From Noise to Knowledge: Diffusion Probabilistic Model-Based Neural Inference of Gene Regulatory Networks.

Understanding gene regulatory networks (GRNs) is crucial for elucidating cellular mechanisms and advancing therapeutic interventions. Original methods for GRN inference from bulk expression data often struggled with the high dimensionality and inherent noise in the data. Here we introduce RegDiffusion, a new class of Denoising Diffusion Probabilistic Models focusing on the regulatory effects among feature variables. RegDiffusion introduces Gaussian noise to the input data following a diffusion schedule and uses a neural network with a parameterized adjacency matrix to predict the added noise. We show that using this process, GRNs can be learned effectively with a surprisingly simple model architecture. In our benchmark experiments, RegDiffusion shows superior performance compared to several baseline methods in multiple datasets. We also demonstrate that RegDiffusion can infer biologically meaningful regulatory networks from real-world single-cell data sets with over 15,000 genes in under 5 minutes. This work not only introduces a fresh perspective on GRN inference but also highlights the promising capacity of diffusion-based models in the area of single-cell analysis. The RegDiffusion software package and experiment data are available at https://github.com/TuftsBCB/RegDiffusion.