Epigenomics-Guided Flow Matching for 3D Genome Super-Resolution

Mapping fine-scale 3D chromatin landscapes is critical for understanding gene regulation, yet the resolution of Hi-C data remains fundamentally constrained by both physical bottlenecks and sequencing costs. Although deep learning has shown promise in super-resolving Hi-C data, existing methods suffer from absolute coordinate loss during localized patching and a lack of structural and epigenomic priors in unconditioned generation. We propose a novel epigenomics-guided flow matching framework EpiFlow for 3D genome super-resolution. EpiFlow introduces two key innovations: (1) an EpiCond module that deterministically maps 1D epigenomic features to 2D spatial constraints via orthogonal expansion with built-in positional grounding, avoiding quadratic attention complexity; and (2) a Toeplitz-regularized classifier-free guidance mechanism that enforces distance-decay priors using a learnable symmetric prototype matrix. Extensive evaluation shows that our method achieves state-of-the-art cross-cell-type loop detection, improving recall by $2.8\times$ over raw Hi-C on unseen H1-hESC (Loop $F_1$ of $0.325$ vs. $0.199$) and outperforming all baselines on same-cell HFFc6 ($F_1=0.520$). Aggregate Peak Analysis (APA) confirms biological validity, and strong generalization to a held-out cell line demonstrates that the model learns transferable principles of 3D genome folding rather than cell-specific biases.