Enhancing Single-Cell and Bulk Hi-C Data Using a Generative Transformer Model

The 3D organization of chromatin in the nucleus plays a critical role in regulating gene expression and maintaining cellular functions in eukaryotic cells. High-throughput chromosome conformation capture (Hi-C) and its derivative technologies have been developed to map genome-wide chromatin interactions at the population and single-cell levels. However, insufficient sequencing depth and high noise levels in bulk Hi-C data, particularly in single-cell Hi-C (scHi-C) data, result in low-resolution contact matrices, thereby limiting diverse downstream computational analyses in identifying complex chromosomal organizations. To address these challenges, we developed a transformer-based deep learning model, HiCENT, to impute and enhance both scHi-C and Hi-C contact matrices. Validation experiments on large-scale bulk Hi-C and scHi-C datasets demonstrated that HiCENT achieves superior enhancement effects compared to five popular methods. When applied to real Hi-C data from the GM12878 cell line, HiCENT effectively enhanced 3D structural features at the scales of topologically associated domains and chromosomal loops. Furthermore, when applied to scHi-C data from five human cell lines, it significantly improved clustering performance, outperforming five widely used methods. The adaptability of HiCENT across different datasets and its capacity to improve the quality of chromatin interaction data will facilitate diverse downstream computational analyses in 3D genome research, single-cell studies and other large-scale omics investigations.