Unveiling Multi-Scale Architectural Features in Single-Cell Hi-C Data Using scCAFE

Single-cell Hi-C (scHi-C) has provided unprecedented insights into the heterogeneity of 3D genome organization. However, its sparse and noisy nature poses challenges for computational analyses, such as chromatin architectural feature identification. Here, scCAFE is introduced, which is a deep learning model for the multi-scale detection of architectural features at the single-cell level. scCAFE provides a unified framework for annotating chromatin loops, TAD-like domains (TLDs), and compartments across individual cells. This model outperforms previous scHi-C loop calling methods and delivers accurate predictions of TLDs and compartments that are biologically consistent with previous studies. The resulting single-cell annotations also offer a measure to characterize the heterogeneity of different levels of architectural features across cell types. This heterogeneity is then leveraged to identify a series of marker loop anchors, demontrating the potential of the 3D genome data to annotate cell identities without the aid of simultaneously sequenced omics data. Overall, scCAFE not only serves as a useful tool for analyzing single-cell genomic architecture, but also paves the way for precise cell-type annotations solely based on 3D genome features. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.