Genome-wide profiling of histone modifications can reveal not only the location and activity state of regulatory elements, but also the regulatory mechanisms involved in cell-type-specific gene expression during development and disease pathology. Conventional assays to profile histone modifications in bulk tissues lack single-cell resolution. Here we describe an ultra-high-throughput method, Paired-Tag, for joint profiling of histone modifications and transcriptome in single cells to produce cell-type-resolved maps of chromatin state and transcriptome in complex tissues. We used this method to profile five histone modifications jointly with transcriptome in the adult mouse frontal cortex and hippocampus. Integrative analysis of the resulting maps identified distinct groups of genes subject to divergent epigenetic regulatory mechanisms. Our single-cell multiomics approach enables comprehensive analysis of chromatin state and gene regulation in complex tissues and characterization of gene regulatory programs in the constituent cell types.

组蛋白修饰的全基因组分析不仅可以揭示调控元件的位置和活性状态，还可以揭示发育和疾病病理过程中细胞类型特异性基因表达所涉及的调控机制。分析大块组织中组蛋白修饰的常规测定缺乏单细胞分辨率。在这里，我们描述了一种超高通量方法，即配对标签，用于对单细胞中的组蛋白修饰和转录组进行联合分析，以生成复杂组织中染色质状态和转录组的细胞类型解析图。我们使用这种方法与成年小鼠额叶皮层和海马体中的转录组联合分析了五种组蛋白修饰。对所得图谱的综合分析确定了受不同表观遗传调控机制影响的不同基因组。我们的单细胞多组学方法能够全面分析复杂组织中的染色质状态和基因调控，以及组成细胞类型中基因调控程序的表征。