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 (2023). A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2. Nature Communications, 14(1), pp. 1-20. Springer Nature 10.1038/s41467-023-39443-z
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Osterwalder, Marco |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2041-1723 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
10 Jul 2023 14:12 |
Last Modified: |
10 Jul 2023 14:21 |
Publisher DOI: |
10.1038/s41467-023-39443-z |
PubMed ID: |
37414772 |
BORIS DOI: |
10.48350/184570 |
URI: |
https://boris.unibe.ch/id/eprint/184570 |
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