Single-cell three-dimensional (3D) genome techniques have been instrumental in elucidating cell-type-specific chromatin structures within complex tissues, yet current methodologies are limited in cell throughput. Here we introduce a high-throughput single-cell Hi-C approach (dscHiC) and its transcriptome co-assay (dscHiC-multiome) based on droplet microfluidics. dscHiC generates tens of thousands of high-quality single-cell data in a single reaction, facilitating the characterization of cell types, the detection of copy number and structural variations, thus making it suitable for functional genomic studies. Using dscHiC, we investigated chromatin structural changes during mouse brain aging by profiling 32,776 single cells from the cerebellum across three developmental stages (3 month, 12 month and 23 month), yielding a median of 78,220 unique contacts. Our findings revealed that genes exhibiting prominent structural changes are enriched in pathways related to metabolic process, morphology change in neurons and innate immune response in glial cells, offering new insights into how three-dimensional genome organization contributes to physiological brain ageing. Additionally, our multi-omics joint assay, dscHiC-multiome, enabled the precise identification of cell types in the adult mouse brain and uncovered the intricate relationship between genome architecture and gene expression. Collectively, we developed a sensitive and high-throughput dscHiC and its multiomics derivatives, dscHiC-multiome, and demonstrated their applications in studying the aging process, providing unique opportunities for large-scale cell atlas studies in development and disease.
 

single cell Hi-C,single-cell multiomics,mouse brain ageing