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Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability

Compact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. Here, we propose a broader view: chromatin compaction can be both a cause and a consequen...

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Autores principales: Miangolarra, Ander Movilla, Saxton, Daniel S, Yan, Zhi, Rine, Jasper, Howard, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461966/
https://www.ncbi.nlm.nih.gov/pubmed/37645983
http://dx.doi.org/10.1101/2023.08.12.552948
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author Miangolarra, Ander Movilla
Saxton, Daniel S
Yan, Zhi
Rine, Jasper
Howard, Martin
author_facet Miangolarra, Ander Movilla
Saxton, Daniel S
Yan, Zhi
Rine, Jasper
Howard, Martin
author_sort Miangolarra, Ander Movilla
collection PubMed
description Compact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. Here, we propose a broader view: chromatin compaction can be both a cause and a consequence of the histone modification state, and this tight bidirectional interaction can underpin bistable transcriptional states. To test this theory, we developed a mathematical model for the dynamics of the HMR locus in S. cerevisiae, that incorporates activating histone modifications, silencing proteins and a dynamic, acetylation-dependent, three-dimensional locus size. Chromatin compaction enhances silencer protein binding, which in turn feeds back to remove activating histone modifications, leading to further compaction. The bistable output of the model was in good agreement with prior quantitative data, including switching rates from expressed to silent states, and vice versa, and protein binding levels within the locus. We then tested the model by predicting changes in switching rates as the genetic length of the locus was increased, which were then experimentally verified. This bidirectional feedback between chromatin compaction and the histone modification state may be an important regulatory mechanism at many loci.
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spelling pubmed-104619662023-08-29 Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability Miangolarra, Ander Movilla Saxton, Daniel S Yan, Zhi Rine, Jasper Howard, Martin bioRxiv Article Compact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. Here, we propose a broader view: chromatin compaction can be both a cause and a consequence of the histone modification state, and this tight bidirectional interaction can underpin bistable transcriptional states. To test this theory, we developed a mathematical model for the dynamics of the HMR locus in S. cerevisiae, that incorporates activating histone modifications, silencing proteins and a dynamic, acetylation-dependent, three-dimensional locus size. Chromatin compaction enhances silencer protein binding, which in turn feeds back to remove activating histone modifications, leading to further compaction. The bistable output of the model was in good agreement with prior quantitative data, including switching rates from expressed to silent states, and vice versa, and protein binding levels within the locus. We then tested the model by predicting changes in switching rates as the genetic length of the locus was increased, which were then experimentally verified. This bidirectional feedback between chromatin compaction and the histone modification state may be an important regulatory mechanism at many loci. Cold Spring Harbor Laboratory 2023-08-14 /pmc/articles/PMC10461966/ /pubmed/37645983 http://dx.doi.org/10.1101/2023.08.12.552948 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Miangolarra, Ander Movilla
Saxton, Daniel S
Yan, Zhi
Rine, Jasper
Howard, Martin
Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability
title Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability
title_full Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability
title_fullStr Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability
title_full_unstemmed Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability
title_short Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability
title_sort two-way feedback between chromatin compaction and histone modification state explains s. cerevisiae heterochromatin bistability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461966/
https://www.ncbi.nlm.nih.gov/pubmed/37645983
http://dx.doi.org/10.1101/2023.08.12.552948
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