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-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. Analysis of cis -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.

中文翻译：

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发育中的人类皮层中的细胞类型特异性 3D 表观基因组

由于样本可用性和组织异质性的挑战，人类皮质发生过程中谱系特异性表观基因组变化一直难以研究。例如，以前使用单细胞 RNA 测序的研究仅在背侧皮质中就鉴定出至少 9 种主要细胞类型和多达 26 种不同的亚型 1 、 2 。在这里，我们描述了从人类皮层的中期妊娠样本中分离出的放射状胶质细胞、中间祖细胞、兴奋性神经元和中间神经元的细胞类型特异性顺式调节染色质相互作用、开放染色质峰和转录组。我们表明，染色质相互作用是基因调控的几个方面的基础，转座因子和疾病相关变体以细胞类型特异性方式在远端相互作用区域富集。此外，染色质相互作用水平增加的启动子——称为超相互作用启动子——富含谱系特异性基因，表明这些基因座的相互作用有助于转录的微调。最后，我们开发了 CRISPRview，这是一种集成免疫染色、CRISPR 干扰、RNAscope 和图像分析的技术，以验证异质原代细胞群中的细胞类型特异性顺式调节元件。我们的研究结果提供了对发育中的人类皮层中细胞类型特异性基因表达模式的见解，并促进了我们在这个关键的发育窗口期间对基因调控和谱系规范的理解。独联体调节染色质相互作用的分析，