Journal ArticleUnicorn: enhancing single-cell Hi-C data with blind super-resolution for 3D genome structure reconstructionChandrashekar, Mohan_Kumar B; Menon, Rohit; Olowofila, Samuel; Oluwadare, OluwatosinMotivation: Single-cell Hi-C (scHi-C) data provide critical insights into chromatin interactions at individual cell levels, uncovering unique genomic 3D structures. However, scHi-C datasets are characterized by sparsity and noise, complicating efforts to accurately reconstruct high-resolution chromosomal structures. In this study, we present ScUnicorn, a novel blind super-resolution framework for scHi-C data enhancement. ScUnicorn uses an iterative degradation kernel optimization process, unlike traditional super-resolution approaches, which rely on downsampling, predefined degradation ratios, or constant assumptions about the input data to reconstruct high-resolution interaction matrices. Hence, our approach more reliably preserves critical biological patterns and minimizes noise. Additionally, we propose 3DUnicorn, a maximum likelihood algorithm that leverages the enhanced scHi-C data to infer precise 3D chromosomal structures. Result: Our evaluation demonstrates that ScUnicorn achieves superior performance over the state-of-the-art methods in terms of Peak Signal-to-Noise Ratio, Structural Similarity Index Measure, and GenomeDisco scores. Moreover, 3DUnicorn’s reconstructed structures align closely with experimental 3D-FISH data, underscoring its biological relevance. Together, ScUnicorn and 3DUnicorn provide a robust framework for advancing genomic research by enhancing scHi-C data fidelity and enabling accurate 3D genome structure reconstruction. Availability and implementation: Unicorn implementation is publicly accessible at https://github.com/OluwadareLab/Unicorn.Oxford University Press2025-07-0110615502Bioinformatics41Supplement_1i475 to i4831367-4803https://doi.org/10.1093/bioinformatics/btaf1772153205National Science Foundation