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Topology identifies concurrent cyclic processes in single-cell transcriptomics and androgen receptor function

Kelly MaggsiD, Markus K. YoussefiD, Cyril PulveriD, Jovan IsmaiD, Tâm J. Nguyên, Matthias Arzt, Wouter R. KarthausiD, Heather A. Harrington, Kathryn P. HessiD, G. Paolo Dotto

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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