Genome-wide profile of Notch pathway co-repressors and their role in shaping the Notch response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA382403 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Several co-repressors interact directly with the DNA-binding protein CSL [Su(H) in Drosophila] and are proposed to keep target genes silenced in the absence of Notch activity. To investigate co-repressor activity in the context of this well defined signalling pathway, we analysed the genome-wide binding profile of the best-characterized CSL co-repressor in Drosophila, Hairless, in Kc cells and in wing imaginal discs. The binding profile in wing discs of a second CSL interacting repressor, SMRTER, was also analysed. There was significant overlap between Hairless and Su(H), both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. The Hairless complex was widely present at some Notch regulated enhancers in the wing disc,but no binding was detected at others, indicating that it is not essential for silencing per se. Analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate the enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved.
2017-12-31 | GSE97603 | GEO
Project description:This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and to see how well they work in treating patients with advanced or metastatic sarcoma. Vismodegib may slow the growth of tumor cells. Gamma-secretase/notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vismodegib together with gamma-secretase/notch signalling pathway inhibitor RO4929097 may be an effective treatment for sarcoma.
| 2091475 | ecrin-mdr-crc
Project description:The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting, in a context-dependent manner, processes of proliferation, differentiation, and apoptosis1. It has been implicated in human cancer both as an oncogene and a tumor suppressor2. Here we report, for the first time, novel inactivating mutations in the Notch pathway components in over forty percent of the human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the US male population3. Thus far, driver mutations in the FGFR3 and less commonly RAS proteins have been identified4,5. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual specificity phosphatases (DUSPs), thus reducing ERK1/2 phosphorylation. In mouse models, genetic inactivation of Notch signaling leads to ERK1/2 phosphorylation resulting in tumorigenesis in the urinary tract. In recent years, the tumor suppressor role of Notch has been recognized by loss-of-function mutations identified in myeloid cancers6 as well as squamous cell carcinomas of the skin, lung7, and the head and neck8,9. Of the 4 Notch receptors (N1-4), only N1 and 2 have been implicated in human cancer. two biological replicates from normal and tumor urothelial tissue were hybridized on Affymetrix mm 430 2.0 chips
2014-07-01 | E-GEOD-54589 | biostudies-arrayexpress
Project description:Repressors are frequently deployed to limit the transcriptional response to signalling pathways. For example, several co-repressors interact directly with the DNA-binding protein CSL and are proposed to keep target genes silenced in the absence of Notch activity. However, the scope of their contributions remains unclear. To investigate co-repressor activity in the context of this well defined signalling pathway, we have analysed the genome-wide binding profile of the best-characterized CSL co-repressor in Drosophila, Hairless, and of a second CSL interacting repressor, SMRTER. As predicted there was significant overlap between Hairless and its CSL DNA-binding partner, both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. However, while the Hairless complex was widely present at some Notch regulated enhancers in the wing disc, no binding was detected at others, indicating that it is not essential for silencing per se. Further analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved.
| S-EPMC5714389 | biostudies-literature
Project description:The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting, in a context-dependent manner, processes of proliferation, differentiation, and apoptosis1. It has been implicated in human cancer both as an oncogene and a tumor suppressor2. Here we report, for the first time, novel inactivating mutations in the Notch pathway components in over forty percent of the human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the US male population3. Thus far, driver mutations in the FGFR3 and less commonly RAS proteins have been identified4,5. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual specificity phosphatases (DUSPs), thus reducing ERK1/2 phosphorylation. In mouse models, genetic inactivation of Notch signaling leads to ERK1/2 phosphorylation resulting in tumorigenesis in the urinary tract. In recent years, the tumor suppressor role of Notch has been recognized by loss-of-function mutations identified in myeloid cancers6 as well as squamous cell carcinomas of the skin, lung7, and the head and neck8,9. Of the 4 Notch receptors (N1-4), only N1 and 2 have been implicated in human cancer.
2014-07-01 | GSE54589 | GEO
Project description:Notch signalling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighbouring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and together with the transcription factor moiety of Notch (NICD) it regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole genome binding profiles were generated for RBPJ, its coactivator p300, NICD and the histone H3 modifications H3K4me3, H3K4me1 and H3K27ac in myogenic cells under active or inhibitory Notch signalling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300, and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signalling mediate their activities and consequently impact on cell fate decisions. ChIP (chromatin immunoprecipitation) is followed by deep sequencing to generate genome-wide patterns of RBP-J binding in mouse C2C12 cells under various conditions. Cells were either Notch activated by exposure to immobilized ligand or by overexpression of NICDGFP, or Notch inhibited by treatment with DAPT. Notch activation and inhibition treatments were applied for 6h and 24h. In addition to RBP-J, p300 and NICDGFP were profiled by ChIP-Seq and gene expression was assessed by RNA-Seq.
2013-05-13 | E-GEOD-37184 | biostudies-arrayexpress
Project description:Notch signaling is a core patterning module for vascular morphogenesis, which co-determines the sprouting behaviour of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability, and diminished Notch-induced target gene expression in ECs. In mice, loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase, which fine-tunes endothelial Notch responses during angiogenic sprouting.
2019-04-11 | PXD013192 | Pride
Project description:Several co-repressors interact directly with the DNA-binding protein CSL [Su(H) in Drosophila] and are proposed to keep target genes silenced in the absence of Notch activity. To investigate co-repressor activity in the context of this well defined signalling pathway, we analysed the genome-wide binding profile of the best-characterized CSL co-repressor in Drosophila, Hairless, in Kc cells and in wing imaginal discs. The binding profile in wing discs of a second CSL interacting repressor, SMRTER, was also analysed. There was significant overlap between Hairless and Su(H), both in Kc cells and in wing discs, where they were predominantly found in chromatin with active enhancer marks. The Hairless complex was widely present at some Notch regulated enhancers in the wing disc,but no binding was detected at others, indicating that it is not essential for silencing per se. Analysis of target enhancers confirmed differential requirements for Hairless. SMRTER binding significantly overlapped with Hairless, rather than complementing it, and many enhancers were apparently co-bound by both factors. Our analysis indicates that the actions of Hairless and SMRTER gate the enhancers to Notch activity and to Ecdysone signalling respectively, to ensure that the appropriate levels and timing of target gene expression are achieved.
2017-12-31 | GSE97598 | GEO
Project description:Notch signalling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighbouring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and together with the transcription factor moiety of Notch (NICD) it regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole genome binding profiles were generated for RBPJ, its coactivator p300, NICD and the histone H3 modifications H3K4me3, H3K4me1 and H3K27ac in myogenic cells under active or inhibitory Notch signalling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300, and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signalling mediate their activities and consequently impact on cell fate decisions.
2013-05-13 | GSE37184 | GEO
Project description:Sivakumar2011 - Notch Signaling Pathway
Notch is a transmembrane receptor that mediates local cell-cell communication and coordinates a signaling cascade. It plays a key role in modulating cell fate decisions throughout the development of invertebrate and vertebrate species and the misregulation leads to a number of human diseases.
References:
Notch signaling: from the outside in.
Notch signaling in hematopoiesis and early lymphocyte development.
An overview of the Notch signalling pathway.
Notch and cancer: best to avoid the ups and downs.
Notch signaling: control of cell communication and cell fate.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
This model is hosted on BioModels Database and identified by: BIOMD0000000396.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000396 | BioModels