Abstract
Mutations of the FOXP2 gene cause a severe speech and language disorder, providing a molecular window into the neurobiology of language. Individuals with FOXP2 mutations have structural and functional alterations affecting brain circuits that overlap with sites of FOXP2 expression, including regions of the cortex, striatum, and cerebellum. FOXP2 displays complex patterns of expression in the brain, as well as in non-neuronal tissues, suggesting that sophisticated regulatory mechanisms control its spatio-temporal expression. However, to date, little is known about the regulation of FOXP2 or the genomic elements that control its expression. Using chromatin conformation capture (3C), we mapped the human FOXP2 locus to identify putative enhancer regions that engage in long-range interactions with the promoter of this gene. We demonstrate the ability of the identified enhancer regions to drive gene expression. We also show regulation of the FOXP2 promoter and enhancer regions by candidate regulators – FOXP family and TBR1 transcription factors. These data point to regulatory elements that may contribute to the temporal- or tissue-specific expression patterns of human FOXP2. Understanding the upstream regulatory pathways controlling FOXP2 expression will bring new insight into the molecular networks contributing to human language and related disorders.
Highlights
FOXP2 is the first and most well-studied gene to be implicated in human speech and language skills
While it is clear that disruptions of the FOXP2 coding region result in speech/language deficits, it may be the case that dysregulation of this gene can contribute to similar phenotypes
Our data show that TSS1 is an active promoter in human cell lines and identify eighteen different genomic regions that are in physical contact with this promoter across the cell lines tested, which differ in origin and endogenous FOXP2 expression
Summary
FOXP2 is the first and most well-studied gene to be implicated in human speech and language skills. Structural mutations near the FOXP2 locus that do not disrupt the coding sequence have been identified in individuals with speech and language problems (Feuk et al, 2006; Adegbola et al, 2015; Moralli et al, 2015). In a child with delayed speech development, a complex structural mutation was found including a balanced inversion with a breakpoint downstream of FOXP2 (Moralli et al, 2015) Downstream of this breakpoint, a functional enhancer was identified that was suggested to alter FOXP2 expression and contribute to the disorder (Becker et al, 2015). While it is clear that disruptions of the FOXP2 coding region result in speech/language deficits, it may be the case that dysregulation of this gene can contribute to similar phenotypes
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