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GSE43716
Mus musculus
32 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the Integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switch to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study was to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP induces the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly activated by both CHOP and ATF4. Knock-down of ATF5 increased cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have pro-apoptotic functions. Transcriptome analyses of ATF5-dependent genes revealed targets involved in apoptosis, including, NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feed-forward loop of stress induced transcriptional regulators, each subject to transcriptional and translational control that can switch cell fate towards apoptosis.
Publication Title
CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the Integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switch to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study was to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP induces the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly activated by both CHOP and ATF4. Knock-down of ATF5 increased cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have pro-apoptotic functions. Transcriptome analyses of ATF5-dependent genes revealed targets involved in apoptosis, including, NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feed-forward loop of stress induced transcriptional regulators, each subject to transcriptional and translational control that can switch cell fate towards apoptosis.
Publication Title
CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK.
Publication Title
The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 19 Downloadable Samples
- Affymetrix Human Gene 2.1 ST Array (hugene21st)
Description
10 male subjects performed ~45 min one-legged cycling and 4 x 7 maximal concentric-eccentric knee extensions for each leg 15 min later. Thus, one limb performed aerobic and resistance exercise (AE+RE), while the opposing leg did resistance exercise only (RE). Biopsies were obtained from m. vastus lateralis of each leg 3 h after the resistance exercise bout.
Publication Title
Aerobic exercise augments muscle transcriptome profile of resistance exercise.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Glomerular RNA comparison between wild-type and podocyte specific deletion of the PTIP gene in 1 month old kidneys. The PTIP gene was deleted using a floxed allele and a Podocin-Cre driver strain.
Publication Title
Altering a histone H3K4 methylation pathway in glomerular podocytes promotes a chronic disease phenotype.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The transcription factor MEF2C is specifically induced by VEGF in endothelial cells. To delineate target genes of MEF2C in endothelial cells, which might be important during angiogenesis also, MEF2C was overexpressed adenovirally in human umbilical vein endothelial cells (HUVECs) over a period of 8 to 32 hours.
Publication Title
The transcription factor MEF2C negatively controls angiogenic sprouting of endothelial cells depending on oxygen.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Shiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and LPS. Data were analyzed using a rigorous combinatorial approach with three separate statistical algorithms. Thirty-six genes met the criteria of up-regulated expression in response to Stx1 treatment with 14 genes uniquely up-regulated by Stx1. Microarray data were validated by real time RT-PCR for genes encoding Egr-1 (transcriptional regulator), COX-2 (inflammation), and DUSP1, 5 and 10 (regulation of MAPK signaling). Stx1-mediated signaling through ERK1/2 and Egr-1 appears to be involved in the increased expression of the proinflammatory mediator TNF-. Activation of COX-2 expression is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins.
Publication Title
Global transcriptional response of macrophage-like THP-1 cells to Shiga toxin type 1.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 406 Downloadable Samples
IlluminaHiSeq2000
Description
We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dupASD). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes. Overall design: We reprogrammed skin fibroblasts from patients harbouring a 7q11.23 hemi-deletion (WBS, 4 patients; +1 atypical deletion, AtWBS) or microduplication (7dupASD; 2 patients), as well as from one unaffected relative and two unrelated controls, using integration-free mRNA-reprogramming, leading to the establishment of a total of 27 characterized iPSC clones. We profiled these by RNAseq (either polyA or ribo-zero). To isolate the contribution of GTF2I to the transcriptional dysregulation, we created stable lines expressing a short hairpin against GTF2I from a representative subset of these iPSC clones, and profiled by RNAseq 7 such lines along with their respective scramble controls. Finally, we also profiled by RNAseq mesenchymal stem cells (MSC) derived from a representative subset of the lines.
Publication Title
RNAontheBENCH: computational and empirical resources for benchmarking RNAseq quantification and differential expression methods.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 287 Downloadable Samples
- Illumina HiSeq 2500
Description
Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we used single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven individuals. Unbiased clustering analysis reveals the existence of three distinct epithelial cell populations, one basal and two luminal cell types, which we identify as secretory L1- and hormone-responsive L2-type cells. Pseudotemporal reconstruction of differentiation trajectories produc one continuous lineage hierarchy that closely connects the basal lineage to the two differentiated luminal branches. Our comprehensive cell atlas provides novel insights into cellular blueprint of the human breast epithelium and will form the foundation to understand how the system goes awry during breast cancer. Overall design: Microfluidics-enabled Single Cell RNA sequencing libraries were generated for 3 adult human women using the Fluidigm C1 and sequenced on the Illumina HighSeq 2500
Publication Title
Single-cell landscape in mammary epithelium reveals bipotent-like cells associated with breast cancer risk and outcome.
Sample Metadata Fields
Sex, Specimen part, Subject
View Samples