Epigenetic cell memory: The gene’s inner chromatin modification circuit
<jats:p>Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chrom...
| Main Authors: | , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022
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| Online Access: | https://hdl.handle.net/1721.1/142624 |
| _version_ | 1826216447545704448 |
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| author | Bruno, Simone Williams, Ruth J Del Vecchio, Domitilla |
| author2 | Massachusetts Institute of Technology. Department of Mechanical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Mechanical Engineering Bruno, Simone Williams, Ruth J Del Vecchio, Domitilla |
| author_sort | Bruno, Simone |
| collection | MIT |
| description | <jats:p>Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit’s constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.</jats:p> |
| first_indexed | 2024-09-23T16:47:50Z |
| format | Article |
| id | mit-1721.1/142624 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:47:50Z |
| publishDate | 2022 |
| publisher | Public Library of Science (PLoS) |
| record_format | dspace |
| spelling | mit-1721.1/1426242023-01-10T16:20:29Z Epigenetic cell memory: The gene’s inner chromatin modification circuit Bruno, Simone Williams, Ruth J Del Vecchio, Domitilla Massachusetts Institute of Technology. Department of Mechanical Engineering <jats:p>Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit’s constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.</jats:p> 2022-05-20T12:18:16Z 2022-05-20T12:18:16Z 2022-04 2022-05-20T11:57:13Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/142624 Bruno, Simone, Williams, Ruth J and Del Vecchio, Domitilla. 2022. "Epigenetic cell memory: The gene’s inner chromatin modification circuit." PLOS Computational Biology, 18 (4). en 10.1371/journal.pcbi.1009961 PLOS Computational Biology Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0 application/pdf Public Library of Science (PLoS) PLoS |
| spellingShingle | Bruno, Simone Williams, Ruth J Del Vecchio, Domitilla Epigenetic cell memory: The gene’s inner chromatin modification circuit |
| title | Epigenetic cell memory: The gene’s inner chromatin modification circuit |
| title_full | Epigenetic cell memory: The gene’s inner chromatin modification circuit |
| title_fullStr | Epigenetic cell memory: The gene’s inner chromatin modification circuit |
| title_full_unstemmed | Epigenetic cell memory: The gene’s inner chromatin modification circuit |
| title_short | Epigenetic cell memory: The gene’s inner chromatin modification circuit |
| title_sort | epigenetic cell memory the gene s inner chromatin modification circuit |
| url | https://hdl.handle.net/1721.1/142624 |
| work_keys_str_mv | AT brunosimone epigeneticcellmemorythegenesinnerchromatinmodificationcircuit AT williamsruthj epigeneticcellmemorythegenesinnerchromatinmodificationcircuit AT delvecchiodomitilla epigeneticcellmemorythegenesinnerchromatinmodificationcircuit |