Systematic evaluation of single-cell multimodal data integration enhances cell type resolution and discovery of clinically relevant states in complex tissues

作者：Mario Acera-Mateos, Xian Adiconis, Jessica Li, Domenica Marchese, G. Caratù, C. Hon, Prabha Tiwari, Miki Kojima, B. Vieth, Michael Murphy, Sean K. Simmons, Thomas Lefevre, Irene Claes, C. L. O'Connor, R. Menon, E. Otto, Yoshinari Ando, K. Vandereyken, M. Kretzler, M. Bitzer, Ernest Fraenkel, Thierry Voet, W. Enard, P. Carninci, H. Heyn, Joshua Z. Levin, E. Mereu · 发表于：Genome Biology · 年份：2026 · DOI：10.1186/s13059-026-04002-4 · 被引用次数：7 · 研究领域：Medicine

Background The integration of multimodal single-cell data enables comprehensive organ reference atlases, yet its impact remains largely unexplored, particularly in complex tissues. Using the kidney as an emblematic example of a complex organ, we perform a systematic evaluation of multimodal single-cell integration strategies, with heart tissue used for additional methodological validation. Results We generate a benchmarking dataset for the renal cortex by integrating 3' and 5' scRNA-seq with joint snRNA-seq and snATAC-seq, profiling 119,744 high-quality nuclei/cells from 19 donors. To align cell identities and enable consistent comparisons, we develop the interpretable machine learning tool scOMM (single-cell Omics Multimodal Mapping) and systematically assess integration strategies. "Horizontal" integration of scRNA and snRNA-seq improves cell-type identification, while "vertical" integration of snRNA-seq and snATAC-seq has an additive effect, enhancing resolution in homogeneous populations and difficult-to-identify states. Global integration is especially effective in identifying adaptive states and rare cell types, including WFDC2-expressing Thick Ascending Limb and Norn cells, previously undetected in kidney atlases. Conclusions Our work establishes a robust framework for multimodal reference atlas generation, advancing single-cell analysis and extending its applicability to diverse tissues. Supplementary Information The online version contains supplementary material avai...