Dataset Information

Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes.

ABSTRACT: 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.

SUBMITTER: Hickey SL

PROVIDER: S-EPMC6794152 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes.

Hickey Stephanie L SL Berto Stefano S Konopka Genevieve G

Cell reports 20190501 6

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 n ...[more]

PMID: 31067457

Similar Datasets

Project description:Heterozygous disruption of FOXP2 causes a rare form of speech and language impairment. Screens of the FOXP2 sequence in individuals with speech/language-related disorders have identified several rare protein-altering variants, but their phenotypic relevance is often unclear. FOXP2 encodes a transcription factor with a forkhead box DNA-binding domain, but little is known about the functions of protein regions outside this domain.We performed detailed functional analyses of seven rare FOXP2 variants found in affected cases, including three which have not been previously characterized, testing intracellular localization, transcriptional regulation, dimerization, and interaction with other proteins. To shed further light on molecular functions of FOXP2, we characterized the interaction between this transcription factor and co-repressor proteins of the C-terminal binding protein (CTBP) family. Finally, we analysed the functional significance of the polyglutamine tracts in FOXP2, since tract length variations have been reported in cases of neurodevelopmental disorder.We confirmed etiological roles of multiple FOXP2 variants. Of three variants that have been suggested to cause speech/language disorder, but never before been characterized, only one showed functional effects. For the other two, we found no effects on protein function in any assays, suggesting that they are incidental to the phenotype. We identified a CTBP-binding region within the N-terminal portion of FOXP2. This region includes two amino acid substitutions that occurred on the human lineage following the split from chimpanzees. However, we did not observe any effects of these amino acid changes on CTBP binding or other core aspects of FOXP2 function. Finally, we found that FOXP2 variants with reduced polyglutamine tracts did not exhibit altered behaviour in cellular assays, indicating that such tracts are non-essential for core aspects of FOXP2 function, and that tract variation is unlikely to be a highly penetrant cause of speech/language disorder.Our findings highlight the importance of functional characterization of novel rare variants in FOXP2 in assessing the contribution of such variants to speech/language disorder and provide further insights into the molecular function of the FOXP2 protein.

Dataset Information

Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes.

Publications

Chromatin Decondensation by FOXP2 Promotes Human Neuron Maturation and Expression of Neurodevelopmental Disease Genes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure