Transcriptional and DNA Binding Activity of the Foxp1/2/4 Family Is Modulated by Heterotypic and Homotypic Protein Interactions

Abstract

Foxp1, Foxp2, and Foxp4 are large multidomain transcriptional regulators belonging to the family of winged-helix DNA binding proteins known as the Fox family. Foxp1 and Foxp2 have been shown to act as transcriptional repressors, while regulatory activity of the recently identified Foxp4 has not been determined. Given the importance of this Fox gene subfamily in neural and lung development, we sought to elucidate the mechanisms by which Foxp1, Foxp2, and Foxp4 repress gene transcription. We show that like Foxp1 and Foxp2, Foxp4 represses transcription. Analysis of the N-terminal repression domain in Foxp1, Foxp2, and Foxp4 shows that this region contains two separate and distinct repression subdomains that are highly homologous termed subdomain 1 and subdomain 2. However, subdomain 2 is not functional in Foxp4. Screening for proteins that interact with subdomains 1 and 2 of Foxp2 using yeast two-hybrid analysis revealed that subdomain 2 binds to C-terminal binding protein 1, which can synergistically repress transcription with Foxp1 and Foxp2, but not Foxp4. Subdomain 1 contains a highly conserved leucine zipper similar to that found in N-myc and confers homo-and heterodimerization to the Foxp1/2/4 family members. These interactions are dependent on the conserved leucine zipper motif. Finally, we show that the integrity of this subdomain is essential for DNA binding, making Foxp1, Foxp2, and Foxp4 the first Fox proteins that require dimerization for DNA binding. These data reveal a complex regulatory mechanism underlying Foxp1, Foxp2, and Foxp4 activity, demonstrating that Foxp1, Foxp2, and Foxp4 are the first Fox proteins reported whose activity is regulated by homo-and heterodimerization.

Shining a light on CNTNAP2: complex functions to complex disorders

“…16 FOXP1 and FOXP2 show highly overlapping expression patterns and can interact to co-regulate gene expression. [57][58][59][60] A single autistic proband was recently identified carrying mutations in both FOXP1 and CNTNAP2, suggesting a potential link between FOXP1-CNTNAP2 and ASD. 16 This discovery is intriguing given that both FOXP1 and CNTNAP2 mutations have been identified in patients with mild-to-moderate ID, in the presence or absence of autistic features.…”

FOXP1, an Estrogen-Inducible Transcription Factor, Modulates Cell Proliferation in Breast Cancer Cells and 5-Year Recurrence-Free Survival of Patients with Tamoxifen-Treated Breast Cancer

“…FOXP1 is a FOX family member consisting of a wingedhelix DNA-binding domain and an N-terminal transcriptional repression domain and represses its target genes by forming homodimers or heterodimers with FOXP2 and FOXP4 [8,9]. Alteration of FOXP1 expression is associated with various types of tumors, including breast and prostate cancers [10][11][12][13][14].…”

A de novo FOXP1 variant in a patient with autism, intellectual disability and severe speech and language impairment

“…22 Of note, FOXP1 and FOXP2 show partly overlapping neural expression patterns 23,24 such that FOXP1/FOXP2 heterodimers could regulate downstream targets, including those involved in language development, such as CNTNAP2. 16,25 Therefore, we investigated the effect of the de novo FOXP1 variant on the ability of the protein to homodimerize and to interact with WT FOXP1 and FOXP2 using the BRET assay.…”