Transcriptional dynamics elicited by a short pulse of notch activation involves feed-forward regulation by E(spl)/Hes genes

Autor: Steven Russell, Sarah J. Bray, Simon Tavaré, Benjamin E. Housden, Bettina Fischer, Fred Bernard, Audrey Qiuyan Fu, Alena Krejci
Přispěvatelé: Fischer, Bettina [0000-0003-2821-6287], Russell, Steve [0000-0003-0546-3031], Bray, Sarah [0000-0002-1642-599X], Apollo - University of Cambridge Repository
Rok vydání: 2020
Předmět:
Transcriptional Activation
Cancer Research
lcsh:QH426-470
Transcription
Genetic
Notch signaling pathway
Repressor
Gene Expression
RNA polymerase II
03 medical and health sciences
0302 clinical medicine
Gene expression
Molecular Cell Biology
Genetics
Basic Helix-Loop-Helix Transcription Factors
Animals
Drosophila Proteins
Humans
Molecular Biology
Gene
Transcription factor
Biology
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Conserved Sequence
030304 developmental biology
Regulation of gene expression
0303 health sciences
Binding Sites
biology
Receptors
Notch
Gene Expression Regulation
Developmental
Genomics
Molecular Development
Molecular biology
Signaling
Hairless
DNA-Binding Proteins
Repressor Proteins
lcsh:Genetics
biology.protein
Drosophila
RNA Polymerase II
Genome Expression Analysis
030217 neurology & neurosurgery
Research Article
Developmental Biology
Signal Transduction
Zdroj: PLoS Genetics
PLoS Genetics, Vol 9, Iss 1, p e1003162 (2013)
DOI: 10.17863/cam.50923
Popis: Dynamic activity of signaling pathways, such as Notch, is vital to achieve correct development and homeostasis. However, most studies assess output many hours or days after initiation of signaling, once the outcome has been consolidated. Here we analyze genome-wide changes in transcript levels, binding of the Notch pathway transcription factor, CSL [Suppressor of Hairless, Su(H), in Drosophila], and RNA Polymerase II (Pol II) immediately following a short pulse of Notch stimulation. A total of 154 genes showed significant differential expression (DE) over time, and their expression profiles stratified into 14 clusters based on the timing, magnitude, and direction of DE. E(spl) genes were the most rapidly upregulated, with Su(H), Pol II, and transcript levels increasing within 5–10 minutes. Other genes had a more delayed response, the timing of which was largely unaffected by more prolonged Notch activation. Neither Su(H) binding nor poised Pol II could fully explain the differences between profiles. Instead, our data indicate that regulatory interactions, driven by the early-responding E(spl)bHLH genes, are required. Proposed cross-regulatory relationships were validated in vivo and in cell culture, supporting the view that feed-forward repression by E(spl)bHLH/Hes shapes the response of late-responding genes. Based on these data, we propose a model in which Hes genes are responsible for co-ordinating the Notch response of a wide spectrum of other targets, explaining the critical functions these key regulators play in many developmental and disease contexts.
Author Summary Signaling via the Notch pathway conveys important information that helps to shape tissues and, when misused, contributes to diseases. Cells respond to the Notch signal by changing which genes are transcribed. Most previous studies have looked at changes in gene activity at a single time point, long after the start of signaling. By looking at carefully timed intervals immediately after Notch pathway activation, we have been able to follow the dynamic changes in transcription of all the genes and have found that they exhibit different patterns of activity. For example, activity of some genes, especially a previously characterised family called the E(spl) genes, starts very early, whereas others show more delayed upregulation. Our investigations into the underlying mechanisms reveal that cross-regulatory interactions driven by the early genes are required to shape the timing of the delayed response. This feed-forward mechanism is important because it explains why the E(spl)/Hes genes can play such a pivotal role in the Notch response, despite the fact that many other genes are regulated by the signal, a finding that will be valuable for understanding the contribution of E(spl)/Hes genes in diseases associated with altered Notch.
Databáze: OpenAIRE
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