Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA^1,2,3. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells^4,5,6,7. Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and RNA–chromatin associations within individual nuclei. When applied to 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types and states. We observed that nuclei exhibiting fewer short-range chromatin interactions were correlated with both an ‘older’ transcriptomic signature and Alzheimer’s disease pathology. Furthermore, the cell type exhibiting chromatin contacts between cis expression quantitative trait loci and a promoter tends to be that in which these cis expression quantitative trait loci specifically affect the expression of their target gene. In addition, female cortical cells exhibit highly heterogeneous interactions between XIST non-coding RNA and chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploration of chromatin architecture and transcription at cellular resolution in complex tissues.

动态组织的染色质复合物通常涉及多重染色质相互作用，有时还涉及染色质相关 RNA ^1,2,3。染色质复合体组成在细胞分化和衰老过程中发生变化，并且预计在终末分化的单细胞中具有高度异质性^4,5,6,7。在这里，我们介绍单细胞多核酸相互作用作图 (MUSIC) 技术，用于同时分析单个细胞核内的多重染色质相互作用、基因表达和 RNA-染色质关联。当应用于来自老年捐赠者的 14 个人类额叶皮层样本时，MUSIC 描绘了不同的皮层细胞类型和状态。我们观察到，表现出较少短程染色质相互作用的细胞核与“较旧”的转录组特征和阿尔茨海默病病理学相关。此外，在顺式表达数量性状基因座和启动子之间表现出染色质接触的细胞类型往往是其中这些顺式表达数量性状基因座特异性影响其靶基因的表达的细胞类型。此外，女性皮质细胞表现出 XIST 非编码 RNA 和 X 染色体之间高度异质的相互作用，以及 X 染色体的不同空间组织。 MUSIC 为探索复杂组织中细胞分辨率的染色质结构和转录提供了有力的工具。