Single-cell EpiChem jointly measures drug–chromatin binding and multimodal epigenome

IF 36.1 1区生物学 Q1 BIOCHEMICAL RESEARCH METHODS

Nature Methods Pub Date : 2024-07-18 DOI:10.1038/s41592-024-02360-0

Chao Dong, Xiaoxuan Meng, Tong Zhang, Zhifang Guo, Yaxi Liu, Peihuang Wu, Shiwei Chen, Fanqi Zhou, Yanni Ma, Haiqing Xiong, Shaokun Shu, Aibin He

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Abstract

Studies of molecular and cellular functions of small-molecule inhibitors in cancer treatment, eliciting effects by targeting genome and epigenome associated proteins, requires measurement of drug-target engagement in single-cell resolution. Here we present EpiChem for in situ single-cell joint mapping of small molecules and multimodal epigenomic landscape. We demonstrate single-cell co-assays of three small molecules together with histone modifications, chromatin accessibility or target proteins in human colorectal cancer (CRC) organoids. Integrated multimodal analysis reveals diverse drug interactions in the context of chromatin states within heterogeneous CRC organoids. We further reveal drug genomic binding dynamics and adaptive epigenome across cell types after small-molecule drug treatment in CRC organoids. This method provides a unique tool to exploit the mechanisms of cell type-specific drug actions. EpiChem enables the co-profiling of small molecule–DNA interactions and multiple epigenomic features in single cells.

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单细胞 EpiChem 联合测量药物染色质结合和多模式表观基因组。

研究小分子抑制剂在癌症治疗中的分子和细胞功能，通过靶向基因组和表观基因组相关蛋白激发效应，需要以单细胞分辨率测量药物与靶点的接触情况。在这里，我们介绍了用于原位单细胞联合绘制小分子和多模式表观基因组图谱的 EpiChem。我们在人类结直肠癌（CRC）组织细胞中展示了三种小分子与组蛋白修饰、染色质可及性或靶蛋白的单细胞联合检测。综合多模态分析揭示了异质性 CRC 有机体内染色质状态背景下的多种药物相互作用。我们进一步揭示了小分子药物治疗 CRC 有机体后不同细胞类型的药物基因组结合动态和适应性表观基因组。这种方法为利用细胞类型特异性药物作用机制提供了一种独特的工具。

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来源期刊

Nature Methods 生物-生化研究方法

CiteScore

58.70

自引率

1.70%

发文量

326

审稿时长

1 months

期刊介绍： Nature Methods is a monthly journal that focuses on publishing innovative methods and substantial enhancements to fundamental life sciences research techniques. Geared towards a diverse, interdisciplinary readership of researchers in academia and industry engaged in laboratory work, the journal offers new tools for research and emphasizes the immediate practical significance of the featured work. It publishes primary research papers and reviews recent technical and methodological advancements, with a particular interest in primary methods papers relevant to the biological and biomedical sciences. This includes methods rooted in chemistry with practical applications for studying biological problems.