A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2
© 2023. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 06. Juli, Seite 3993 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Losa, Marta [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.07.2023 Date Revised 18.11.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-39443-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35915882X |
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| 100 | 1 | |a Losa, Marta |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 |
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| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a Pre-B-Cell Leukemia Transcription Factor 1 |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 650 | 7 | |a Pbx1 protein, mouse |2 NLM | |
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| 700 | 1 | |a Barozzi, Iros |e verfasserin |4 aut | |
| 700 | 1 | |a Osterwalder, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Hermosilla-Aguayo, Viviana |e verfasserin |4 aut | |
| 700 | 1 | |a Morabito, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Chacón, Brandon H |e verfasserin |4 aut | |
| 700 | 1 | |a Zarrineh, Peyman |e verfasserin |4 aut | |
| 700 | 1 | |a Girdziusaite, Ausra |e verfasserin |4 aut | |
| 700 | 1 | |a Benazet, Jean Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Jianjian |e verfasserin |4 aut | |
| 700 | 1 | |a Mackem, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Capellini, Terence D |e verfasserin |4 aut | |
| 700 | 1 | |a Dickel, Diane |e verfasserin |4 aut | |
| 700 | 1 | |a Bobola, Nicoletta |e verfasserin |4 aut | |
| 700 | 1 | |a Zuniga, Aimée |e verfasserin |4 aut | |
| 700 | 1 | |a Visel, Axel |e verfasserin |4 aut | |
| 700 | 1 | |a Zeller, Rolf |e verfasserin |4 aut | |
| 700 | 1 | |a Selleri, Licia |e verfasserin |4 aut | |
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