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Input integration by the circadian clock exhibits nonadditivity and fold-change detection

Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex t...

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Autores principales: Manella, Gal, Bolshette, Nityanand, Golik, Marina, Asher, Gad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636907/
https://www.ncbi.nlm.nih.gov/pubmed/36279450
http://dx.doi.org/10.1073/pnas.2209933119
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author Manella, Gal
Bolshette, Nityanand
Golik, Marina
Asher, Gad
author_facet Manella, Gal
Bolshette, Nityanand
Golik, Marina
Asher, Gad
author_sort Manella, Gal
collection PubMed
description Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex temporal dynamics, raising the question of how clocks integrate information in response to multiple signals. To investigate different modes of signal integration by the circadian clock, we used Circa-SCOPE, a method we recently developed for high-throughput phase resetting analysis. We found that simultaneous exposure to different combinations of known pharmacological resetting agents elicits a diverse range of responses. Often, the response was nonadditive and could not be readily predicted by the response to the individual signals. For instance, we observed that dexamethasone is dominant over other tested inputs. In the case of signals administered sequentially, the background levels of a signal attenuated subsequent resetting by the same signal, but not by signals acting through a different pathway. This led us to examine whether the circadian clock is sensitive to relative rather than absolute levels of the signal. Importantly, our analysis revealed the involvement of a signal-specific fold-change detection mechanism in the clock response. This mechanism likely stems from properties of the signaling pathway that are upstream to the clock. Overall, our findings elucidate modes of input integration by the circadian clock, with potential relevance to clock resetting under both physiological and pathological conditions.
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spelling pubmed-96369072023-04-24 Input integration by the circadian clock exhibits nonadditivity and fold-change detection Manella, Gal Bolshette, Nityanand Golik, Marina Asher, Gad Proc Natl Acad Sci U S A Biological Sciences Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex temporal dynamics, raising the question of how clocks integrate information in response to multiple signals. To investigate different modes of signal integration by the circadian clock, we used Circa-SCOPE, a method we recently developed for high-throughput phase resetting analysis. We found that simultaneous exposure to different combinations of known pharmacological resetting agents elicits a diverse range of responses. Often, the response was nonadditive and could not be readily predicted by the response to the individual signals. For instance, we observed that dexamethasone is dominant over other tested inputs. In the case of signals administered sequentially, the background levels of a signal attenuated subsequent resetting by the same signal, but not by signals acting through a different pathway. This led us to examine whether the circadian clock is sensitive to relative rather than absolute levels of the signal. Importantly, our analysis revealed the involvement of a signal-specific fold-change detection mechanism in the clock response. This mechanism likely stems from properties of the signaling pathway that are upstream to the clock. Overall, our findings elucidate modes of input integration by the circadian clock, with potential relevance to clock resetting under both physiological and pathological conditions. National Academy of Sciences 2022-10-24 2022-11-01 /pmc/articles/PMC9636907/ /pubmed/36279450 http://dx.doi.org/10.1073/pnas.2209933119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Manella, Gal
Bolshette, Nityanand
Golik, Marina
Asher, Gad
Input integration by the circadian clock exhibits nonadditivity and fold-change detection
title Input integration by the circadian clock exhibits nonadditivity and fold-change detection
title_full Input integration by the circadian clock exhibits nonadditivity and fold-change detection
title_fullStr Input integration by the circadian clock exhibits nonadditivity and fold-change detection
title_full_unstemmed Input integration by the circadian clock exhibits nonadditivity and fold-change detection
title_short Input integration by the circadian clock exhibits nonadditivity and fold-change detection
title_sort input integration by the circadian clock exhibits nonadditivity and fold-change detection
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636907/
https://www.ncbi.nlm.nih.gov/pubmed/36279450
http://dx.doi.org/10.1073/pnas.2209933119
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