Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution

Genetic perturbations of cortical development can lead to neurodevelopmental disease, including autism spectrum disorder (ASD). To identify genomic regions crucial to corticogenesis, we mapped the activity of gene-regulatory elements generating a single-cell atlas of gene expression and chromatin accessibility both independently and jointly. This revealed waves of gene regulation by key transcription factors (TFs) across a nearly continuous differentiation trajectory, distinguished the expression programs of glial lineages, and identified lineage-determining TFs that exhibited strong correlation between linked gene-regulatory elements and expression levels. These highly connected genes adopted an active chromatin state in early differentiating cells, consistent with lineage commitment. Base-pair-resolution neural network models identified strong cell-type-specific enrichment of noncoding mutations predicted to be disruptive in a cohort of ASD individuals and identified frequently disrupted TF binding sites. This approach illustrates how cell-type-specific mapping can provide insights into the programs governing human development and disease.

Automated summary

Genetic perturbations of cortical development can lead to neurodevelopmental disease like autism spectrum disorder (ASD). Mapping the activity of gene-regulatory elements generating a single-cell atlas of gene expression and chromatin accessibility reveals gene regulation by key transcription factors, differentiates glial lineages' expression programs, and identifies lineage-determining TFs. High connection genes in early differentiating cells exhibit an active chromatin state consistent with lineage commitment. Neural network models pinpoint cell-type-specific enrichment of noncoding mutations associated with ASD in individuals and frequently disrupted TF binding sites. This highlights how cell-type-specific mapping can unveil insights into human development and disease programs.