We have used an agnostic approach to identify drug combinations by using combination high throughput screening (cHTS) technology and make the surprising discovery that adenosine A2A and beta-2 adrenergic receptor agonists are highly synergistic, selective and novel agents that enhance glucocorticoid activity in B-cell malignancies.
Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening.
Specimen part, Cell line
View SamplesTo determine the physiological targets of the NELF complex, and provide insight into the mechanism of NELF activity in vivo.
NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly.
No sample metadata fields
View SamplesWe use mice containing a gene trap in the first intron of the Rest gene, which effectively eliminates transcription from all coding exons, to prematurely remove REST from neural progenitors. We find catastrophic DNA damage that occurs during S-phase of the cell cycle and concominant with activation of p53 pro-apoptotic sgnalling, with consequences including abnormal chromosome separation, apoptosis, and smaller brains.
The REST remodeling complex protects genomic integrity during embryonic neurogenesis.
Specimen part
View SamplesWe use mice containing a gene trap in the first intron of the Rest gene, which effectively eliminates transcription from all coding exons, to prematurely remove REST from neural progenitors. We find catastrophic DNA damage that occurs during S-phase of the cell cycle, with consequences including abnormal chromosome separation, apoptosis, and smaller brains. Further support for persistent effects is the latent appearance of proneural glioblastomas in adult mice also lacking the tumor suppressor, p53. A Rest deficient mouse line generated previously, using a conventional gene targeting approach, does not exhibit these phenotypes, likely due to a remaining C terminal peptide that still binds chromatin and recruits REST chromatin modifiers.Our results indicate that REST-mediated chromatin remodeling is required for proper S-phase dynamics, prior to its well-established role in relieving repression of neuronal genes at terminal differentiation.
The REST remodeling complex protects genomic integrity during embryonic neurogenesis.
Specimen part
View SamplesRegulation of gene expression is integral to the development and survival of all organisms. Transcription begins with the assembly of a pre-initiation complex at the gene promoter, followed by initiation of RNA synthesis and the transition to productive elongation. In many cases, recruitment of RNA polymerase II (Pol II) to a promoter is necessary and sufficient for activation of gene. However, there are a few notable exceptions to this paradigm, including heat shock genes and several proto-oncogenes, whose expression is attenuated by regulated stalling of polymerase elongation within the promoter-proximal region. To determine the importance of polymerase stalling for transcription regulation, we performed a genome-wide search for Drosophila genes with promoter-proximally stalled Pol II. Our data reveal that stalling is widespread, occurring at hundreds of genes that respond to stimuli and developmental signals, indicating a role for regulation of polymerase elongation in the transcriptional responses to dynamic environmental and developmental cues.
RNA polymerase is poised for activation across the genome.
No sample metadata fields
View SamplesAn assessment of a role of Ebf1 in committed B lineage cells.
Transcription factor EBF1 is essential for the maintenance of B cell identity and prevention of alternative fates in committed cells.
Specimen part
View SamplesmRNA profiles of astrocytes infected with Borrelia burdorferi for 24 hours, 48 hours, and 24 hour uninfected controls were generated by deep sequencing, in triplicate, using Illumina HiSeq. Overall design: mRNA profiles of astrocytes infected with Borrelia burdorferi for 24 hours, 48 hours, and 24 hour uninfected controls were generated by deep sequencing, in triplicate, using Illumina HiSeq.
MicroRNA and mRNA Transcriptome Profiling in Primary Human Astrocytes Infected with Borrelia burgdorferi.
Specimen part, Subject, Time
View SamplesTranscription cofactor Rcor1 has been linked biochemically both to neurogenesis and hematopoiesis. Here we studied the function of Rcor1 in vivo and showed it is essential to erythropoeisis during embryonic development. Rcor1 mutant proerythroblasts, unlike normal cells, can form myeloid colonies in vitro. To investigate the underlying molecular mechanisms for block of erythropoiesis and increased myeloid potential, we used RNA-seq to reveal the differentially expressed genes from erythroid progenitors due to depletion of Rcor1. Overall design: RNA were extracted from FACS sorted CD71+,TER119- erythroid progenitors from control (Rcor1+/+ and Rcor1+/-) or Mutant (Rcor1-/- ) E13.5 fetal liver. Each library was made by pooling RNA from several fetal livers. Two biological replicates were made for either control or mutant condition.
Corepressor Rcor1 is essential for murine erythropoiesis.
Specimen part, Subject
View SamplesAnalysis of global gene expression in myeloid cells infiltrating tumors after irradiation. Cell death induces recruitment of myeloid cells into irradiated tumors thereby stimulating tumor recurrence. Results provide insights into molecular mechanisms regulating tumorigenic functions of myeloid cells in tumors re-growing after radiation therapy. Overall design: Samples were collected at day 4 from irradiated tumors in WT, TLR9KO and Stat3KO (MxCre/Stat3flox). There were total 11 samples with  3-4 replicates of each sample type.
TLR9 signaling in the tumor microenvironment initiates cancer recurrence after radiotherapy.
Specimen part, Subject
View SamplesHepatitis C virus (HCV) is widely used to investigate host-virus interactions and cellular responses to infection have been extensively studied in vitro. In human liver, interferon (IFN) stimulated gene expression can mask direct transcriptional responses to virus infection. To better characterize the direct effects of HCV infection in vivo, we analyze the transcriptomes of HCV-infected patients lacking an activated endogenous IFN system. We show that the expression changes observed in these patients predominantly reflect immune cell infiltrates rather than changes in cell-intrinsic metabolic pathways. We also investigate the transcriptomes of patients with endogenous IFN activation, which paradoxically cannot eradicate viral infection. We find that most IFN-stimulated genes (ISGs) are induced by both the endogenous IFN system and by recombinant IFN therapy, but with significantly higher induction levels in the latter. We conclude that the innate host immune response in chronic hepatitis C is too weak to clear the virus. Overall design: In this study, we aimed to disentangle the direct and indirect effects of HCV infection on cellular transcriptional profiles, by performing a detailed characterization of the gene expression changes associated with HCV infection, endogenous IFN system activation and pegIFNa treatment in the human liver. With this objective, we generated and analyzed high-throughput transcriptome sequencing profiles from liver biopsies derived from different categories of HCV-infected and non-infected patients, prior to and during treatment. First, to unveil HCV-induced cell-autonomous effects and to separate them from IFN-induced changes in the transcriptome, we selected liver biopsies from patients with chronic hepatitis C (CHC) without hepatic ISG induction, and compared them with un-infected control biopsies. Second, we examined the transcriptomic changes associated with the endogenous activation of the IFN system. Finally, we analyzed the gene expression changes resulting from pegIFNa/ribavirin treatment, by comparing transcriptome data from liver biopsies obtained before treatment and at different time points during the first week of therapy.
Transcriptional response to hepatitis C virus infection and interferon-alpha treatment in the human liver.
Specimen part, Treatment, Subject
View Samples