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Homo sapiens
9 Downloadable Samples
NextSeq 500
Description
Asymmetric cell division results in two distinctly fated daughter cells to generate cellular diversity. A major molecular hallmark of an asymmetric division is the unequal partitioning of cell-fate determinant proteins. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which in turns drives migration and metastasis. Here, we report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell-fate determinants Numb (Notch antagonist) and ß-catenin (canonical Wnt regulator) through the activity of a depalmitoylating enzyme, APT1. Using point mutants, we show specific palmitoylated residues on proteins, such as Numb, are required for asymmetric localization. Furthermore, by live-cell imaging, we show that reciprocal interactions between APT1 and CDC42 regulate the asymmetric localization of Numb and ß-catenin to the plasma membrane. This in turn restricts Notch and Wnt transcriptional activity to one daughter cell. Moreover, we show altering APT1 expression changes the transcriptional signatures to those resembling that of Notch and ß-catenin in MDA-MB-231 cells. We also show loss of APT1 depletes the population of CD44+/CD24lo/ALDH+ tumorigenic cells in colony formation assays. Together, the findings of this study demonstrate that palmitoylation, via APT1, is a major mechanism of asymmetric cell division regulating Notch and Wnt-associated protein dynamics, gene expression, and cellular functions. Overall design: Gene expression by RNAseq of MDA-MB-231 triple receptor negative breast cancer cells expressing scramble control vector, shAPT1 knockdown, and APT1wt performed in triplicate. Total of 9 samples were analyzed.
Publication Title
The depalmitoylase APT1 directs the asymmetric partitioning of Notch and Wnt signaling during cell division.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 22 Downloadable Samples
- NextSeq 500
Description
The pathognomonic EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has not been successful; therefore identifying mediators of the EWS/ETS function could offer new therapeutic targets. Here we describe the dependency of chromatin reader BET bromodomain proteins in EWS/ETS driven transcription and investigate the potential of BET inhibitors in treating this lethal cancer. Similar to EWS/ETS fusions, knockdown of BET proteins BRD2/3/4 severely impaired the oncogenic phenotype of EWS cells. Notably, EWS/FLI1 and EWS/ERG was found to be in a transcriptional complex consisting of BRD4. RNA-Seq analysis upon BRD4 knockdown or its pharmacologic inhibition by the BET inhibitor JQ1 revealed an attenuated EWS/ETS transcriptional signature. In contrast to other reports, JQ1 reduced proliferation, and induced apoptosis through MYC-independent mechanism without affecting EWS/ETS protein levels, which was further confirmed by depleting BET proteins using PROTAC-BET degrader (BETd). Interestingly, polycomb repressive complex 2 (PRC2) associated factor PHF19 was downregulated by JQ1/BETd or BRD4 knockdown in multiple EWS cells. ChIP-seq analysis revealed occupancy of EWS/FLI1 at a distal regulatory element of PHF19 and its subsequent knockdown resulted in downregulation of PHF19 expression. Furthermore, deletion of PHF19 by CRISPR-Cas9 system lead to a decreased tumorigenic phenotype and increased sensitivity to JQ1. Importantly, PHF19 expression was associated with worse prognosis of Ewing sarcoma patients. In vivo, JQ1 demonstrated anti-tumor efficacy in multiple mouse xenograft models of EWS. Together, these results indicate that EWS/ETS require BET epigenetic reader proteins for its transcriptional program including PHF19 expression, which can be mitigated by BET inhibitors. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating Ewing sarcoma. Overall design: Gene epxression by RNAseq in the ewing sarcoma cell lines with knockdown of EWS-FLI1, BRD4 or JQ1 treament, knockout of PHF19
Publication Title
EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples
GSE144612- Mus musculus, Homo sapiens
- 6 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st), Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes.
Publication Title
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The microenvironment has profound effect on macrophage phenotype. Here we examine the phenotype of macrophages infiltrating murine undifferentiated pleomorphic sarcomas. We used microarray to examine gene expression profile of tumor-associated macrophages in murine undifferentiated pleomorphic sarcomas.
Publication Title
Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 58 Downloadable Samples
- IlluminaGenomeAnalyzerII, IlluminaGenomeAnalyzer
Description
Noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease and to reveal uncharacterized aspects of tumor biology. Here we discover 121 unannotated prostate cancer–associated ncRNA transcripts (PCATs) by ab initio assembly of high-throughput sequencing of polyA+ RNA (RNA-Seq) from a cohort of 102 prostate tissues and cells lines. We characterized one ncRNA, PCAT-1, as a prostate-specific regulator of cell proliferation and show that it is a target of the polycomb repressive complex 2 (PRC2). We further found that patterns of PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1–repressed target genes. Taken together, our findings suggest that PCAT-1 is a transcriptional repressor implicated in a subset of prostate cancer patients. These findings establish the utility of RNA-Seq to identify disease-associated ncRNAs that may improve the stratification of cancer subtypes. Overall design: 21 prostate cell lines sequenced on the Illumina Genome Analyzer and GAII. Variable number of replicates per sample. RNA-Seq data from prostate cancer tissues used in this study will be made available on dbGAP.
Publication Title
Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 6 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Placentation differs in the BN rat strain when compared to HSD and DSS rat strains. Intrauterine trophoblast invasion is shallow and the junctional zone is underdeveloped in the BN rat. These structural differences are striking but their quantification is not conducive to high throughput analyses. In the rat, the junctional zone can be readily dissected and is more homogenous than other components of the placentation site. HSD and BN rat gestation day 18.5 junctional zone gene expression profiles were determined using DNA microarray analysis to identity placenta-associate quantitate traits.
Publication Title
Chromosome-substituted rat strains provide insights into the genetics of placentation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
During development of the mammalian central nervous system (CNS), neurons and glial cells (astrocytes and oligodendrocytes) are generated from common neural precursor cells (NPCs). However, neurogenesis precedes gliogenesis, which normally commences at later stages of fetal telencephalic development. Astrocyte differentiation of mouse NPCs at embryonic day (E) 14.5 (relatively late gestation) is induced by activation of the transcription factor STAT3, whereas at E11.5 (mid-gestation) NPCs do not differentiate into astrocytes even when stimulated by STAT3-activating cytokines such as leukemia inhibitory factor (LIF). This can be explained in part by the fact that astrocyte-specific gene promoters are highly methylated in NPCs at E11.5, but other mechanisms are also likely to play a role. We therefore sought to identify genes involved in the inhibition of astrocyte differentiation of NPCs at midgestation. We first examined gene expression profiles in E11.5 and E14.5 NPCs, using Affymetrix GeneChip analysis, applying the Percellome method to normalize gene expression level. We then conducted in situ hybridization analysis for selected genes found to be highly expressed in NPCs at midgestation. Among these genes, we found that N-myc and high mobility group AT-hook 2 (Hmga2) were highly expressed in the E11.5 but not the E14.5 ventricular zone of mouse brain, where NPCs reside. Transduction of N-myc and Hmga2 by retroviruses into E14.5 NPCs, which normally differentiate into astrocytes in response to LIF, resulted in suppression of astrocyte differentiation. However, sustained expression of N-myc and Hmga2 in E11.5 NPCs failed to maintain the hypermethylated status of an astrocyte-specific gene promoter. Taken together, our data suggest that astrocyte differentiation of NPCs is regulated not only by DNA methylation but also by genes whose expression is controlled spatio-temporally during brain development.
Publication Title
Identification of genes that restrict astrocyte differentiation of midgestational neural precursor cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Microarray analysis on germfree mice elucidates the primary target of a traditional Japanese medicine juzentaihoto: acceleration of IFN-α response via affecting the ISGF3-IRF7 signaling cascade.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
Juzehtaihoto, a Japanese traditional medicine has been used for the treatment of various kinds of diseases or disorders in an enteric-flora dependent manner.
Publication Title
Microarray analysis on germfree mice elucidates the primary target of a traditional Japanese medicine juzentaihoto: acceleration of IFN-α response via affecting the ISGF3-IRF7 signaling cascade.
Sample Metadata Fields
Sex, Specimen part
View Samples