| Summary: | Summary: Forkhead box P2 (FOXP2) is a transcription factor expressed in the human brain that peaks during fetal development, and disruption in its ability to regulate downstream target genes leads to vulnerability to neurodevelopmental disorders. However, the mechanisms by which FOXP2 exerts regulatory control over targets during neuronal maturation have not been fully elucidated. Here, we use genome-wide chromatin accessibility assays and transcriptome-wide expression analyses in differentiating human neurons to show that FOXP2 represses proliferation-promoting genes in a DNA-binding-dependent manner. In contrast, FOXP2 and its cofactors, NFIA and NFIB, activate neuronal maturation genes in a manner that does not require FOXP2 to interact with DNA directly. Moreover, comparisons with expression data from the developing human brain suggest that FOXP2 and NFIA- or NFIB-dependent chromatin alterations drive maturation of excitatory cortical neurons. Thus, FOXP2 and its NFI cofactors may be specifically important for the development of cortical circuits underlying neurodevelopmental disorders. : Hickey et al. use genome-wide chromatin accessibility assays and transcriptome-wide expression analyses in human neurons to show that chromatin accessibility modifications made by FOXP2 drive networks that promote neuron maturation and are at risk in neurodevelopmental disorders. Moreover, they identify NFIA and NFIB as FOXP2 coactivators enriched in early-maturing excitatory subplate neurons. Keywords: language, autism, schizophrenia, neuron development, cortex
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