High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer
High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer
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DOI：
10.1038/s41588-019-0424-9
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发表时间：
2019-06-01
期刊：
影响因子：
30.8
通讯作者：
Gerard, Annabelle
中科院分区：
文献类型：
--
作者：
Grosselin, Kevin;Durand, Adeline;Gerard, Annabelle
通过组蛋白修饰调节染色质结构是基因表达的主要表观遗传机制和调节剂。然而，染色质特征对肿瘤异质性和演变的贡献仍然未知。在这里，我们描述了一个高通量液滴微流体平台，以单细胞分辨率描绘数千个细胞的染色质景观。使用乳腺癌中对化疗和靶向治疗获得性耐药的患者来源的异种移植模型，我们发现未经治疗的药物敏感性肿瘤中的一部分细胞与耐药细胞共享共同的染色质特征，使用批量方法无法检测到。这些细胞，以及来自耐药肿瘤的细胞，已经失去了染色质标记H3K27me3，这与稳定的转录抑制有关，用于已知促进对治疗的耐药性的基因。这种单细胞染色质免疫沉淀然后测序的方法为研究染色质异质性的作用铺平了道路，不仅在癌症中，而且在其他疾病和健康系统中，特别是在细胞分化和发育过程中。
Modulation of chromatin structure via histone modification is a major epigenetic mechanism and regulator of gene expression. However, the contribution of chromatin features to tumor heterogeneity and evolution remains unknown. Here we describe a high-throughput droplet microfluidics platform to profile chromatin landscapes of thousands of cells at single-cell resolution. Using patient-derived xenograft models of acquired resistance to chemotherapy and targeted therapy in breast cancer, we found that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature with resistant cells, undetectable using bulk approaches. These cells, and cells from the resistant tumors, have lost chromatin marks-H3K27me3, which is associated with stable transcriptional repression-for genes known to promote resistance to treatment. This single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.