To uncover molecular mechanisms specifically involved in the pathogenesis of colitis-associated colon cancer (CAC), we studied tumorigenesis in experimental models of CAC and sporadic CRC that mimic characteristics of human CRC. Using comparative whole genome expression profiling, we observed differential expression of epiregulin (Ereg) in mouse models of colitis-associated, but not sporadic colorectal cancer. Similarly, highly significant upregulation of Ereg expression was found in cohorts of patients with colitis-associated cancer in inflammatory bowel disease but not in sporadic colorectal cancer. Furthermore, tumor-associated fibroblasts were identified as major source of Ereg in colitis-associated neoplasias. Functional studies showed that Ereg-deficient mice, although more prone to colitis, are strongly protected from colitis-associated tumors, and data from serial endoscopic studies revealed that Ereg promotes growth rather than initiation of tumors.
Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK.
Sex, Specimen part
View SamplesMutations in GRIN2B are associated with intellectual disability in humans. We generated iPSC derived mature cortical neurons with mutations in GRIN2B and compared them to isogenic control cells. We found that both loss of function (LOF) and reduced dosage (RD) mutations in GRIN2B lead to reduced expression of NMDAR genes and increased expression of marker of immaturity, including KI67 and MET. Overall design: Examination of transcriptome in iPSC-derved mature neurons with and without the presence of mutations in GRIN2B
Disruption of GRIN2B Impairs Differentiation in Human Neurons.
Subject
View SamplesConfluent C3H10T1/2 cells stimulated to differentiate using IDMB (1uM BRL49653, 1uM Dexamethasone, 0.5uM IBMX, 10ug/mL Insulin). Expression was examined 24 hours after IDMB treatment. Additionally, the effects of addition of TCDD 48 hours prior to IDMB treatment, and EGF addition concurrent with IDMB treatment were examined.
Identification of novel TCDD-regulated genes by microarray analysis.
No sample metadata fields
View SamplesIn eukaryotes, regulation of mRNA translation enables a fast, localized and finely tuned expression of gene products. Within the translation process, the first stage of translation initiation is most rigorously modulated by the actions of eukaryotic initiation factors (eIFs) and their associated proteins. These 11 eIFs catalyze the joining of the tRNA, mRNA and rRNA into a functional translation complex. Their activity is influenced by a wide variety of extra- and intracellular signals, ranging from global, such as hormone signaling and unfolded proteins, to specific, such as single amino acid imbalance and iron deficiency. Their action is correspondingly comprehensive, in increasing or decreasing recruitment and translation of most cellular mRNAs, and specialized, in targeting translation of mRNAs with regulatory features such as a 5 terminal oligopyrimidine tract (TOP), upstream open reading frames (uORFs), or an internal ribosomal entry site (IRES). In mammals, two major pathways are linked to targeted mRNA translation. The target of rapamycin (TOR) kinase induces translation of TOP and perhaps other subsets of mRNAs, whereas a family of eIF2 kinases does so with mRNAs containing uORFs or an IRES. TOR targets translation of mRNAs that code for proteins involved in translation, an action compatible with its widely accepted role in regulating cellular growth. The four members of the eIF2 kinase family increase translation of mRNAs coding for stress response proteins such as transcription factors and chaperones. Though all four kinases act on one main substrate, eIF2, published literature demonstrates both common and unique effects by each kinase in response to its specific activating stress. This suggests that the activated eIF2 kinases regulate the translation of both a global and a specific set of mRNAs. Up to now, few studies have attempted to test such a hypothesis; none has been done in mammals.
eIF2alpha kinases GCN2 and PERK modulate transcription and translation of distinct sets of mRNAs in mouse liver.
No sample metadata fields
View SamplesPurpose:To dissect the mechanisms underlying altered gene expression in aneuploids, we measured transcript abundance in colonies of haploid yeast strain F45 and derived strains, including strains disomic for chromosomes XV and XVI, using RNA-seq. F45 colonies display complex “fluffy” morphologies, while the disomic colonies are smooth, resembling laboratory strains Methods: RNA-seq analysis was carried out on RNA isolated from fully developed S. cerevisiae colonies, grown on solid medium for four days, either in triplicate or quadruplicate. Stranded, paired-end sequencing was carried out in two batches. In the first batch 2x51 bp sequencing was carried out on an Illumina Hiseq2000 and in the second batch 2x75 bp sequencing was carried out on an Illumina NextSeq. Readpairs were aligned using Bowtie2 (version 2.1.0)with the parameters [-N 1 -I 50 -X 450 -p 6 --reorder -x -S] and allowing 1 mismatch per read. Differential transcription was detected and quantified using EdgeR (v. 3.6.8) Results: Our two disomes displayed similar transcriptional profiles, a phenomenon not driven by their shared smooth colony morphology nor specified purely by the karyotype. Surprisingly, the environmental stress response (ESR) was induced in euploid F45, relative to the two disomes, rather than vice-versa. We also identified genes whose expression reflected a non-linear interaction between the copy number of a transcriptional regulatory gene on chromosome XVI, DIG1, and the copy number of other chromosome XVI genes. DIG1 and the remaining chromosome XVI genes also demonstrated distinct contributions to the effect of the chromosome XVI disome on ESR gene expression. Conclusions: Expression changes in aneuploids reflect a mixture of effects shared between different aneuploidies, including stress responses, and effects unique to perturbing the copy number of particular chromosomes, including non-linear copy number interactions between genes. The balance between these two phenomena is likely to be genotype and environment specific. Overall design: mRNA profiles of 4 day old haploid F45 colonies, and colonies derived from F45 were generated by deep sequencing, in triplicate or quadruplicate, using Illumina Hiseq2000 or Illumina Nextseq sequencing.
Transcriptional Profiling of Biofilm Regulators Identified by an Overexpression Screen in <i>Saccharomyces cerevisiae</i>.
Cell line, Subject
View SamplesIt has been shown previously that endothelial cells and LepR+ stromal cells are the main sources of SCF in vivo in the mouse bone marrow. We tested whether SCF from endothelial cells and/or LepR+ stromal cells is important for the maintenance of hematopoietic progenitors and erythroid progenitors in mouse bone marrow by conditional deletion of Scf from these two cell types. We discovered that Scf deletion from LepR+ stromal cells, but not endothelial cells, reduced the numbers of hematopoietic progenitors and erythroid progenitors in mice. We performed RNA-Seq on PreCFU-E and CFU-E progenitors from control mice and from mice with Scf deletion from LepR+ stromal cells. We discovered that lack of SCF from LepR+ cells induces a premature differentiation of PreCFU-E and CFU-E progenitors. Overall design: Examination of gene expression profile in 2 cell tyeps from 3 different genetic backgrounds
Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow.
Sex, Specimen part, Subject
View SamplesGene expression profiling of zebrafish early eye development on 3 to 5 days post fertilization (dpf)
Integrating multiple genome annotation databases improves the interpretation of microarray gene expression data.
Specimen part
View SamplesConjunctival samples from 60 individuals with and without the clinical signs of active trachoma were analysed on the U133 Plus 2.0 arrays. Global transcriptional changes characteristic of disease and infection phenotypes were identified. Two analysis methods found large numbers of differentially regulated genes and the existence of networks of co-expressed genes. There were signatures characteristic of the host defence response with evidence supporting infiltration of various types of leukocytes and activation of innate responses of epithelial cells. Two separate methods could classify disease and infection phenotype based on transcription signatures with 70% accuracy. These results provide an insight into the complexity of the acute response in trachoma but are able to partly explain the biology of trachoma through the identification of pathways and gene expression sets useful to future studies on chlamydial immunopathogenesis.
Human conjunctival transcriptome analysis reveals the prominence of innate defense in Chlamydia trachomatis infection.
Sex, Age, Specimen part, Disease, Race
View SamplesMetzincins and related genes (MARGS) play important roles in ECM remodeling in fibrotic conditions.
Renal Fibrosis mRNA Classifier: Validation in Experimental Lithium-Induced Interstitial Fibrosis in the Rat Kidney.
Sex, Specimen part
View SamplesCardiogenesis involves multiple biological processes acting in concert during development, a coordination achieved by the regulation of diverse cardiac genes by a finite set of transcription factors (TFs). Previous work from our laboratory identified the roles of two Forkhead TFs, Checkpoint suppressor homologue (CHES-1-like) and Jumeau (Jumu) in governing cardiac progenitor cell divisions by regulating Polo kinase activity. These TFs were also implicated in the regulation of numerous other cardiac genes. Here we show that these two Forkhead TFs play an additional and mutually redundant role in specifying the cardiac mesoderm (CM): eliminating the functions of both CHES-1-like and jumu in the same embryo results in defective hearts with missing hemisegments. Our observations indicate that this process is mediated by the Forkhead TFs regulating the fibroblast growth factor receptor Heartless (Htl) and the Wnt receptor Frizzled (Fz), both previously known to function in cardiac progenitor specification: CHES-1-like and jumu exhibit synergistic genetic interactions with htl and fz in CM specification, thereby implying function through the same genetic pathways, and transcriptionally activate the expression of both receptor-encoding genes. Furthermore, ectopic overexpression of either htl or fz in the mesoderm partially rescues the defective CM specification phenotype seen in embryos doubly homozygous for mutations in jumu and CHES-1-like. Together, these data emphasize the functional redundancy that leads to robustness in the cardiac progenitor specification process mediated by Forkhead TFs regulating the expression of signaling pathway receptors, and illustrate the pleiotropic functions of this class of TFs in different aspects of cardiogenesis.
Two forkhead transcription factors regulate the division of cardiac progenitor cells by a Polo-dependent pathway.
Specimen part
View Samples