Biology subjects

Zinati, Y.

Publications and source records attributed to Zinati, Y..

2 recordsLinked to original sources

bioRxiv2025

Causal single-cell RNA-seq simulation, in silico perturbation, and GRN inference benchmarking using GRouNdGAN-Toolkit

BackgroundRapid advances in high-throughput single-cell sequencing technologies, coupled with the development of computational methods capable of leveraging large datasets, have led to the emergence of numerous approaches for deciphering regulatory interactions in the form of Gene Regulatory Networks (GRNs). However, in the absence of context-specific gold-standard ground truths, particularly those containing causal interactions, systematically benchmarking GRN inference methods remains a challenge. Thus, we previously developed GRouNdGAN, a causal implicit generative model capable of simulating realistic observational and interventional scRNA-seq data following a user-defined GRN on any biological system of interest. Importantly, we demonstrated that GRouNdGAN generates datasets that bridge the gap between experimentation and simulation for GRN inference benchmarking. MethodBuilding upon the GRouNdGAN framework, we developed an extended toolkit that offers additional features, including interactive model visualization, training monitoring, more customizable GRN creation options, synthetic data similarity and GRN inference benchmarking metrics, and an intuitive TF knockout prediction module. Here, we provide a step-by-step procedure for implementing the protocol from start to finish and introduce alternative variations to adapt GRouNdGAN to studies with different experimental setups. GRouNdGAN-Toolkit is publicly available as a python code repository and containerized application and is accompanied by a tutorial website featuring a collection of simulated datasets. Model training largely depends on graphic hardware and the size and density of the input GRN, and typically takes around 75h to complete on a single GPU. Excluding model training, this protocol typically takes less than 25min to complete. DiscussionGRouNdGAN-Toolkit is a versatile simulator with user friendly interface that does not assume advanced computational genomics expertise, enhancing its usability and accessibility across a wide range of users.

bioinformatics↗

bioRxiv2023

GRouNdGAN: GRN-guided simulation of single-cell RNA-seq data using causal generative adversarial networks

We introduce GRouNdGAN, a gene regulatory network (GRN)-guided causal implicit generative model for simulating single-cell RNA-seq data, in-silico perturbation experiments, and benchmarking GRN inference methods. Through the imposition of a user-defined GRN in its architecture, GRouNdGAN simulates steady-state and transient-state single-cell datasets where genes are causally expressed under the control of their regulating transcription factors (TFs). Training on three experimental datasets, we show that our model captures non-linear TF-gene dependences and preserves gene identities, cell trajectories, pseudo-time ordering, and technical and biological noise, with no user manipulation and only implicit parameterization. Despite imposing rigid causality constraints, it outperforms state-of-the-art simulators in generating realistic cells. GRouNdGAN learns meaningful causal regulatory dynamics, allowing sampling from both observational and interventional distributions. This enables it to synthesize cells under conditions that do not occur in the dataset at inference time, allowing to perform in-silico TF knockout experiments. Our results show that in-silico knockout of cell type-specific TFs significantly reduces cells of that type being generated. Interactions imposed through the GRN are emphasized in the simulated datasets, resulting in GRN inference algorithms assigning them much higher scores than interactions not imposed but of equal importance in the experimental training dataset. Benchmarking various GRN inference algorithms reveals that GRouNdGAN effectively bridges the existing gap between simulated and biological data benchmarks of GRN inference algorithms, providing gold standard ground truth GRNs and realistic cells corresponding to the biological system of interest. Our results show that GRouNdGAN is a stable, realistic, and effective simulator with various applications in single-cell RNA-seq analysis.

bioinformatics↗