RepliChrom: predicting 3D genome folding from DNA replication timing signals

Differentiating between the gene targets influenced by distal regulatory elements and those of other nearby transcribed genes is a challenging problem. However, identifying this distinction holds promise for revealing the underlying causal basis of complex diseases. Despite advances in recent high-throughput experimental methods that facilitate reconstruction of the regulatory landscape across the genome, it remains largely unclear to what extent DNA replication timing signals contribute to guiding enhancer-promoter interactions. Here we introduce RepliChrom, a computational method for predicting enhancer-promoter interactions based on replication timing features. Assessing these features revealed replication timing conservation within the same cell types and specificity across different cell types. Our results across six cell types demonstrate that replication timing features effectively predict enhancer-promoter interactions. As a proof-of-principle, we applied RepliChrom to identify interactions from various chromatin conformation capture technologies, such as Hi-C, Hi-TrAC, ChIA-PET, and 5C. Moreover, we leveraged RepliChrom to screen for significant chromatin interactions in acute lymphoblastic leukemia samples, differentiating them precisely from normal samples. This work uncovers that replication timing signals shape the three-dimensional structure of fine-grained regulatory interactions.