Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.

Signaling pathways are interconnected to regulatory circuits for sensing the environment and expressing the appropriate genetic profile. In particular, gradients of diffusing molecules (morphogens) determine cell fate at a given position, dictating development and spatial organization. The feedforwa...

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Autores principales:	Guillermo Rodrigo, Santiago F Elena
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/effa54a08e20471c8cd1ec687e33f136
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spelling	oai:doaj.org-article:effa54a08e20471c8cd1ec687e33f1362021-11-18T06:58:50ZStructural discrimination of robustness in transcriptional feedforward loops for pattern formation.1932-620310.1371/journal.pone.0016904https://doaj.org/article/effa54a08e20471c8cd1ec687e33f1362011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21340024/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Signaling pathways are interconnected to regulatory circuits for sensing the environment and expressing the appropriate genetic profile. In particular, gradients of diffusing molecules (morphogens) determine cell fate at a given position, dictating development and spatial organization. The feedforward loop (FFL) circuit is among the simplest genetic architectures able to generate one-stripe patterns by operating as an amplitude detection device, where high output levels are achieved at intermediate input ones. Here, using a heuristic optimization-based approach, we dissected the design space containing all possible topologies and parameter values of the FFL circuits. We explored the ability of being sensitive or adaptive to variations in the critical morphogen level where cell fate is switched. We found four different solutions for precision, corresponding to the four incoherent architectures, but remarkably only one mode for adaptiveness, the incoherent type 4 (I4-FFL). We further carried out a theoretical study to unveil the design principle for such structural discrimination, finding that the synergistic action and cooperative binding on the downstream promoter are instrumental to achieve absolute adaptive responses. Subsequently, we analyzed the robustness of these optimal circuits against perturbations in the kinetic parameters and molecular noise, which has allowed us to depict a scenario where adaptiveness, parameter sensitivity and noise tolerance are different, correlated facets of the robustness of the I4-FFL circuit. Strikingly, we showed a strong correlation between the input (environment-related) and the intrinsic (mutation-related) susceptibilities. Finally, we discussed the evolution of incoherent regulations in terms of multifunctionality and robustness.Guillermo RodrigoSantiago F ElenaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e16904 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guillermo Rodrigo Santiago F Elena Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
description	Signaling pathways are interconnected to regulatory circuits for sensing the environment and expressing the appropriate genetic profile. In particular, gradients of diffusing molecules (morphogens) determine cell fate at a given position, dictating development and spatial organization. The feedforward loop (FFL) circuit is among the simplest genetic architectures able to generate one-stripe patterns by operating as an amplitude detection device, where high output levels are achieved at intermediate input ones. Here, using a heuristic optimization-based approach, we dissected the design space containing all possible topologies and parameter values of the FFL circuits. We explored the ability of being sensitive or adaptive to variations in the critical morphogen level where cell fate is switched. We found four different solutions for precision, corresponding to the four incoherent architectures, but remarkably only one mode for adaptiveness, the incoherent type 4 (I4-FFL). We further carried out a theoretical study to unveil the design principle for such structural discrimination, finding that the synergistic action and cooperative binding on the downstream promoter are instrumental to achieve absolute adaptive responses. Subsequently, we analyzed the robustness of these optimal circuits against perturbations in the kinetic parameters and molecular noise, which has allowed us to depict a scenario where adaptiveness, parameter sensitivity and noise tolerance are different, correlated facets of the robustness of the I4-FFL circuit. Strikingly, we showed a strong correlation between the input (environment-related) and the intrinsic (mutation-related) susceptibilities. Finally, we discussed the evolution of incoherent regulations in terms of multifunctionality and robustness.
format	article
author	Guillermo Rodrigo Santiago F Elena
author_facet	Guillermo Rodrigo Santiago F Elena
author_sort	Guillermo Rodrigo
title	Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
title_short	Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
title_full	Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
title_fullStr	Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
title_full_unstemmed	Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
title_sort	structural discrimination of robustness in transcriptional feedforward loops for pattern formation.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/effa54a08e20471c8cd1ec687e33f136
work_keys_str_mv	AT guillermorodrigo structuraldiscriminationofrobustnessintranscriptionalfeedforwardloopsforpatternformation AT santiagofelena structuraldiscriminationofrobustnessintranscriptionalfeedforwardloopsforpatternformation
_version_	1718424142405959680

Structural discrimination of robustness in transcriptional feedforward loops for pattern formation.

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