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

Marta Losa, Iros Barozzi, Marco Osterwalder, Viviana Hermosilla-Aguayo, Angela Morabito, Brandon H. Chacón, Peyman Zarrineh, Ausra Girdziusaite, Jean Denis Benazet, Jianjian Zhu, Susan Mackem, Terence D. Capellini, Diane Dickel, Nicoletta Bobola, Aimée Zuniga, Axel Visel, Rolf Zeller and Licia Selleri ()
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Marta Losa: University of California San Francisco
Iros Barozzi: Medical University of Vienna
Marco Osterwalder: Lawrence Berkeley National Laboratory
Viviana Hermosilla-Aguayo: University of California San Francisco
Angela Morabito: University of Basel
Brandon H. Chacón: University of California San Francisco
Peyman Zarrineh: University of Manchester
Ausra Girdziusaite: University of Basel
Jean Denis Benazet: University of California San Francisco
Jianjian Zhu: National Cancer Institute
Susan Mackem: National Cancer Institute
Terence D. Capellini: Harvard University
Diane Dickel: Lawrence Berkeley National Laboratory
Nicoletta Bobola: University of Manchester
Aimée Zuniga: University of Basel
Axel Visel: Lawrence Berkeley National Laboratory
Rolf Zeller: University of Basel
Licia Selleri: University of California San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39443-z

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