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The autism risk factor CHD8 is a chromatin activator in human neurons and functionally dependent on the ERK-MAPK pathway effector ELK1. | LitMetric

AI Article Synopsis

  • - CHD8 is a key protein linked to autism spectrum disorder, acting as a chromatin regulator that influences gene transcription in the human brain, although its specific functions are not fully understood.
  • - Researchers created a special type of human stem cells to study how CHD8 interacts with chromatin and found that it acts as a transcriptional activator, with its activity being dependent on the cell type.
  • - The study identified a relationship between CHD8 and the transcription factor ELK1, where ELK1 helps direct CHD8 to specific genes, suggesting their cooperation may play a role in neurodevelopmental disorders linked to CHD8 mutations.

Article Abstract

The chromodomain helicase DNA-binding protein CHD8 is the most frequently mutated gene in autism spectrum disorder. Despite its prominent disease involvement, little is known about its molecular function in the human brain. CHD8 is a chromatin regulator which binds to the promoters of actively transcribed genes through genomic targeting mechanisms which have yet to be fully defined. By generating a conditional loss-of-function and an endogenously tagged allele in human pluripotent stem cells, we investigated the molecular function and the interaction of CHD8 with chromatin in human neurons. Chromatin accessibility analysis and transcriptional profiling revealed that CHD8 functions as a transcriptional activator at its target genes in human neurons. Furthermore, we found that CHD8 chromatin targeting is cell context-dependent. In human neurons, CHD8 preferentially binds at ETS motif-enriched promoters. This enrichment is particularly prominent on the promoters of genes whose expression significantly changes upon the loss of CHD8. Indeed, among the ETS transcription factors, we identified ELK1 as being most highly correlated with CHD8 expression in primary human fetal and adult cortical neurons and most highly expressed in our stem cell-derived neurons. Remarkably, ELK1 was necessary to recruit CHD8 specifically to ETS motif-containing sites. These findings imply that ELK1 and CHD8 functionally cooperate to regulate gene expression and chromatin states at MAPK/ERK target genes in human neurons. Our results suggest that the MAPK/ERK/ELK1 axis potentially contributes to the pathogenesis caused by CHD8 mutations in human neurodevelopmental disorders.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9794786PMC
http://dx.doi.org/10.1038/s41598-022-23614-xDOI Listing

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