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

  • Author(s): Song, Michael
  • Pebworth, Mark-Phillip
  • Yang, Xiaoyu
  • Abnousi, Armen
  • Fan, Changxu
  • Wen, Jia
  • Rosen, Jonathan D
  • Choudhary, Mayank NK
  • Cui, Xiekui
  • Jones, Ian R
  • Bergenholtz, Seth
  • Eze, Ugomma C
  • Juric, Ivan
  • Li, Bingkun
  • Maliskova, Lenka
  • Lee, Jerry
  • Liu, Weifang
  • Pollen, Alex A
  • Li, Yun
  • Wang, Ting
  • Hu, Ming
  • Kriegstein, Arnold R
  • Shen, Yin
  • et al.

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.

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