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

Article

关键词: INTERMEDIATE PROGENITOR CELLS;    GENOME-WIDE ASSOCIATION;    ENHANCER ACTIVITY;    GENE-EXPRESSION;    RADIAL GLIA;    ELEMENTS;    ARCHITECTURE;    NEURONS;   

DOI  :  10.1038/s41586-020-2825-4

来源: SCIE

【 摘 要 】

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(1,2). Here we characterize cell-type-specificcis-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-specificcis-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. Analysis ofcis-regulatory chromatin interactions, open chromatin and transcriptomes for different cell types isolated from mid-gestational human cortex samples provides insights into gene regulation during development.

【 授权许可】

Free