Advances in genomic signatures have begun to dissect breast cancer heterogeneity, and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc effects on the mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer.
Prediction and genetic demonstration of a role for activator E2Fs in Myc-induced tumors.
Specimen part
View SamplesThe juvenile onset of spermatogenesis in mice is analyzed by combining cytological and transcriptomic data in a novel computational analysis, resulting in meiotic substage-specific transcriptomes and the discovery of a transcription factor network that regulates the substages of meiosis. Overall design: Germ cells from testes of individual mice were obtained at two-day intervals from 8 to 18 days post-partum (dpp), with five biological replicates at each age (samples 8_1 through 18_5). Eight stages were discriminated cytologically by combinatorial antibody labeling, and RNA-seq was performed on the same samples. A novel permutation-based maximum covariance analysis (PMCA) method was developed to deconvolve genes into meiotic substages. To verify PMCA derived pachytene/diplotene substage-specific genes, we isolated enriched populations of adult pachytene germ cells (samples rep1 through rep4), followed the same RNA-seq protocol, and compared the PMCA derived substage-specific gene lists to the genes expressed in the pachytene/diplotene enriched germ cells.
Regulatory complexity revealed by integrated cytological and RNA-seq analyses of meiotic substages in mouse spermatocytes.
Sex, Age, Cell line, Subject
View SamplesTo uncover molecular mechanisms underlying reduction of responses to restraint stress by racemic (R,S)-linalool inhalation, gene expression profiling at the hypothalamus of restraint stressed rats exposed to racemic (R,S)-linalool was carried out.
Inhalation of a racemic mixture (R,S)-linalool by rats experiencing restraint stress alters neuropeptide and MHC class I gene expression in the hypothalamus.
Sex, Age, Specimen part
View SamplesRecent studies point to a pivotal role of polycomb repressive complex 2 (PRC2) in stem cell function and cancer. Loss of function approaches targeting individual PRC2 subunits have however generated findings that are difficult to reconcile.
Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner.
Specimen part
View SamplesWe used microarrays to detail the role of Polycomb proteins including Ezh2 and Eed in maintaining ES cell identity and executing pluripotency.
EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency.
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View SamplesAs an attempt to assess physio-psychological effects elicited in odorant-inhaled rats, gene expression profiling in the central nervous system was carried out with rats housed under stressful conditions. (R)-(-)-linalool inhalation to rats during 2 h restraint significantly up-regulated the expression of genes in hypothalamus, which were found to be related to neuron differentiation and regulation of transcription as well as immediate early genes. The expressions of 104 among focused stress-regulated genes were significantly altered by the inhalation. The (R)-(-)-linalool inhalation significantly repressed the restraint-induced changes in the expression levels of 77 of the 104. It also promoted the expression of the remaining 27 genes including those related to anti-apoptotic heat shock proteins. The differences in their hypothalamic gene expressions revealed that the inhaled odorants actually influenced stress responses, based on the restraint-induced hypothalamic gene expressions related to apoptosis. These results indicate that the analysis of gene expression profiles in rats subjected to a stressful condition is useful to evaluate odorant-induced effects as shown by the particular results that (R)-(-)-linalool inhalation under only 2 h restraint- stressed condition induces neuron differentiation against apoptosis.
Neuron differentiation-related genes are up-regulated in the hypothalamus of odorant-inhaling rats subjected to acute restraint stress.
Sex, Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells.
Specimen part
View SamplesWe used microarrays to detail the role of JMJ in ES cell function.
Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells.
Specimen part
View SamplesGATA factors interact with simple DNA motifs (WGATAR) to regulate critical processes, including hematopoiesis, but very few WGATAR motifs are occupied in genomes. Given the rudimentary knowledge of mechanisms underlying this restriction, and how GATA factors establish genetic networks, we used ChIP-seq to define GATA-1 and GATA-2 occupancy genome-wide in erythroid cells. Coupled with genetic complementation analysis and transcriptional profiling, these studies revealed a rich collection of targets containing a characteristic binding motif of greater complexity than WGATAR. GATA factors occupied loci encoding multiple components of the Scl/TAL1 complex, a master regulator of hematopoiesis and leukemogenic target. Mechanistic analyses provided evidence for cross-regulatory and autoregulatory interactions among components of this complex, including GATA-2 induction of the hematopoietic corepressor ETO-2 and an ETO-2 negative autoregulatory loop. These results establish fundamental principles underlying GATA factor mechanisms in chromatin and illustrate a complex network of considerable importance for the control of hematopoiesis.
Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.
Specimen part, Cell line
View SamplesTotal RNA was analyzed from either uninduced or -estradiol treated G1E-ER-GATA cells to determine changes in gene expression upon induction of erythroid maturation (treated).
Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy.
Specimen part
View Samples