Cell-type-specific 3D epigenomes in the developing human cortex

Nature. 2020 Nov;587(7835):644-649. doi: 10.1038/s41586-020-2825-4. Epub 2020 Oct 14.

Abstract

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone1,2. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.

Publication types

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

MeSH terms

  • CRISPR-Cas Systems
  • Cell Lineage / genetics
  • Cells / classification*
  • Cells / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / embryology*
  • Chromatin / genetics
  • Chromatin / metabolism
  • DNA Transposable Elements
  • Epigenome*
  • Epigenomics*
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Imaging, Three-Dimensional
  • Methylation
  • Multifactorial Inheritance / genetics
  • Organogenesis / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Promoter Regions, Genetic / genetics
  • Regulatory Elements, Transcriptional
  • Reproducibility of Results
  • Transcription, Genetic

Substances

  • Chromatin
  • DNA Transposable Elements
  • Histones