1. A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2.
- Author
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Losa M, Barozzi I, Osterwalder M, Hermosilla-Aguayo V, Morabito A, Chacón BH, Zarrineh P, Girdziusaite A, Benazet JD, Zhu J, Mackem S, Capellini TD, Dickel D, Bobola N, Zuniga A, Visel A, Zeller R, and Selleri L
- Subjects
- Animals, Mice, Homeodomain Proteins metabolism, Pre-B-Cell Leukemia Transcription Factor 1 genetics, Gene Regulatory Networks, Transcription Factors genetics, Transcription Factors metabolism
- 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., (© 2023. The Author(s).)
- Published
- 2023
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