In order to find a relationship between gene expression of blood and brain in Rett Syndrome (RTT), we performed RNA sequencing on from cerebella and blood of 7 week-old male Mecp2-null mice (a model of RTT) and WT controls. Overall design: Transcriptional profiles were generated from cerebellum and blood of 3 Mecp2-null and 3 WT 7 week-old male mice, by RNAseq performed on an Illumina HiSeq 2000 System, generating approximately 60 million 2x75bp paired-end reads/sample. Blood and cerebellum samples originate from the same animal
Transcriptomic Analysis of <i>Mecp2</i> Mutant Mice Reveals Differentially Expressed Genes and Altered Mechanisms in Both Blood and Brain.
Age, Specimen part, Cell line, Subject
View SamplesSelective RAF inhibitors including vemurafenib (PLX4032) have demonstrated clinical efficacy in mutant BRAF driven metastatic melanoma. The clinical effectiveness of RAF inhibitors depends on near complete abolition of the MAPK pathway output in tumors harboring BRAF mutations. However these compounds paradoxically activate the MAPK pathway in cells bearing oncogenic RAS or elevated upstream receptor signaling. This paradox can promote cellular proliferation and can manifest clinically with progression of secondary malignancies such as cutaneous squamous cell carcinomas (cuSCC). We have identified next generation RAF inhibitors (paradox breakers, e.g. PLX7904) that inhibit mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation.
RAF inhibitors that evade paradoxical MAPK pathway activation.
Specimen part, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.
Specimen part, Subject
View SamplesBromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is over-expressed in CLL and is enriched proximal to genes up-regulated or de novo expressed in CLL with known function in disease pathogenesis and progression. These genes, including key members of the BCR signaling pathway, provide rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in pre-clinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.
BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.
Specimen part, Subject
View SamplesZinc (Zn2+) is an integral component of many proteins and has been shown to act in a regulatory capacity in different mammalian systems, including as a neurotransmitter in neurons throughout the brain. While Zn2+ plays an important role in modulating neuronal potentiation and synaptic plasticity, little is known about the signaling mechanisms of this regulation. In dissociated rat hippocampal neuron cultures, we used fluorescent Zn2+ sensors to rigorously define resting Zn2+ levels and stimulation-dependent intracellular Zn2+ dynamics, and we performed RNA-Seq to characterize Zn2+-dependent transcriptional effects upon stimulation. We found that relatively small changes in cytosolic Zn2+ during stimulation altered expression levels of 931 genes, and these Zn2+ dynamics induced transcription of many genes implicated in neurite expansion and synaptic growth. Additionally, while we were unable to verify the presence of synaptic Zn2+ in these cultures, we did detect the synaptic vesicle Zn2+ transporter ZnT3 and found it to be substantially upregulated by cytosolic Zn2+ increases. These results provide the first global sequencing-based examination of Zn2+-dependent changes in transcription and identify genes that may mediate Zn2+-dependent processes and functions. Overall design: 3 replicates of each of 3 conditions (KCl treatment, KCl/Zn treatment, KCl/TPA treatment), none of which are control conditions. KCl treatment was used as the reference condition for all comparisons. TPA = tris(2-pyridylmethyl)amine, a Zn2+ chelator.
Intracellular Zn<sup>2+</sup> transients modulate global gene expression in dissociated rat hippocampal neurons.
Specimen part, Cell line, Treatment, Subject
View SamplesThe gastrointestinal (GI) tract can have significant impact on the regulation of the whole body metabolism and may contribute to the development of obesity and diabetes. To systemically elucidate the role of the GI tract in obesity, we performed a transcriptomic analyses in different parts of the GI tract of two obese mouse models: ob/ob and high-fat diet (HFD) fed mice. Compared to their lean controls, both obese mouse groups had significant amount of gene expression changes in the stomach (ob/ob: 959; HFD: 542), much more than the number of changes in the intestine. Despite the difference in genetic background, the two mouse models shared 296 similar gene expression changes in the stomach. Among those genes, some had known associations to obesity, diabetes and insulin resistance. In addition, the gene expression profile strongly suggested an increased gastric acid secretion in both obese mouse models, probably through an activation of the gastrin pathway. In conclusion, our data reveal a previously unknown dominant connection between the stomach and obesity.
Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice.
Specimen part
View SamplesTotal RNA from three replicate cultures of wild-type and mutant strains was isolated and the expression profiles were determined using Affymetrix arrays. Comparisons between the sample groups allow the identification of genes regulated by histone H2B K111A mutant.
Novel functional residues in the core domain of histone H2B regulate yeast gene expression and silencing and affect the response to DNA damage.
No sample metadata fields
View SamplesTotal RNA from three replicate cultures of wild-type and mutant strains was isolated and the expression profiles were determined using Affymetrix arrays. Comparisons between the sample groups allow the identification of genes regulated by histone H2B R102A mutant.
Novel functional residues in the core domain of histone H2B regulate yeast gene expression and silencing and affect the response to DNA damage.
No sample metadata fields
View SamplesBACKGROUND: p53 is an important tumor suppressor with a known role in the later stages of colorectal cancer, but its relevance to the early stages of neoplastic initiation remains somewhat unclear. Although p53-dependent regulation of Wnt signalling activity is known to occur, the importance of these regulatory mechanisms during the early stages of intestinal neoplasia has not been demonstrated.
A limited role for p53 in modulating the immediate phenotype of Apc loss in the intestine.
Specimen part
View SamplesTo characterize how symbiotic bacteria affect the lolecular and cellular mechanisms of epithelial homeostasis, human colonic Caco-2 cells
Epithelial cell proliferation arrest induced by lactate and acetate from Lactobacillus casei and Bifidobacterium breve.
No sample metadata fields
View Samples