Current methods for analyzing chromatin architecture are not readily scalable to heterogeneous tissues. Here we introduce Droplet Hi-C, which uses a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture of the mouse cortex and analyzed gene regulatory programs in major cortical cell types. In addition, we used this technique to detect copy number variations, structural variations and extrachromosomal DNA in human glioblastoma, colorectal and blood cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We refined the technique to allow joint profiling of chromatin architecture and transcriptome in single cells, facilitating exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C both addresses critical gaps in chromatin analysis of heterogeneous tissues and enhances understanding of gene regulation.

目前分析染色质结构的方法不容易扩展到异质组织。在这里，我们介绍了 Droplet Hi-C，它使用商用微流控设备对液滴进行高通量、单细胞染色质构象分析。使用 Droplet Hi-C，我们绘制了小鼠皮层的染色质结构，并分析了主要皮层细胞类型的基因调控程序。此外，我们使用该技术检测人胶质母细胞瘤、结直肠癌和血癌细胞中的拷贝数变异、结构变异和染色体外 DNA，揭示治疗过程中的克隆动力学和其他致癌事件。我们改进了该技术，以允许对单细胞中的染色质结构和转录组进行联合分析，从而促进探索正常组织和肿瘤中染色质结构与基因表达之间的联系。因此，Droplet Hi-C 既解决了异质组织染色质分析中的关键差距，又增强了对基因调控的理解。