Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms.
Epigenetic regulatory mechanisms allow multicellular organisms to develop distinct specialized cell identities despite having the same total genome. Cell-fate choices are based on gene expression programs and environmental cues that cells experience during embryonic development, and are usually main...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-02-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1010889 |
| _version_ | 1811155462703284224 |
|---|---|
| author | Maryl Lambros Yehonatan Sella Aviv Bergman |
| author_facet | Maryl Lambros Yehonatan Sella Aviv Bergman |
| author_sort | Maryl Lambros |
| collection | DOAJ |
| description | Epigenetic regulatory mechanisms allow multicellular organisms to develop distinct specialized cell identities despite having the same total genome. Cell-fate choices are based on gene expression programs and environmental cues that cells experience during embryonic development, and are usually maintained throughout the life of the organism despite new environmental cues. The evolutionarily conserved Polycomb group (PcG) proteins form Polycomb Repressive Complexes that help orchestrate these developmental choices. Post-development, these complexes actively maintain the resulting cell fate, even in the face of environmental perturbations. Given the crucial role of these polycomb mechanisms in providing phenotypic fidelity (i.e. maintenance of cell fate), we hypothesize that their dysregulation after development will lead to decreased phenotypic fidelity allowing dysregulated cells to sustainably switch their phenotype in response to environmental changes. We call this abnormal phenotypic switching phenotypic pliancy. We introduce a general computational evolutionary model that allows us to test our systems-level phenotypic pliancy hypothesis in-silico and in a context-independent manner. We find that 1) phenotypic fidelity is an emergent systems-level property of PcG-like mechanism evolution, and 2) phenotypic pliancy is an emergent systems-level property resulting from this mechanism's dysregulation. Since there is evidence that metastatic cells behave in a phenotypically pliant manner, we hypothesize that progression to metastasis is driven by the emergence of phenotypic pliancy in cancer cells as a result of PcG mechanism dysregulation. We corroborate our hypothesis using single-cell RNA-sequencing data from metastatic cancers. We find that metastatic cancer cells are phenotypically pliant in the same manner as predicted by our model. |
| first_indexed | 2024-04-10T04:34:20Z |
| format | Article |
| id | doaj.art-f7c8a5b5efa2440b9269a3baa10a0ef4 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-10T04:34:20Z |
| publishDate | 2023-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-f7c8a5b5efa2440b9269a3baa10a0ef42023-03-10T05:31:32ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582023-02-01192e101088910.1371/journal.pcbi.1010889Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms.Maryl LambrosYehonatan SellaAviv BergmanEpigenetic regulatory mechanisms allow multicellular organisms to develop distinct specialized cell identities despite having the same total genome. Cell-fate choices are based on gene expression programs and environmental cues that cells experience during embryonic development, and are usually maintained throughout the life of the organism despite new environmental cues. The evolutionarily conserved Polycomb group (PcG) proteins form Polycomb Repressive Complexes that help orchestrate these developmental choices. Post-development, these complexes actively maintain the resulting cell fate, even in the face of environmental perturbations. Given the crucial role of these polycomb mechanisms in providing phenotypic fidelity (i.e. maintenance of cell fate), we hypothesize that their dysregulation after development will lead to decreased phenotypic fidelity allowing dysregulated cells to sustainably switch their phenotype in response to environmental changes. We call this abnormal phenotypic switching phenotypic pliancy. We introduce a general computational evolutionary model that allows us to test our systems-level phenotypic pliancy hypothesis in-silico and in a context-independent manner. We find that 1) phenotypic fidelity is an emergent systems-level property of PcG-like mechanism evolution, and 2) phenotypic pliancy is an emergent systems-level property resulting from this mechanism's dysregulation. Since there is evidence that metastatic cells behave in a phenotypically pliant manner, we hypothesize that progression to metastasis is driven by the emergence of phenotypic pliancy in cancer cells as a result of PcG mechanism dysregulation. We corroborate our hypothesis using single-cell RNA-sequencing data from metastatic cancers. We find that metastatic cancer cells are phenotypically pliant in the same manner as predicted by our model.https://doi.org/10.1371/journal.pcbi.1010889 |
| spellingShingle | Maryl Lambros Yehonatan Sella Aviv Bergman Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms. PLoS Computational Biology |
| title | Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms. |
| title_full | Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms. |
| title_fullStr | Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms. |
| title_full_unstemmed | Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms. |
| title_short | Phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms. |
| title_sort | phenotypic pliancy and the breakdown of epigenetic polycomb mechanisms |
| url | https://doi.org/10.1371/journal.pcbi.1010889 |
| work_keys_str_mv | AT maryllambros phenotypicpliancyandthebreakdownofepigeneticpolycombmechanisms AT yehonatansella phenotypicpliancyandthebreakdownofepigeneticpolycombmechanisms AT avivbergman phenotypicpliancyandthebreakdownofepigeneticpolycombmechanisms |