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Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks
Elucidating the design principles of regulatory networks driving cellular decision-making has important implications for understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell fates can exhibit multistab...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9775907/ https://www.ncbi.nlm.nih.gov/pubmed/36551270 http://dx.doi.org/10.3390/biom12121842 |
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author | Harlapur, Pradyumna Duddu, Atchuta Srinivas Hari, Kishore Kulkarni, Prakash Jolly, Mohit Kumar |
author_facet | Harlapur, Pradyumna Duddu, Atchuta Srinivas Hari, Kishore Kulkarni, Prakash Jolly, Mohit Kumar |
author_sort | Harlapur, Pradyumna |
collection | PubMed |
description | Elucidating the design principles of regulatory networks driving cellular decision-making has important implications for understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell fates can exhibit multistable dynamics enabling “single-positive” phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two motifs have been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these motifs in complex larger networks of varying sizes and connectivity to identify hallmarks under which these motifs maintain their canonical dynamical behavior. We show that an increased number of incoming edges onto a motif leads to a decay in their canonical stand-alone behaviors. We also show that this decay can be exacerbated by adding self-inhibition but not self-activation loops on the ‘master regulators’. These observations offer insights into the design principles of biological networks containing these motifs and can help devise optimal strategies for the integration of these motifs into larger synthetic networks. |
format | Online Article Text |
id | pubmed-9775907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97759072022-12-23 Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks Harlapur, Pradyumna Duddu, Atchuta Srinivas Hari, Kishore Kulkarni, Prakash Jolly, Mohit Kumar Biomolecules Article Elucidating the design principles of regulatory networks driving cellular decision-making has important implications for understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell fates can exhibit multistable dynamics enabling “single-positive” phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two motifs have been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these motifs in complex larger networks of varying sizes and connectivity to identify hallmarks under which these motifs maintain their canonical dynamical behavior. We show that an increased number of incoming edges onto a motif leads to a decay in their canonical stand-alone behaviors. We also show that this decay can be exacerbated by adding self-inhibition but not self-activation loops on the ‘master regulators’. These observations offer insights into the design principles of biological networks containing these motifs and can help devise optimal strategies for the integration of these motifs into larger synthetic networks. MDPI 2022-12-09 /pmc/articles/PMC9775907/ /pubmed/36551270 http://dx.doi.org/10.3390/biom12121842 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Harlapur, Pradyumna Duddu, Atchuta Srinivas Hari, Kishore Kulkarni, Prakash Jolly, Mohit Kumar Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks |
title | Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks |
title_full | Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks |
title_fullStr | Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks |
title_full_unstemmed | Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks |
title_short | Functional Resilience of Mutually Repressing Motifs Embedded in Larger Networks |
title_sort | functional resilience of mutually repressing motifs embedded in larger networks |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9775907/ https://www.ncbi.nlm.nih.gov/pubmed/36551270 http://dx.doi.org/10.3390/biom12121842 |
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