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CocycleHunter: cohomology-based circular gene setenrichment and genetic phase estimation in single-cell RNA-seq data.

Maggs, K.; Youssef, M. K.; Pulver, C.; Isma, J.; Nguyen, T. J.; Karthaus, W.; Hess, K.; Dotto, G. P.

2025-01-14 bioinformatics
10.1101/2025.01.09.632214 bioRxiv
Show abstract

Standard single-cell RNA-seq analysis frameworks aggregate over-lapping biological processes and impose a single parametrization, conflating distinct programs. Here, we introduce a topological framework that detects and disentangles multiple cyclic processes directly from single-cell transcriptomic data. We validate this approach on synthetic datasets and scRNA-seq profiles of human dermal fibroblasts under control conditions and following androgen receptor (AR) silencing, as well as in vivo mouse prostate regeneration under androgen receptor add-back. We show robust cell cycle structure across conditions, identify an unbiased AR-linked stress signature related to the senescence and proliferation across organisms, and uncover cholesterol homeostasis as an AR-linked program in tissue regeneration. This framework enables identification and separation of concurrent cyclic processes from snapshot single-cell data, revealing complex multi-dimensional regulatory dynamics inaccessible to standard clustering analysis.

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