HiCP2GAN: a plug and play foundation model-based GAN for Hi-C enhancement

Abstract

The 3D organization of chromatin shapes gene regulation and cellular function, and Hi-C has become the primary technique for mapping chromatin interactions genome-wide. However, high-resolution data remain costly and scarce, leaving many studies with sparse contact maps that limit downstream analysis. Deep learning methods, especially generative adversarial networks (GANs), have shown promise for enhancing low-resolution Hi-C data, but most existing GAN-based approaches rely on custom discriminators trained from scratch, which can yield unstable training and limited generalization. Hi-C foundation models pretrained on large-scale data capture rich, transferable representations of chromatin structure, yet their use as discriminators within adversarial enhancement frameworks had not been explored. We introduce HiCP2GAN, a plug-and-play GAN that employs a pretrained Vision Transformer-based Hi-C foundation model as its discriminator. The discriminator was pretrained on 118 million Hi-C patches across diverse species and cell types, providing biologically meaningful gradients for adversarial supervision. The framework is generator-agnostic: any compatible Hi-C resolution enhancement architecture can serve as the generator, enabling fair comparison across methods. The encoder phase of the foundation model was adapted as a discriminator backbone, finetuning the first few layers from the input while freezing the deeper transformer layers to preserve pretrained knowledge while allowing task-specific adaptation. Experiments across various cell lines show that HiCP2GAN outperforms traditional GAN-based methods in most settings and improves the reconstruction quality and biological reproducibility of existing Hi-C enhancement models in most evaluated cases. HiCP2GAN is publicly available at https://github.com/OluwadareLab/HiCP2GAN.