Tri-omic mapping revealed concerted dynamics of 3D epigenome and transcriptome in brain cells

Exploring the genomic basis of transcriptional programs has been a longstanding research focus. Here, we report a high-throughput single-cell tri-omic method to capture chromatin accessibility, interaction, and RNA simultaneously (ChAIR). After validating in cultured cells, we applied ChAIR to brain cells across mouse lifespan and delineated the concerted dynamics of 3D-epigenomic architecture and transcription during maturation and aging. Particularly, ultra-long chromatin megacontacts and promoter-associated 3D-epigenomic states are effective in defining cell identity and revealing spatially-resolved anatomic specificity. Importantly, we found that neurons in different brain regions and non-neuronal cells may undergo divergent genomic mechanisms during differentiation and aging. Our results demonstrated ChAIR's robustness of connecting chromatin folding architecture with cellular property and its potential applications to address complex questions in single-cell resolution and spatial specificity.