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GSE37894
Mus musculus
6 Downloadable Samples
Illumina MouseWG-6 v2.0 expression beadchip
Description
JQ1 is a small-molecule (BET family) bromodomain inhibitor that causes a contraceptive effect in mice by blocking spermatogenesis and reducing sperm motility.
Publication Title
Small-molecule inhibition of BRDT for male contraception.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo-and-extra-terminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2). Co-crystal structures revealed binding modes of RVX-208 and its synthetic precursor and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation
Publication Title
RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 75 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 40 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET inhibitors and their significant activity in diverse tumor models has rapidly translated into clinical studies and has motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of bromodomain protein complexes complicates predictions of consequences of their pharmacological targeting. To address this issue we developed a promiscuous bromodomain inhibitor (bromosporine, BSP) that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle we studied the effect of BSP in leukemic cell-lines known to be sensitive to BET inhibition and found as expected strong anti-proliferative activity. Comparison of the modulation of transcriptional profiles by BSP at short inhibitor exposure resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, non-selective targeting of BRDs identified BETs, but not other BRDs, as master regulators of a context dependent primary transcription response.
Publication Title
Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 35 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET inhibitors and their significant activity in diverse tumor models has rapidly translated into clinical studies and has motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of bromodomain protein complexes complicates predictions of consequences of their pharmacological targeting. To address this issue we developed a promiscuous bromodomain inhibitor (bromosporine, BSP) that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle we studied the effect of BSP in leukemic cell-lines known to be sensitive to BET inhibition and found as expected strong anti-proliferative activity. Comparison of the modulation of transcriptional profiles by BSP at short inhibitor exposure resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, non-selective targeting of BRDs identified BETs, but not other BRDs, as master regulators of a context dependent primary transcription response.
Publication Title
Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We studied adipose tissue from wild type mice, kinin B1 receptor knockout mice (B1KO), and B1KO mice with rescued expression of kinin B1 receptor selectively in fat.
Publication Title
Kinin B1 and B2 receptor deficiency protects against obesity induced by a high-fat diet and improves glucose tolerance in mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
To identify genes dysregulated in bipolar disorder (BD1) we carried out global gene expression profiling using whole-genome microarrays. To minimize genetic variation in gene expression levels between cases and controls we compared expression profiles in lymphoblastoid cell lines from monozygotic twin pairs discordant for the disease. We identified 82 genes that were differentially expressed by 1.3-fold in 3 BD1 cases compared to their co-twins, and which were statistically (p 0.05) differentially expressed between the groups of BD1 cases and controls. Using qRT-PCR we confirmed the differential expression of some of these genes, including: KCNK1, MAL, PFN2, TCF7, PGK1, and PI4KCB, in at least 2 of the twin pairs. In contrast to the findings of a previous study by Kakiuchi and colleagues with similar discordant BD1 twin design1 our data do not support the dysregulation of XBP1 and HSPA5. From pathway and gene ontology analysis we identified up-regulation of the WNT signalling pathway and the biological process of apoptosis. The differentially regulated genes and pathways identified in this study may provide insights into the biology of BD1.
Publication Title
Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
To identify the genes regulated by androgen receptor (AR), we performed the profiling array analysis on the CWR22Rv1 cells and determined the differentially expressed genes upon the knockdown of AR.
Publication Title
The histone demethylase KDM3A regulates the transcriptional program of the androgen receptor in prostate cancer cells.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
During early development, the correct establishment of the body axes is a critical step. The anterior pole of the mouse embryo is established when Distal Visceral Endoderm (DVE) cells migrate to form the Anterior Visceral Endoderm (AVE). Asymmetrical expression of Lefty1, Cerl and Dkk determines the direction of DVE migration and the future anterior side. Besides being implicated in the establishment of Anterior-Posterior axis the AVE has also been correlated with anterior neural specification. In order to better understand the role of the AVE in these processes, this cell population was isolated using a cerlP-EGFP transgenic mouse line, and a differential screening was performed using Affymetrix GeneChip technology. From this differential screening, 175 genes were found to be upregulated in the AVE, whereas 35 genes were upregulated in the Proximal-posterior sample. Using DAVID, here we characterize the AVE cell population regarding cellular component, molecular function and biological processes. Among the genes that were found to be upregulated in the AVE, several novel genes with expression in the AVE were identified. Four of the identified transcripts displaying high-fold change were further characterized by in situ hybridization in early stages of development in order to validate the screening. From those four selected genes, ADTK1 was chosen to be functionally characterized by targeted inactivation in ES cells. ADTK1 encodes for an unknown serine/threonine kinase. ADTK null mutants present short limbs and defects in the eye and ear. Taken together, these data point to the importance of reporting novel genes present in the AVE.
Publication Title
Identification and functional analysis of novel genes expressed in the Anterior Visceral Endoderm.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Double-stranded RNA (dsRNA) can enter different pathways in mammalian cells, including sequence-specific RNA interference, sequence-independent interferon response and editing by adenosine deaminases. To assess the potential of expressed dsRNA to induce interferon stimulated genes in somatic cells, we performed microarray analysis of HEK293 and HeLa cells transfected with a MosIR plasmid expressing an mRNA with a long inverted repeat structure in its 3UTR (MosIR) or with a parental MosIR plasmid (without inverted repeat) as a control.
Publication Title
dsRNA expression in the mouse elicits RNAi in oocytes and low adenosine deamination in somatic cells.
Sample Metadata Fields
Specimen part
View Samples