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 WangMing Hu, Arnold R. Kriegstein, Yin Shen

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)644-649
Number of pages6
JournalNature
Volume587
Issue number7835
DOIs
StatePublished - Nov 26 2020

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