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

Cell. 2021 Sep 16;184(19):5053-5069.e23. doi: 10.1016/j.cell.2021.07.039. Epub 2021 Aug 13.


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.

Keywords: autism spectrum disoder; development; human cerebral cortex; multiome; single-cell ATAC-seq; single-cell RNA-seq.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Astrocytes / cytology
  • Cell Differentiation
  • Cell Lineage / genetics
  • Cerebral Cortex / embryology*
  • Chromatin / metabolism*
  • Cluster Analysis
  • Deep Learning
  • Epigenesis, Genetic
  • Fuzzy Logic
  • Gene Expression Regulation, Developmental*
  • Glutamates / metabolism
  • Humans
  • Mutation / genetics
  • Neurons / metabolism
  • Regulatory Sequences, Nucleic Acid / genetics
  • Single-Cell Analysis*


  • Chromatin
  • Glutamates