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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE197859 | GEO | 2023/04/26

REPOSITORIES: GEO

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

Project 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.

| S-EPMC10325989 | biostudies-literature

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

Project description:During development cell fates are specified by tightly controlled gene expression programs. PBX TALE transcription factors control gene regulatory networks (GRN) that direct vertebrate tissue patterning and organ morphogenesis. How PBX1/2 proteins achieve context-specific functions, despite widespread embryonic Pbx expression, remains elusive. In mouse limbs, mesenchymal-specific loss of PBX1/2 or of the limb regulator HAND2 results in strikingly similar phenotypes, suggesting that PBX1/2- and HAND2-dependent programs converge to control limb development. To investigate this scenario using the murine hindlimb model, we combined tissue-specific and temporally controlled mutagenesis to multi-omics approaches on dissected hindlimb buds. This resulted in the reconstruction of a GRN that is collaboratively directed by PBX1/2-HAND2, demonstrating that Pbx1-Hand2 genetically interact in vivo during pentadactylous hindlimb patterning, with PBX1 concomitantly acting as an upstream regulator of Hand2. At organismal-level resolution the GRN is active within restricted subsets of posterior-proximal hindlimb mesenchymal cells, wherein Pbx1/2 and Hand2 are co-expressed with their target genes. Profiling the binding of Pbx1 and Hand2 genome-wide across multiple tissues revealed that HAND2 can act selectively on a subset of PBX-bound regions to impart limb patterning functionality. Our research elucidates mechanisms on the limb-specific activities of PBX1/2, while informing general principles by which promiscuous transcription factors cooperate with select cofactors to instruct distinct developmental programs.

2023-04-26 | GSE197856 | GEO

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

2023-04-26 | GSE197855 | GEO

A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [bulk RNA-seq]

2023-04-26 | GSE197857 | GEO

A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [single-cell RNA-seq]

2023-04-26 | GSE197858 | GEO

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

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

| PRJNA812516 | ENA

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

Project description:A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [ChIP-seq]

| PRJNA812521 | ENA

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

Project description:A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [ATAC-seq]

| PRJNA812522 | ENA

A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [bulk RNA-seq]

Project description:A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [bulk RNA-seq]

| PRJNA812526 | ENA

A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [single-cell RNA-seq]

Project description:A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2 [single-cell RNA-seq]

| PRJNA812525 | ENA

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