Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Harlapur, Pradyumna, Duddu, Atchuta Srinivas, Hari, Kishore, Kulkarni, Prakash, Jolly, Mohit Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784855748732256256
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
work_keys_str_mv AT harlapurpradyumna functionalresilienceofmutuallyrepressingmotifsembeddedinlargernetworks
AT dudduatchutasrinivas functionalresilienceofmutuallyrepressingmotifsembeddedinlargernetworks
AT harikishore functionalresilienceofmutuallyrepressingmotifsembeddedinlargernetworks
AT kulkarniprakash functionalresilienceofmutuallyrepressingmotifsembeddedinlargernetworks
AT jollymohitkumar functionalresilienceofmutuallyrepressingmotifsembeddedinlargernetworks