Stage-specific dynamic reorganization of genome topology shapes transcriptional neighborhoods in developing human retinal organoids
We have generated high-resolution Hi-C map of developing human retinal organoids to elucidate spatiotemporal dynamics of genomic architecture and its relationship with gene expression patterns. We demonstrate progressive and developmental stage-specific alterations in DNA topology and correlate these changes with transcription of cell type-restricted gene markers during retinal differentiation. Temporal Hi-C reveals a shift towards A compartment for protein-coding genes and B compartment for non-coding RNAs, displaying high and low expression respectively. Notably, retina-enriched genes are clustered near lost boundaries of topologically associated domains (TADs), and higher-order assemblages of TADs (i.e., TAD cliques) tend to localize in the active chromatin regions with binding sites for eye-field transcription factors. These genes show a gain of chromatin contacts at their transcription start site as organoid differentiation proceeds. Our study provides a global view of chromatin architecture dynamics associated with diversification of cell types during retinal development and serves as a foundational resource for in-depth functional investigations of retinal developmental traits. Overall design: High resolution Hi-C at five time points in retinal organoid development (D60, D70, D90, D120, D200).