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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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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. |
format | Online Article Text |
id | pubmed-10461966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
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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