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Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations
The transfer of regulatory information between distal loci on chromatin is thought to involve physical proximity, but key biophysical features of these contacts remain unclear. For instance, it is unknown how close and for how long two loci need to be in order to productively interact. The main chal...
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/PMC10659377/ https://www.ncbi.nlm.nih.gov/pubmed/37986912 http://dx.doi.org/10.1101/2023.11.07.566032 |
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author | Fu, Yi Clark, Finnegan Nomikou, Sofia Tsirigos, Aristotelis Lionnet, Timothee |
author_facet | Fu, Yi Clark, Finnegan Nomikou, Sofia Tsirigos, Aristotelis Lionnet, Timothee |
author_sort | Fu, Yi |
collection | PubMed |
description | The transfer of regulatory information between distal loci on chromatin is thought to involve physical proximity, but key biophysical features of these contacts remain unclear. For instance, it is unknown how close and for how long two loci need to be in order to productively interact. The main challenge is that it is currently impossible to measure chromatin dynamics with high spatiotemporal resolution at scale. Polymer simulations provide an accessible and rigorous way to test biophysical models of chromatin regulation, yet there is a lack of simple and general methods for extracting the values of model parameters. Here we adapt the Nelder-Mead simplex optimization algorithm to select the best polymer model matching a given Hi-C dataset, using the MYC locus as an example. The model’s biophysical parameters predict a compartmental rearrangement of the MYC locus in leukemia, which we validate with single-cell measurements. Leveraging trajectories predicted by the model, we find that loci with similar Hi-C contact frequencies can exhibit widely different contact dynamics. Interestingly, the frequency of productive interactions between loci exhibits a non-linear relationship with their Hi-C contact frequency when we enforce a specific capture radius and contact duration. These observations are consistent with recent experimental observations and suggest that the dynamic ensemble of chromatin configurations, rather than average contact matrices, is required to fully predict long-range chromatin interactions. |
format | Online Article Text |
id | pubmed-10659377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-106593772023-11-20 Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations Fu, Yi Clark, Finnegan Nomikou, Sofia Tsirigos, Aristotelis Lionnet, Timothee bioRxiv Article The transfer of regulatory information between distal loci on chromatin is thought to involve physical proximity, but key biophysical features of these contacts remain unclear. For instance, it is unknown how close and for how long two loci need to be in order to productively interact. The main challenge is that it is currently impossible to measure chromatin dynamics with high spatiotemporal resolution at scale. Polymer simulations provide an accessible and rigorous way to test biophysical models of chromatin regulation, yet there is a lack of simple and general methods for extracting the values of model parameters. Here we adapt the Nelder-Mead simplex optimization algorithm to select the best polymer model matching a given Hi-C dataset, using the MYC locus as an example. The model’s biophysical parameters predict a compartmental rearrangement of the MYC locus in leukemia, which we validate with single-cell measurements. Leveraging trajectories predicted by the model, we find that loci with similar Hi-C contact frequencies can exhibit widely different contact dynamics. Interestingly, the frequency of productive interactions between loci exhibits a non-linear relationship with their Hi-C contact frequency when we enforce a specific capture radius and contact duration. These observations are consistent with recent experimental observations and suggest that the dynamic ensemble of chromatin configurations, rather than average contact matrices, is required to fully predict long-range chromatin interactions. Cold Spring Harbor Laboratory 2023-11-10 /pmc/articles/PMC10659377/ /pubmed/37986912 http://dx.doi.org/10.1101/2023.11.07.566032 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Fu, Yi Clark, Finnegan Nomikou, Sofia Tsirigos, Aristotelis Lionnet, Timothee Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations |
title | Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations |
title_full | Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations |
title_fullStr | Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations |
title_full_unstemmed | Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations |
title_short | Connecting Chromatin Structures to Gene Regulation Using Dynamic Polymer Simulations |
title_sort | connecting chromatin structures to gene regulation using dynamic polymer simulations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659377/ https://www.ncbi.nlm.nih.gov/pubmed/37986912 http://dx.doi.org/10.1101/2023.11.07.566032 |
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