Homo sapiens Raw sequence reads. Homo sapiens

we report scCAT-seq, a technique for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. By applying our integrated approach to multiple cancer cell lines, we discovered genomic loci with coordinated epigenomic and transcriptomic variability. In addition, decomposition of combined single-cell chromatin accessibility and gene expression features by a non-negative matrix factorization (NMF) based method identified signatures reflecting cell type specificity and revealed a profound regulatory relationship between the two layers of omics. We further characterized subpopulations associated with distinct regulatory patterns within patient-derived xenograft models and discovered epigenomic and transcriptomic clues that drive tumor heterogeneity. The ability to obtain these two layers of omics data will help provide more accurate definitions of “single cell states” and enable the deconvolution of regulatory heterogeneity from complex cell populations.

我们报道了scCAT-seq技术——一种可在同一单细胞内同时检测染色质可及性与转录组的实验方法。通过将该整合检测方法应用于多种癌细胞系，我们发现了兼具表观基因组与转录组协同变异的基因组位点。此外，借助基于非负矩阵分解（non-negative matrix factorization, NMF）的方法对单细胞染色质可及性与基因表达特征的联合数据进行分解，我们识别出了反映细胞类型特异性的特征谱，并揭示了两层组学数据间的深层调控关系。我们进一步在患者来源的异种移植模型中，对与特定调控模式相关的细胞亚群开展了表征分析，并发现了驱动肿瘤异质性的表观基因组与转录组线索。获取这两层组学数据的能力，将有助于更精准地定义“单细胞状态”，并实现从复杂细胞群体中解析调控异质性。