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Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in the fly and mouse

ABSTRACT: Identification of Gsx2 genomic binding patterns from E12.5 mouse lateral ganglionic eminence (LGEs).

ORGANISM(S): Mus musculus

PROVIDER: GSE162589 | GEO | 2020/12/04

REPOSITORIES: GEO

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Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in flies and mice.

Project description:How homeodomain proteins gain sufficient specificity to control different cell fates has been a long-standing problem in developmental biology. The conserved Gsx homeodomain proteins regulate specific aspects of neural development in animals from flies to mammals, and yet they belong to a large transcription factor family that bind nearly identical DNA sequences in vitro. Here, we show that the mouse and fly Gsx factors unexpectedly gain DNA binding specificity by forming cooperative homodimers on precisely spaced and oriented DNA sites. High-resolution genomic binding assays revealed that Gsx2 binds both monomer and homodimer sites in the developing mouse ventral telencephalon. Importantly, reporter assays showed that Gsx2 mediates opposing outcomes in a DNA binding site-dependent manner: Monomer Gsx2 binding represses transcription, whereas homodimer binding stimulates gene expression. In Drosophila, the Gsx homolog, Ind, similarly represses or stimulates transcription in a site-dependent manner via an autoregulatory enhancer containing a combination of monomer and homodimer sites. Integrating these findings, we test a model showing how the homodimer to monomer site ratio and the Gsx protein levels defines gene up-regulation versus down-regulation. Altogether, these data serve as a new paradigm for how cooperative homeodomain transcription factor binding can increase target specificity and alter regulatory outcomes.

| S-EPMC7778271 | biostudies-literature

Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in the fly and mouse

Project description:Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in the fly and mouse

| PRJNA682340 | ENA

Transcriptomic analysis from lateral ganglionic eminence (LGE) of wild type and Gsx2 germline knock-out mice.

Project description:RNA-seq analysis was used to identify genes that are differentially expressed between wild type and Gsx2 null mouse LGEs.

2020-12-04 | GSE162590 | GEO

GSX2 Regulates Progenitor Maturation and Regional Identity Through Transcriptional Repression in the Developing Basal Ganglia [ATAC-seq]

Project description:Transgenic mouse models have demonstrated the critical role of the homeodomain transcription factor Genetic-Screened Homeobox 2 (‍‍Gsx2) in the developing basal ganglia. However, the technical limitations of the existing in vivo approaches, such as progenitor heterogeneity and lack of temporal resolution, have impeded the investigation of direct regulatory targets . This study engineered a Dox-inducible human embryonic stem cell (‍‍hESC) line to investigate the function of GSX2 protein in directed differentiation cultures that model developing lateral ganglionic eminence-like (LGE-like) progenitors. Transcriptomic, chromatin accessibility, and genomic binding studies revealed that GSX2: (1) binds to both high- and low-accessibility chromatin using varying binding site preferences; (‌‌‌‌2) alters chromatin accessibility largely through indirect mechanisms; (3) functions primarily as a transcriptional repressor; and (4) regulates key conserved target genes of both progenitor maturation and regional specification. These results provide insight into the key regulatory roles and targets of GSX2, thereby establishing a new tractable experimental system to investigate basal ganglia development.

2025-09-30 | GSE306350 | GEO

GSX2 Regulates Progenitor Maturation and Regional Identity Through Transcriptional Repression in the Developing Basal Ganglia [RNA-Seq]

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GSX2 Regulates Progenitor Maturation and Regional Identity Through Transcriptional Repression in the Developing Basal Ganglia [ChIP-Seq]

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Transcriptomic analysis from lateral ganglionic eminence (LGE) of wild type and Gsx2 germline knock-out mice.

Project description:Transcriptomic analysis from lateral ganglionic eminence (LGE) of wild type and Gsx2 germline knock-out mice.

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Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

Project description:Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

| PRJNA598224 | ENA

Cooperative Gsx2-DNA binding requires DNA bending and a novel Gsx2 homeodomain interface.

Project description:The conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the following question: How do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich sites and as a cooperative homodimer to two sites spaced precisely 7 bp apart. However, the mechanistic basis for Gsx-DNA binding and cooperativity is poorly understood. Here, we used biochemical, biophysical, structural and modeling approaches to (i) show that Gsx factors are monomers in solution and require DNA for cooperative complex formation, (ii) define the affinity and thermodynamic binding parameters of Gsx2/DNA interactions, (iii) solve a high-resolution monomer/DNA structure that reveals that Gsx2 induces a 20° bend in DNA, (iv) identify a Gsx2 protein-protein interface required for cooperative DNA binding and (v) determine that flexible spacer DNA sequences enhance Gsx2 cooperativity on dimer sites. Altogether, our results provide a mechanistic basis for understanding the protein and DNA structural determinants that underlie cooperative DNA binding by Gsx factors.

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Cooperative Gsx2-DNA Binding Requires DNA Bending and a Novel Gsx2 Homeodomain Interface.

Project description:The conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the question - how do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich sites and as a cooperative homodimer to two sites spaced precisely seven base pairs apart. However, the mechanistic basis for Gsx DNA binding and cooperativity are poorly understood. Here, we used biochemical, biophysical, structural, and modeling approaches to (1) show that Gsx factors are monomers in solution and require DNA for cooperative complex formation; (2) define the affinity and thermodynamic binding parameters of Gsx2/DNA interactions; (3) solve a high-resolution monomer/DNA structure that reveals Gsx2 induces a 20° bend in DNA; (4) identify a Gsx2 protein-protein interface required for cooperative DNA binding; and (5) determine that flexible spacer DNA sequences enhance Gsx2 cooperativity on dimer sites. Altogether, our results provide a mechanistic basis for understanding the protein and DNA structural determinants that underlie cooperative DNA binding by Gsx factors, thereby providing a deeper understanding of HD specificity.

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