High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders.
We previously discovered that mutations of the human FOXP2 gene cause a monogenic communication disorder, primarily characterized by difficulties in learning to make coordinated sequences of articulatory gestures that underlie speech. Affected people have deficits in expressive and receptive linguistic processing and display structural and/or functional abnormalities in cortical and subcortical brain regions. FOXP2 provides a unique window into neural processes involved in speech and language. In particular, its role as a transcription factor gene offers powerful functional genomic routes for dissecting critical neurogenetic mechanisms. Here, we employ chromatin immunoprecipitation coupled with promoter microarrays (ChIP-chip) to successfully identify genomic sites that are directly bound by FOXP2 protein in native chromatin of human neuron-like cells. We focus on a subset of downstream targets identified by this approach, showing that altered FOXP2 levels yield significant changes in expression in our cell-based models and that FOXP2 binds in a specific manner to consensus sites within the relevant promoters. Moreover, we demonstrate significant quantitative differences in target expression in embryonic brains of mutant mice, mediated by specific in vivo Foxp2-chromatin interactions. This work represents the first identification and in vivo verification of neural targets regulated by FOXP2. Our data indicate that FOXP2 has dual functionality, acting to either repress or activate gene expression at occupied promoters. The identified targets suggest roles in modulating synaptic plasticity, neurodevelopment, neurotransmission, and axon guidance and represent novel entry points into in vivo pathways that may be disturbed in speech and language disorders.
Vernes
Sonja C
SC
Wellcome Trust Centre for Human Genetics, The University of Oxford, Oxford, OX3 7BN, UK.
Spiteri
Elizabeth
E
Nicod
Jérôme
J
Groszer
Matthias
M
Taylor
Jennifer M
JM
Davies
Kay E
KE
Geschwind
Daniel H
DH
Fisher
Simon E
SE
D001921:Brain / Q000502:physiology* / Q000503:physiopathology; D002460:Cell Line; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005784:Gene Amplification; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D007806:Language Disorders / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D013064:Speech Disorders / Q000235:genetics*; D014162:Transfection
C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors