Single-cell multiplex chromatin and RNA interactions in ageing human brain

Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells. We developed 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 (Nature 2024). 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. This project further analyzes these data and other brain single-cell datasets to evaluate the hypothesis of a chromatin “clock” of single-cell ageing, and delineate the cell-type specific gene regulatory programs.