biostudies-literatureWen XNICHD NIH HHSNIA NIH HHSNIDDK NIH HHSNCI NIH HHSNINDS NIH HHSNIGMS NIH HHS648-656https://www.ebi.ac.uk/biostudies/studies/S-EPMC11023937biostudies-literatureUnknown628(8008)Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA^1-3. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells^4-7. 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.NatureSingle-cell multiplex chromatin and RNA interactions in ageing human brain.PMC11023937U24 NS072026U01 CA200147R01 HD107206P30 AG019610UH3 CA256960P30 AG072980R01 GM138852DP1 DK126138Wen XNguyen TCCalandrelli RLuo ZZhong SZhao WCharles Richard JLWan XfalseSingle-cell multiplex chromatin and RNA interactions in ageing human brain.Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA^1-3. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells^4-7. 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.2024-01-01T00:00:00Z2024 Apr2026-03-16T09:58:25.909Z2025-08-15T03:06:56.946ZS-EPMC110239373853878910.1038/s41586-024-07239-w