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A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2

A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed p...

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Autores principales: Losa, Marta, Barozzi, Iros, Osterwalder, Marco, Hermosilla-Aguayo, Viviana, Morabito, Angela, Chacón, Brandon H., Zarrineh, Peyman, Girdziusaite, Ausra, Benazet, Jean Denis, Zhu, Jianjian, Mackem, Susan, Capellini, Terence D., Dickel, Diane, Bobola, Nicoletta, Zuniga, Aimée, Visel, Axel, Zeller, Rolf, Selleri, Licia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10325989/
https://www.ncbi.nlm.nih.gov/pubmed/37414772
http://dx.doi.org/10.1038/s41467-023-39443-z
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author Losa, Marta
Barozzi, Iros
Osterwalder, Marco
Hermosilla-Aguayo, Viviana
Morabito, Angela
Chacón, Brandon H.
Zarrineh, Peyman
Girdziusaite, Ausra
Benazet, Jean Denis
Zhu, Jianjian
Mackem, Susan
Capellini, Terence D.
Dickel, Diane
Bobola, Nicoletta
Zuniga, Aimée
Visel, Axel
Zeller, Rolf
Selleri, Licia
author_facet Losa, Marta
Barozzi, Iros
Osterwalder, Marco
Hermosilla-Aguayo, Viviana
Morabito, Angela
Chacón, Brandon H.
Zarrineh, Peyman
Girdziusaite, Ausra
Benazet, Jean Denis
Zhu, Jianjian
Mackem, Susan
Capellini, Terence D.
Dickel, Diane
Bobola, Nicoletta
Zuniga, Aimée
Visel, Axel
Zeller, Rolf
Selleri, Licia
author_sort Losa, Marta
collection PubMed
description A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs.
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spelling pubmed-103259892023-07-08 A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 Losa, Marta Barozzi, Iros Osterwalder, Marco Hermosilla-Aguayo, Viviana Morabito, Angela Chacón, Brandon H. Zarrineh, Peyman Girdziusaite, Ausra Benazet, Jean Denis Zhu, Jianjian Mackem, Susan Capellini, Terence D. Dickel, Diane Bobola, Nicoletta Zuniga, Aimée Visel, Axel Zeller, Rolf Selleri, Licia Nat Commun Article A lingering question in developmental biology has centered on how transcription factors with widespread distribution in vertebrate embryos can perform tissue-specific functions. Here, using the murine hindlimb as a model, we investigate the elusive mechanisms whereby PBX TALE homeoproteins, viewed primarily as HOX cofactors, attain context-specific developmental roles despite ubiquitous presence in the embryo. We first demonstrate that mesenchymal-specific loss of PBX1/2 or the transcriptional regulator HAND2 generates similar limb phenotypes. By combining tissue-specific and temporally controlled mutagenesis with multi-omics approaches, we reconstruct a gene regulatory network (GRN) at organismal-level resolution that is collaboratively directed by PBX1/2 and HAND2 interactions in subsets of posterior hindlimb mesenchymal cells. Genome-wide profiling of PBX1 binding across multiple embryonic tissues further reveals that HAND2 interacts with subsets of PBX-bound regions to regulate limb-specific GRNs. Our research elucidates fundamental principles by which promiscuous transcription factors cooperate with cofactors that display domain-restricted localization to instruct tissue-specific developmental programs. Nature Publishing Group UK 2023-07-06 /pmc/articles/PMC10325989/ /pubmed/37414772 http://dx.doi.org/10.1038/s41467-023-39443-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Losa, Marta
Barozzi, Iros
Osterwalder, Marco
Hermosilla-Aguayo, Viviana
Morabito, Angela
Chacón, Brandon H.
Zarrineh, Peyman
Girdziusaite, Ausra
Benazet, Jean Denis
Zhu, Jianjian
Mackem, Susan
Capellini, Terence D.
Dickel, Diane
Bobola, Nicoletta
Zuniga, Aimée
Visel, Axel
Zeller, Rolf
Selleri, Licia
A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
title A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
title_full A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
title_fullStr A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
title_full_unstemmed A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
title_short A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
title_sort spatio-temporally constrained gene regulatory network directed by pbx1/2 acquires limb patterning specificity via hand2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10325989/
https://www.ncbi.nlm.nih.gov/pubmed/37414772
http://dx.doi.org/10.1038/s41467-023-39443-z
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