Contact-Guided 3D Genome Structure Generation of E. coli via Diffusion Transformers

We study whether the loss design of High-Fidelity Generative Image Compression (HiFiC), a GAN-based neural codec originally built for natural photographs, can be adapted to preserve biologically meaningful structure in Hi-C chromatin contact maps under lossy compression. Standard image compression, including HiFiC in its original form, optimizes for human visual perception; but a Hi-C contact map is normally distributed together with its numeric matrix file (.cool/.mcool), which downstream genomic analysis tools consume directly. Aggressive compression that looks acceptable to the eye can nonetheless blur or delete loops and topologically associating domain (TAD) boundaries that these tools depend on. We modify HiFiC's distortion term with a spatially-weighted MSE that up-weights biologically salient regions (loops, TAD boundaries, stripes, compartment structure) and add an insulation-score loss term that directly penalizes loss of TAD boundary sharpness. We describe a three-phase fine-tuning strategy that adapts a pretrained HiFiC checkpoint to the Hi-C domain without catastrophic forgetting. We evaluate the resulting system, HiFiC-G, using both conventional image-quality metrics (PSNR, SSIM) and genomics-domain preservation metrics (loop/TAD/compartment/stripe preservation percentage) across two cell lines. HiFiC-G preserves local structure, meaning stripes and TAD boundaries, substantially better than the metrics alone would suggest, while long-range A/B compartment structure remains poorly preserved; we show this gap tracks genomic scale and is consistent with a specific architectural cause, the fixed-size tiling that both HiFiC-G and the original HiFiC rely on for memory efficiency.

Locating genomic features from genomic contact maps, such as centromere identification from genome-wide chromosome conformation capture techniques, notably Hi-C, can be formulated as an inverse problem: infer one parameter per entity given a map summarizing pairwise interactions through blocks of variable numbers and sizes. In this work, we introduce a data-driven approach that leverages shared structure between these contact maps, such as global alignment between localized patterns, while handling the variability in number and size of chromosomes arising in real-world data. Our approach relies on a transformer architecture capable of handling such variability and a custom simulator to generate abundant, yet computationally cheap synthetic data for training. Applied to the problem of centromere localization, the method recovers genomic positions at or below the map resolution across species with various genome sizes using a coarse-to-fine refinement step when chromosome sizes fall outside the training range. We concentrate our evaluation on Hi-C data, where the block structure is well characterized and ground truth is available.

De novo protein generation has transformative potential in therapeutic design, enzyme engineering, and synthetic biology. While diffusion-based and flow matching approaches have achieved progress, they typically operate at single resolution and lack mechanisms for incorporating functional constraints. We introduce ProHiFlo, a hierarchical flow matching framework with three innovations: (1) coarse-to-fine generation that models backbone geometry before refining to all-atom coordinates, reducing computational cost while maintaining accuracy; (2) functional guidance leveraging pretrained predictors to steer generation toward desired properties without retraining; (3) adaptive SE(3)-equivariant architecture for efficient multi-scale processing. Experiments on unconditional generation, motif scaffolding, and functional design demonstrate state-ofthe-art performance while requiring 4 fewer sampling steps. On enzyme active site scaffolding, ProHiFlo achieves 58.9% success rate compared to 41.2% for RFDiffusion.