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Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock
The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used quantitative imaging to track dynamic changes in end...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983044/ https://www.ncbi.nlm.nih.gov/pubmed/35285799 http://dx.doi.org/10.7554/eLife.73976 |
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author | Koch, Alex A Bagnall, James S Smyllie, Nicola J Begley, Nicola Adamson, Antony D Fribourgh, Jennifer L Spiller, David G Meng, Qing-Jun Partch, Carrie L Strimmer, Korbinian House, Thomas A Hastings, Michael H Loudon, Andrew SI |
author_facet | Koch, Alex A Bagnall, James S Smyllie, Nicola J Begley, Nicola Adamson, Antony D Fribourgh, Jennifer L Spiller, David G Meng, Qing-Jun Partch, Carrie L Strimmer, Korbinian House, Thomas A Hastings, Michael H Loudon, Andrew SI |
author_sort | Koch, Alex A |
collection | PubMed |
description | The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used quantitative imaging to track dynamic changes in endogenous labelled proteins across peripheral tissues and the SCN. We determine the contribution of multiple rhythmic processes coordinating BMAL1 DNA binding, including cycling molecular abundance, binding affinities, and repression. We find nuclear BMAL1 concentration determines corresponding CLOCK through heterodimerisation and define a DNA residence time of this complex. Repression of CLOCK:BMAL1 is achieved through rhythmic changes to BMAL1:CRY1 association and high-affinity interactions between PER2:CRY1 which mediates CLOCK:BMAL1 displacement from DNA. Finally, stochastic modelling reveals a dual role for PER:CRY complexes in which increasing concentrations of PER2:CRY1 promotes removal of BMAL1:CLOCK from genes consequently enhancing ability to move to new target sites. |
format | Online Article Text |
id | pubmed-8983044 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-89830442022-04-06 Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock Koch, Alex A Bagnall, James S Smyllie, Nicola J Begley, Nicola Adamson, Antony D Fribourgh, Jennifer L Spiller, David G Meng, Qing-Jun Partch, Carrie L Strimmer, Korbinian House, Thomas A Hastings, Michael H Loudon, Andrew SI eLife Cell Biology The mammalian circadian clock exerts control of daily gene expression through cycles of DNA binding. Here, we develop a quantitative model of how a finite pool of BMAL1 protein can regulate thousands of target sites over daily time scales. We used quantitative imaging to track dynamic changes in endogenous labelled proteins across peripheral tissues and the SCN. We determine the contribution of multiple rhythmic processes coordinating BMAL1 DNA binding, including cycling molecular abundance, binding affinities, and repression. We find nuclear BMAL1 concentration determines corresponding CLOCK through heterodimerisation and define a DNA residence time of this complex. Repression of CLOCK:BMAL1 is achieved through rhythmic changes to BMAL1:CRY1 association and high-affinity interactions between PER2:CRY1 which mediates CLOCK:BMAL1 displacement from DNA. Finally, stochastic modelling reveals a dual role for PER:CRY complexes in which increasing concentrations of PER2:CRY1 promotes removal of BMAL1:CLOCK from genes consequently enhancing ability to move to new target sites. eLife Sciences Publications, Ltd 2022-03-14 /pmc/articles/PMC8983044/ /pubmed/35285799 http://dx.doi.org/10.7554/eLife.73976 Text en © 2022, Koch et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Koch, Alex A Bagnall, James S Smyllie, Nicola J Begley, Nicola Adamson, Antony D Fribourgh, Jennifer L Spiller, David G Meng, Qing-Jun Partch, Carrie L Strimmer, Korbinian House, Thomas A Hastings, Michael H Loudon, Andrew SI Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
title | Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
title_full | Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
title_fullStr | Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
title_full_unstemmed | Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
title_short | Quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
title_sort | quantification of protein abundance and interaction defines a mechanism for operation of the circadian clock |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8983044/ https://www.ncbi.nlm.nih.gov/pubmed/35285799 http://dx.doi.org/10.7554/eLife.73976 |
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