One model fits all: Combining inference and simulation of gene regulatory networks

• DOI: 10.1371/journal.pcbi.1010962
• Publication Date: 2023-03-27T17:33:37Z
• Authors: Elias Ventre; Ulysse Herbach; Thibault Espinasse; Gérard Benoit; Olivier Gandrillon
• Keywords: 570; QH301-705.5; 0206 medical engineering; 610; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry; 02 engineering and technology; Gene regulatory networks; Mice; Stochastic gene expression; [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]; Animals; Gene Regulatory Networks; Computer Simulation; [MATH]Mathematics [math]; Biology (General); Time-course profiles; Molecular Biology/Genomics [q-bio.GN]; Gene Expression Profiling; Transcriptional bursting; Lineage commitment; [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]; Data simulation; Single-cell transcriptomics; Algorithms; Causal inference; Research Article

The rise of single-cell data highlights the need for a nondeterministic view of gene expression, while offering new opportunities regarding gene regulatory network inference. We recently introduced two strategies that specifically exploit time-course data, where single-cell profiling is performed after a stimulus: HARISSA, a mechanistic network model with a highly efficient simulation procedure, and CARDAMOM, a scalable inference method seen as model calibration. Here, we combine the two approaches and show that the same model driven by transcriptional bursting can be used simultaneously as an inference tool, to reconstruct biologically relevant networks, and as a simulation tool, to generate realistic transcriptional profiles emerging from gene interactions. We verify that CARDAMOM quantitatively reconstructs causal links when the data is simulated from HARISSA, and demonstrate its performance on experimental data collected on in vitro differentiating mouse embryonic stem cells. Overall, this integrated strategy largely overcomes the limitations of disconnected inference and simulation.