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

Michael Song, Mark-Phillip Pebworth, Xiaoyu Yang, Armen Abnousi, Changxu Fan, Jia Wen, Jonathan D. Rosen, Mayank N. K. Choudhary, Xiekui Cui, Ian R. Jones, Seth Bergenholtz, Ugomma C. Eze, Ivan Juric, Bingkun Li, Lenka Maliskova, Jerry Lee, Weifang Liu, Alex A. Pollen, Yun Li, Ting Wang, Ming Hu (), Arnold R. Kriegstein () and Yin Shen ()
Additional contact information
Michael Song: University of California, San Francisco
Mark-Phillip Pebworth: University of California, San Francisco
Xiaoyu Yang: University of California, San Francisco
Armen Abnousi: Lerner Research Institute, Cleveland Clinic Foundation
Changxu Fan: Washington University School of Medicine
Jia Wen: University of North Carolina
Jonathan D. Rosen: University of North Carolina
Mayank N. K. Choudhary: Washington University School of Medicine
Xiekui Cui: University of California, San Francisco
Ian R. Jones: University of California, San Francisco
Seth Bergenholtz: University of California, San Francisco
Ugomma C. Eze: University of California, San Francisco
Ivan Juric: Lerner Research Institute, Cleveland Clinic Foundation
Bingkun Li: University of California, San Francisco
Lenka Maliskova: University of California, San Francisco
Jerry Lee: University of California, San Francisco
Weifang Liu: University of North Carolina
Alex A. Pollen: University of California, San Francisco
Yun Li: University of North Carolina
Ting Wang: Washington University School of Medicine
Ming Hu: Lerner Research Institute, Cleveland Clinic Foundation
Arnold R. Kriegstein: University of California, San Francisco
Yin Shen: University of California, San Francisco

Nature, 2020, vol. 587, issue 7835, 644-649

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2825-4

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