Single‐Cell Hi‐C Technologies and Computational Data Analysis

Abstract Single‐cell chromatin conformation capture (scHi‐C) techniques have evolved to provide significant insights into the structural organization and regulatory mechanisms in individual cells. Although many scHi‐C protocols have been developed, they often involve intricate procedures and the resulting data are sparse, leading to computational challenges for systematic data analysis and limited applicability. This review provides a comprehensive overview, quantitative evaluation of thirteen protocols and practical guidance on computational topics. It is first assessed the efficiency of these protocols based on the total number of contacts recovered per cell and the cis/trans ratio. It is then provided systematic considerations for scHi‐C quality control and data imputation. Additionally, the capabilities and implementations of various analysis methods, covering cell clustering, A/B compartment calling, topologically associating domain (TAD) calling, loop calling, 3D reconstruction, scHi‐C data simulation and differential interaction analysis is summarized. It is further highlighted key computational challenges associated with the specific complexities of scHi‐C data and propose potential solutions.