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Song, Michael; Pebworth, Mark-Phillip; Yang, Xiaoyu; Abnousi, Armen; Fan, Changxu; Wen, Jia; Rosen, Jonathan D; Choudhary, Mayank N K; 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
Nature (London), 11/2020, Volume: 587, Issue: 7835Journal Article
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 alone . 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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