pC-SAC: A method for high-resolution 3D genome reconstruction from low-resolution Hi-C data.

The three-dimensional (3D) organization of the genome is crucial for gene regulation, with disruptions linked to various diseases. High-throughput Chromosome Conformation Capture (Hi-C) and related technologies have advanced our understanding of 3D genome organization by mapping interactions between distal genomic regions. However, capturing enhancer-promoter interactions at high resolution remains challenging due to the high sequencing depth required. We introduce pC-SAC (probabilistically Constrained Self-Avoiding Chromatin), a novel computational method for producing accurate high-resolution Hi-C matrices from low-resolution data. pC-SAC uses adaptive importance sampling with sequential Monte Carlo to generate ensembles of 3D chromatin chains that satisfy physical constraints derived from low-resolution Hi-C data. Our method achieves over 95% accuracy in reconstructing high-resolution chromatin maps and identifies novel interactions enriched with candidate cis-regulatory elements (cCREs) and expression quantitative trait loci (eQTLs). Benchmarking against state-of-the-art deep learning models demonstrates pC-SAC's performance in both short- and long-range interaction reconstruction. pC-SAC offers a cost-effective solution for enhancing the resolution of Hi-C data, thus enabling deeper insights into 3D genome organization and its role in gene regulation and disease. Our tool can be found at https://github.com/G2Lab/pCSAC.