptor 5 response in human primary and cancer cells through interaction with multiple signal transduction pathways.
Cell line
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Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells.
Specimen part, Cell line, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
MicroRNA profiling in mucosal biopsies of eosinophilic esophagitis patients pre and post treatment with steroids and relationship with mRNA targets.
Specimen part, Disease
View SamplesThe effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin or Nutlin-3 led to strikingly different p53 gene binding patterns based on ChIP-seq experiments. While two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was 6-times greater for Nutlin-3 than Doxorubicin, expression changes induced by Nutlin-3 were much less dramatic compared to Doxorubicin. Unexpectedly, the solvent DMSO alone induced p53 binding to many sites common to Doxorubicin; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification H3K4me3. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network.
Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells.
Specimen part, Cell line
View SamplesThis study examined the expression profile of medullary carcioma of the colon compared to adjacent histologically normal colonic mucosa.
Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment.
Specimen part, Disease, Disease stage
View SamplesEosinophlic esophagitis (EoE) is increasely recognized as an antigen-drived disorder. The goal of this study is to reveal the gene expression changes in EoE before and after a successful glucocorticoid steroid treatment.
MicroRNA profiling in mucosal biopsies of eosinophilic esophagitis patients pre and post treatment with steroids and relationship with mRNA targets.
Specimen part, Disease
View SamplesA growing body of literature has proposed cell-autonomous tumor suppressor functions for the mir-143~145 cluster in a variety of human cancers, including lung adenocarcinoma, and has reported therapeutic benefits of delivering mir-143 and mir- 145 to tumors. In contrast to these studies, we found that depletion or forced expression of mir-143 and mir-145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. Surprisingly, we observed that loss of mir-143~145 from the tumor microenvironment significantly reduced tumor burden, indicating a non-cell- autonomous role for these miRNAs in promoting tumorigenesis. By examining the expression patterns of different cell populations isolated in vivo from tumor-bearing lungs using an integrated computational approach, we identified a role for mir-145 in stimulating the proliferation of endothelial cells by downregulating an inhibitory kinase, Camk1d, which prevents mitotic entry. As a consequence, tumors in mir-143~145- deficient animals exhibited diminished hallmarks of neo-angiogenesis, increased apoptosis and their expansion appeared limited by the tumor’s ability to co-opt the alveolar vasculature. These findings show that expression of the mir-143~145 cluster in the tumor stroma promotes rather than suppresses tumorigenesis and cautions against the use of these miRNAs as agents in cancer therapeutics. Overall design: Epcam-positive, CD31-positive, and triple-negative (Epcam-CD31-CD45-) cell populations isolated by flow cytometry from tumor-bearing lungs of K-rasG12D/+, miR-143/145-proficient and -deficient mice. Three independent mice from each genotype were used as biological replicates.
Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development.
No sample metadata fields
View SamplesThe goal of the study is to identify p53 target genes specific to macrophages using the p53 stabilizer, Nutlin-3.
p53 and NF-κB coregulate proinflammatory gene responses in human macrophages.
Sex, Age, Specimen part, Disease, Treatment, Race, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Revealing a human p53 universe.
Specimen part, Subject
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