滴珠Hi-C实现异质组织中染色质构象的可扩展单细胞分析

Droplet Hi-C enables scalable, single-cell profiling of chromatin architecture in heterogeneous tissues

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NATURE BIOTECHNOLOGY

影响因子:41.7

分区:生物学1区 Top / 生物工程与应用微生物1区

发表日期:2024 Oct 18

作者: Lei Chang, Yang Xie, Brett Taylor, Zhaoning Wang, Jiachen Sun, Ethan J Armand, Shreya Mishra, Jie Xu, Melodi Tastemel, Audrey Lie, Zane A Gibbs, Hannah S Indralingam, Tuyet M Tan, Rafael Bejar, Clark C Chen, Frank B Furnari, Ming Hu, Bing Ren

DOI: 10.1038/s41587-024-02447-1

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摘要

当前分析染色质构象的方法难以扩展至异质组织。在此，我们引入滴珠Hi-C技术，利用商业微流控设备在液滴中进行高通量、单细胞染色质构象分析。通过滴珠Hi-C，我们绘制了小鼠大脑皮层的染色质结构图谱，并分析了主要皮层细胞类型的基因调控程序。此外，我们还利用此技术检测了人类胶质母细胞瘤、结直肠癌和血液癌细胞中的拷贝数变异、结构变异和染色体外DNA，揭示了克隆动态和治疗期间的肿瘤驱动事件。我们优化了该技术，实现了染色质结构与转录组的联合分析，促进了正常组织及肿瘤中染色质结构与基因表达关系的研究。滴珠Hi-C不仅填补了异质组织染色质分析的关键空白，也增强了对基因调控机制的理解。

Abstract

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.