3D Epigenomic Characterization Reveals Insights Into Gene Regulation and Lineage Specification During Corticogenesis
Jonathan D Rosen,
Ian R Jones,
Ugomma C. Eze,
Alex A. Pollen,
Posted 25 Feb 2020
bioRxiv DOI: 10.1101/2020.02.24.963652 (published DOI: 10.1038/s41586-020-2825-4)
Posted 25 Feb 2020
Lineage-specific epigenomic changes during human corticogenesis have previously remained elusive due to challenges with tissue heterogeneity and sample availability. Here, we analyze cis-regulatory chromatin interactions, open chromatin regions, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational human brain samples. We show that chromatin looping underlies transcriptional regulation for lineage-specific genes, with transcription factor motifs, families of transposable elements, and disease-associated variants enriched at distal interacting regions in a cell type-specific manner. A subset of promoters exhibit unusually high degrees of chromatin interactivity, which we term super interactive promoters. Super interactive promoters are enriched for critical lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of cell type-specific transcription. Finally, we present CRISPRview, a novel approach for validating distal interacting regions in primary cells. Our study presents the first characterization of cell type-specific 3D epigenomic landscapes during human corticogenesis, advancing our understanding of gene regulation and lineage specification during human brain development.
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