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.
Competing Interests: Declaration of interests W.J.G. was a consultant for 10x Genomics and is named as an inventor on patents describing ATAC-seq methods. H.Y.C. is a co-founder of Accent Therapeutics and Boundless Bio and an advisor of 10x Genomics, Arsenal Biosciences, and Spring Discovery. A.S. is an employee of Insitro, Inc, and receives consulting fees from Myokardia, Inc. K.F. is an employee of Illumina, Inc.
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