Role of co-repressor genomic landscapes in shaping the Notch response
| Autor: | Chan, Stephen KK, Cerda-Moya, Gustavo, Stojnic, Robert, Millen, Kat, Fischer, Bettina, Fexova, Silvie, Skalska, Lenka, Gomez-Lamarca, Maria, Pillidge, Zoe, Russell, Steven, Bray, Sarah J |
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| Přispěvatelé: | Stojnic, Robert [0000-0002-6458-0273], Fischer, Bettina [0000-0003-2821-6287], Russell, Steven [0000-0003-0546-3031], Bray, Sarah J [0000-0002-1642-599X], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Cell Binding
Cell Physiology Computer and Information Sciences Ecdysone animal structures lcsh:QH426-470 Gene Expression Regulatory Sequences Nucleic Acid Biochemistry Infographics RNA interference Cell Signaling Invertebrate Genomics Genetics Animals Drosophila Proteins Notch Signaling Binding Sites Receptors Notch integumentary system Chromosome Biology Data Visualization Biology and Life Sciences Gene Expression Regulation Developmental Cell Biology Genomics Chromatin Nucleic acids DNA-Binding Proteins Repressor Proteins lcsh:Genetics Drosophila melanogaster Genetic interference Animal Genomics Genetic Loci RNA Epigenetics Graphs Co-Repressor Proteins Research Article Protein Binding Signal Transduction Transcription Factors |
| Zdroj: | PLoS Genetics, Vol 13, Iss 11, p e1007096 (2017) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | 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. Author summary The communication between cells that occurs during development, as well as in disease contexts, involves a small number of signalling pathways of which the Notch pathway is one. One outstanding question is how these pathways can bring about different gene responses in different contexts. As gene expression is co-ordinated by a mixture of activators and repressors, we set out to investigate whether the distribution of repressors across the genome is important in shaping whether genes are able to respond to Notch activity. Our results from analyzing the binding profile of two repressors, Hairless and SMRTER, show that, in many cases, they are not essential for preventing a gene from responding. Instead they are deployed at a limited number of genetic loci where they gate the response, helping to set a threshold for gene activation. Perturbations to their function lead to enhanced gene expression in limited territories rather than to new programmes of gene expression. Their main role therefore is to restrict the time or levels of signal that a gene needs to receive before it will respond. |
| Databáze: | OpenAIRE |
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