An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology

Diana Fernandes de Abreu; Antonio Caballero Reyes; Pascal Fardel; Nicholas Stroustrup; Zhunan Chen; KyungHwa Lee; William D Keyes; Zachary M Nash; Isaac F López-Moyado; Federico Vaggi; Astrid Cornils; Martin Regenass; Anca Neagu; Ivan Ostojic; Maureen Liu; Yongmin Cho; Deniz Sifoglu; Yu Shen; Walter Fontana; Hang Lu; Attila Csikasz-Nagy; Coleen T Murphy; Adam Antebi; Eric Blanc; Javier Apfeld; Yun Zhang; Joy Alcedo; QueeLim Ch'ng

doi:10.1371/journal.pgen.1004225

An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology

Diana Fernandes de Abreu, Antonio Caballero Reyes, Pascal Fardel, Nicholas Stroustrup, Zhunan Chen, KyungHwa Lee, William D Keyes, Zachary M Nash, Isaac F López-Moyado, Federico Vaggi, Astrid Cornils, Martin Regenass, Anca Neagu, Ivan Ostojic, Maureen Liu, Yongmin Cho, Deniz Sifoglu, Yu Shen, Walter Fontana, Hang LuAttila Csikasz-Nagy, Coleen T Murphy, Adam Antebi, Eric Blanc, Javier Apfeld, Yun Zhang, Joy Alcedo, QueeLim Ch'ng

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Abstract

Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

Original language	English
Article number	e1004225
Number of pages	15
Journal	PL o S Genetics
Volume	10
Issue number	3
Early online date	27 Mar 2014
DOIs	https://doi.org/10.1371/journal.pgen.1004225
Publication status	Published - Mar 2014

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10.1371/journal.pgen.1004225Licence: CC BY

An Insulin-to-Insulin_FERNANDEZ DE ABREU_Acc22Jan2014Epub24Mar2014_GOLD VoR(CC BY)Final published version, 1.36 MBLicence: CC BY

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Fernandes de Abreu, D., Caballero Reyes, A., Fardel, P., Stroustrup, N., Chen, Z., Lee, K., Keyes, W. D., Nash, Z. M., López-Moyado, I. F., Vaggi, F., Cornils, A., Regenass, M., Neagu, A., Ostojic, I., Liu, M., Cho, Y., Sifoglu, D., Shen, Y., Fontana, W., ... Ch'ng, Q. (2014). An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PL o S Genetics, 10(3), Article e1004225. https://doi.org/10.1371/journal.pgen.1004225

@article{57fa7cd0783c4b7abf13ddce9e76f96c,

title = "An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology",

abstract = "Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.",

author = "{Fernandes de Abreu}, Diana and {Caballero Reyes}, Antonio and Pascal Fardel and Nicholas Stroustrup and Zhunan Chen and KyungHwa Lee and Keyes, {William D} and Nash, {Zachary M} and L{\'o}pez-Moyado, {Isaac F} and Federico Vaggi and Astrid Cornils and Martin Regenass and Anca Neagu and Ivan Ostojic and Maureen Liu and Yongmin Cho and Deniz Sifoglu and Yu Shen and Walter Fontana and Hang Lu and Attila Csikasz-Nagy and Murphy, {Coleen T} and Adam Antebi and Eric Blanc and Javier Apfeld and Yun Zhang and Joy Alcedo and QueeLim Ch'ng",

year = "2014",

month = mar,

doi = "10.1371/journal.pgen.1004225",

language = "English",

volume = "10",

journal = "PL o S Genetics",

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Fernandes de Abreu, D, Caballero Reyes, A, Fardel, P, Stroustrup, N, Chen, Z, Lee, K, Keyes, WD, Nash, ZM, López-Moyado, IF, Vaggi, F, Cornils, A, Regenass, M, Neagu, A, Ostojic, I, Liu, M, Cho, Y, Sifoglu, D, Shen, Y, Fontana, W, Lu, H, Csikasz-Nagy, A, Murphy, CT, Antebi, A, Blanc, E, Apfeld, J, Zhang, Y, Alcedo, J & Ch'ng, Q 2014, 'An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology', PL o S Genetics, vol. 10, no. 3, e1004225. https://doi.org/10.1371/journal.pgen.1004225

TY - JOUR

T1 - An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology

AU - Fernandes de Abreu, Diana

AU - Caballero Reyes, Antonio

AU - Fardel, Pascal

AU - Stroustrup, Nicholas

AU - Chen, Zhunan

AU - Lee, KyungHwa

AU - Keyes, William D

AU - Nash, Zachary M

AU - López-Moyado, Isaac F

AU - Vaggi, Federico

AU - Cornils, Astrid

AU - Regenass, Martin

AU - Neagu, Anca

AU - Ostojic, Ivan

AU - Liu, Maureen

AU - Cho, Yongmin

AU - Sifoglu, Deniz

AU - Shen, Yu

AU - Fontana, Walter

AU - Lu, Hang

AU - Csikasz-Nagy, Attila

AU - Murphy, Coleen T

AU - Antebi, Adam

AU - Blanc, Eric

AU - Apfeld, Javier

AU - Zhang, Yun

AU - Alcedo, Joy

AU - Ch'ng, QueeLim

PY - 2014/3

Y1 - 2014/3

N2 - Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

AB - Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

U2 - 10.1371/journal.pgen.1004225

DO - 10.1371/journal.pgen.1004225

M3 - Article

SN - 1553-7390

VL - 10

JO - PL o S Genetics

JF - PL o S Genetics

IS - 3

M1 - e1004225

ER -

An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology

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