Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution
Cell. 2021-09-16;184(19):5053-5069.
- Abstract
- 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.
Related data
- Available data
- website
- Data summary
- Data used for the analyses presented in this work are available under GEO: GSE162170 and on a supplementary website (see below).
- Available data
- website
- Data summary
- BPNet code can be found at GitHub.
- Available data
- website
- Data summary
- A supplementary website with references to the data, code repositories and tools for interactive data exploration (cell browser and genome browser tracks) can be found at https://scbrainregulation.su.domains/