scDIAGRAM: Detecting Chromatin Compartments from Individual Single-Cell Hi-C Matrix without Imputation or Reference Features

Abstract Single-cell Hi-C (scHi-C) provides unprecedented insight into 3D genome organization, but its sparse and noisy data pose challenges in accurately detecting A/B compartments, which are crucial for understanding chromatin structure and gene regulation. We presented scDIAGRAM, a data-driven method for annotating A/B compartments in single cells using direct statistical modeling and graph community detection. Unlike existing approaches, scDIAGRAM operates without relying on external information, such as the CpG density or imputation techniques, and preserves cell-to-cell heterogeneity. Accuracy and robustness of scDIAGRAM were illustrated through simulated scHi-C datasets and a human cell line. We applied scDIAGRAM to real scHi-C datasets from the mouse brain cortex, mouse embryonic development, and human acute myeloid leukemia (AML), demonstrating its ability to capture compartmental shifts associated with transcriptional variation. This robust framework offers new insights into the functional roles of chromatin compartments at single-cell resolution across various biological contexts. Competing Interest Statement The authors have declared no competing interest.