A Chromatin Accessibility Atlas of the Developing Human Telencephalon

Cell. 2020 Aug 6;182(3):754-769.e18. doi: 10.1016/j.cell.2020.06.002. Epub 2020 Jun 30.


To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.

Keywords: ATAC-seq; autism; chromatin; enhancers; gene regulation; machine learning; neurodevelopment; neuropsychiatric disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics
  • Cell Line
  • Chromatin / genetics*
  • Chromatin / metabolism*
  • Chromatin Immunoprecipitation Sequencing
  • Enhancer Elements, Genetic*
  • Euchromatin / genetics
  • GABA Plasma Membrane Transport Proteins / genetics
  • Gene Expression Regulation, Developmental / genetics*
  • Gene Ontology
  • Genetic Predisposition to Disease
  • Gestational Age
  • Humans
  • Mice
  • Mice, Transgenic
  • Nucleotide Motifs
  • Point Mutation
  • Prefrontal Cortex / embryology*
  • Prefrontal Cortex / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Spatio-Temporal Analysis
  • Telencephalon / embryology*
  • Telencephalon / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • BCL11A protein, human
  • Chromatin
  • Euchromatin
  • FEZF2 protein, human
  • GABA Plasma Membrane Transport Proteins
  • Repressor Proteins
  • SLC6A1 protein, human
  • Transcription Factors