Cell-context dependent Notch target genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE15268 | GEO | 2010/07/13
SECONDARY ACCESSION(S): PRJNA116497
REPOSITORIES: GEO
Similar Datasets
Project description:Notch signaling regulates a variety of developmental cell fates decisions in a cell-context dependent manner. Although Notch signaling directly regulates transcription via the RBP-J/CSL DNA binding protein, little is known about the genes in the respective tissues that are directly activated by Notch. To analyze how Notch signaling mediates its context dependent functions, we utilized a Tamoxifen(OHT)-inducible system (NERT) to activate Notch1 in embryonic stem cells (ESC) at different stages of mesodermal differentiation combined with global transcriptional analyses. Notch1 signaling pathway was analysed in mouse embryonic stem cells (mESCs) that were kept under self-renewal conditions enabling ectodermal, or mesodermal gene expression (ESCe or ESCm respectively), or were differentiated into mesodermal progenitors. NotchIC were induced or not induced by hydroxytamoxifen (OHT) and addititionally in some experiments the cells were treated with protein synthesis inhibitor cycloheximide (CHX) for 4 h.
2010-07-13 | E-GEOD-15268 | biostudies-arrayexpress
Project description:It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-JK, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through up-regulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix remodeling enzymes. In human skin samples, stromal fields adjacent to cutaneous squamous cell carcinomas and multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer. We used microarrays to detail the global changes in gene expression in dermal fibroblasts with in vivo and in vitro deletion of the RBP-Jk gene, compared to corresponding controls Global changes in gene expression in dermal fibroblasts with in vivo and in vitro deletion of the RBP-Jk gene were assessed, in parallel with the corresponding controls
2012-06-11 | E-GEOD-36359 | biostudies-arrayexpress
Project description:Down-modulation or loss-of-function mutations of the Notch 1 and 2 genes are associated with development of squamous cell carcinoma (SCC), a very frequent and therapy-resilient malignancy in skin, head/neck (H/N), lung and other surface epithelia. In this context, surprisingly little is known on the role of CSL (RBP-Jk), key effector of canonical Notch signaling endowed with intrinsic transcription repressive function. CSL expression is decreased in upper epidermal layers and differentiating primary human keratinocytes (HKCs), while it is up-regulated in premalignant and malignant SCC lesions and SCC cell lines from skin, Head/Neck and lung. Increased CSL levels enhance proliferation and self-renewal potential of HKCs and SCC cells, while its silencing induces growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels give rise to rapidly expanding tumors, while upon CSL silencing they form smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKC and SCC cells plus/minus CSL silencing reveals major modulation of apoptotic, cell cycle and pro-inflammatory genes, with no significant association with Notch or keratinocyte differentiation gene signatures. KDM6B, a histone demethylase gene with highly context dependent functions, is a direct CSL negative target, with an inverse role of CSL in HKC and SCC self-renewal and tumorigenesis, with IL6 as a target of likely significance. CSL / KDM6B protein expression could be used as biomarkers of SCC development and novel indicators of cancer treatment.
2017-12-15 | GSE102762 | GEO
Project description:Down-modulation or loss-of-function mutations of the Notch 1 and 2 genes are associated with development of squamous cell carcinoma (SCC), a very frequent and therapy-resilient malignancy in skin, head/neck (H/N), lung and other surface epithelia. In this context, surprisingly little is known on the role of CSL (RBP-Jk), key effector of canonical Notch signaling endowed with intrinsic transcription repressive function. CSL expression is decreased in upper epidermal layers and differentiating primary human keratinocytes (HKCs), while it is up-regulated in premalignant and malignant SCC lesions and SCC cell lines from skin, Head/Neck and lung. Increased CSL levels enhance proliferation and self-renewal potential of HKCs and SCC cells, while its silencing induces growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels give rise to rapidly expanding tumors, while upon CSL silencing they form smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKC and SCC cells plus/minus CSL silencing reveals major modulation of apoptotic, cell cycle and pro-inflammatory genes, with no significant association with Notch or keratinocyte differentiation gene signatures. KDM6B, a histone demethylase gene with highly context dependent functions, is a direct CSL negative target, with an inverse role of CSL in HKC and SCC self-renewal and tumorigenesis, with IL6 as a target of likely significance. CSL / KDM6B protein expression could be used as biomarkers of SCC development and novel indicators of cancer treatment.
2017-12-15 | GSE102761 | GEO
Project description:It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-JK, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through up-regulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix remodeling enzymes. In human skin samples, stromal fields adjacent to cutaneous squamous cell carcinomas and multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer. We used microarrays to detail the global changes in gene expression in dermal fibroblasts with in vivo and in vitro deletion of the RBP-Jk gene, compared to corresponding controls
2012-06-12 | GSE36359 | GEO
Project description:Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1± protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a novel role for CSL in tumorigenesis and regulation of the cellular hypoxic response. CSL +/+ and CSL -/- MDA-MB-231 were subjected to Notch activation/inhibition and xenograft experiment. Total RNA were extracted from the samples and sent to NGS. Single Cell RNA-sequencing was also performed from cells isolated from xenograft tumors.
2016-02-28 | E-GEOD-77308 | biostudies-arrayexpress
Project description:Notch signaling is an important regulator of stem cell differentiation. All canonical Notch signaling is transmitted through the DNA-binding protein CSL and hyperactivated Notch signaling is associated with tumor development; thus it may be anticipated that CSL deficiency should reduce tumor growth. In contrast, we report that genetic removal of CSL in breast tumor cells caused accelerated growth of xenografted tumors. Loss of CSL unleashed a hypoxic response during normoxic conditions, manifested by stabilization of the HIF1± protein and acquisition of a polyploid giant-cell, cancer stem cell-like, phenotype. At the transcriptome level, loss of CSL upregulated more than 1750 genes and less than 3% of those genes were part of the Notch transcriptional signature. Collectively, this suggests that CSL exerts functions beyond serving as the central node in the Notch signaling cascade and reveals a novel role for CSL in tumorigenesis and regulation of the cellular hypoxic response.
2016-02-28 | GSE77308 | GEO
Project description:The conserved Notch pathway functions in diverse developmental and disease-related processes, requiring mechanisms to ensure appropriate target-selection and gene activation in each context. To investigate, we partitioned Drosophila chromatin into different states, based on histone modifications, establishing the preferred chromatin conditions for binding of CSL, the Notch pathway transcription factor. While most histone modifications were unchanged by CSL binding or Notch activation, rapid changes in H3K56 acetylation occurred at Notch regulated-enhancers. This modification extended over large regions, required the histone acetyl-transferase CBP and was independent of transcription. Such rapid changes in H3K56 acetylation are a conserved indicator of enhancer activation, also occurring at mammalian Notch-regulated Hey1 and at Drosophila ecdysone-regulated genes. This core histone modification may therefore underpin the changes in chromatin accessibility needed to promote transcription following signaling activation. Su(H) profile of Kc cells transfected with GFP-Su(H). In total 6 samples, 3 replicates of anti-GFP ChIP and corresponding total input samples in Kc cells.
2015-07-01 | E-GEOD-66226 | biostudies-arrayexpress
Project description:The conserved Notch pathway functions in diverse developmental and disease-related processes, requiring mechanisms to ensure appropriate target-selection and gene activation in each context. To investigate, we partitioned Drosophila chromatin into different states, based on histone modifications, establishing the preferred chromatin conditions for binding of CSL, the Notch pathway transcription factor. While most histone modifications were unchanged by CSL binding or Notch activation, rapid changes in H3K56 acetylation occurred at Notch regulated-enhancers. This modification required the histone acetyl-transferase CBP and was independent of transcription. Such rapid changes in H3K56 acetylation are a conserved indicator of enhancer activation, also occurring at mammalian Notch-regulated Hey1 and at Drosophila ecdysone-regulated genes. This core histone modification may therefore underpin the changes in chromatin accessibility needed to promote transcription following signaling activation. H3K56ac profile of control cells (KP) and of NICD overexpression cells (KN). In total 6 samples, with 2 input files (from 2 different conditions) and 2 replicates of H3K56ac ChIP samples of each condition.
2015-07-01 | E-GEOD-66221 | biostudies-arrayexpress
Project description:The conserved Notch pathway functions in diverse developmental and disease-related processes, requiring mechanisms to ensure appropriate target-selection and gene activation in each context. To investigate, we partitioned Drosophila chromatin into different states, based on histone modifications, establishing the preferred chromatin conditions for binding of CSL, the Notch pathway transcription factor. While most histone modifications were unchanged by CSL binding or Notch activation, rapid changes in H3K56 acetylation occurred at Notch regulated-enhancers. This modification required the histone acetyl-transferase CBP and was independent of transcription. Such rapid changes in H3K56 acetylation are a conserved indicator of enhancer activation, also occurring at mammalian Notch-regulated Hey1 and at Drosophila ecdysone-regulated genes. This core histone modification may therefore underpin the changes in chromatin accessibility needed to promote transcription following signaling activation.
2015-07-01 | GSE66221 | GEO