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

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.

A novel framework for functional annotation of variants of uncertain significance in ID/ASD risk gene CC2D1A.

Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous with hundreds of identified risk genes, most affecting only a few patients. Novel missense variants in these genes are being discovered as clinical exome sequencing is now routinely integrated into diagnosis, yet most of them are annotated as variants of uncertain significance (VUS). VUSs are a major roadblock in using patient genetics to inform clinical action.

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

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 regulate specific target genes ? 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.

Homeodomain complex formation and biomolecular condensates in Hox gene regulation.

Hox genes are a family of homeodomain transcription factors that regulate specialized morphological structures along the anterior-posterior axis of metazoans. Over the past few decades, researchers have focused on defining how Hox factors with similar in vitro DNA binding activities achieve sufficient target specificity to regulate distinct cell fates in vivo. In this review, we highlight how protein interactions with other transcription factors, many of which are also homeodomain proteins, result in the formation of transcription factor complexes with enhanced DNA binding specificity.

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

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.