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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 [ATAC-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 | GSE197855 | GEO

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

2023-04-26 | GSE197856 | 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 [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 [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 [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

Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb.

Project description:Preaxial polydactyly (PPD) is a common limb-associated birth defect characterized by extra digit(s) in the anterior autopod. It often results from ectopic sonic hedgehog (Shh) expression in the anterior limb bud. Although several transcription factors are known to restrict Shh expression to the posterior limb bud, how they function together remains unclear. Here we provide evidence from mouse conditional knockout limb buds that the bHLH family transcription factor gene Twist1 is required to inhibit Shh expression in the anterior limb bud mesenchyme. More importantly, we uncovered genetic synergism between Twist1 and the ETS family transcription factor genes Etv4 and Etv5 (collectively Etv), which also inhibit Shh expression. Biochemical data suggest that this genetic interaction is a result of direct association between TWIST1 and ETV proteins. Previous studies have shown that TWIST1 functions by forming homodimers or heterodimers with other bHLH factors including HAND2, a key positive regulator of Shh expression. We found that the PPD phenotype observed in Etv mutants is suppressed by a mutation in Hand2, indicative of genetic antagonism. Furthermore, overexpression of ETV proteins influences the dimerization of these bHLH factors. Together, our data suggest that through biochemical interactions, the Shh expression regulators ETV, TWIST1 and HAND2 attain a precise balance to establish anterior-posterior patterning of the limb.

| S-EPMC2947755 | biostudies-literature

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