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来引发效应，需要在单细胞分辨率下测量药物靶点的参与。在这里，我们介绍 EpiChem 用于小分子和多模式表观基因组景观的原位单细胞联合图谱。我们展示了人类结直肠癌 (CRC) 类器官中三种小分子以及组蛋白修饰、染色质可及性或靶蛋白的单细胞联合测定。综合多模态分析揭示了异质 CRC 类器官内染色质状态背景下的多种药物相互作用。我们进一步揭示了结直肠癌类器官中小分子药物治疗后跨细胞类型的药物基因组结合动力学和适应性表观基因组。该方法提供了一种独特的工具来利用细胞类型特异性药物作用的机制。© 2024。作者。

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.© 2024. The Author(s).