Spatially Varying Gene Regulatory Networks via Bayesian Nonparametric Covariate-Dependent Directed Cyclic Graphical Models

TL;DR

This paper introduces BNP-DCGx, a Bayesian nonparametric model that captures spatially varying gene regulatory networks with feedback loops, addressing limitations of existing models by allowing continuous variation and ensuring stability.

Contribution

We develop a novel covariate-dependent hierarchical Bayesian model with a random partition to learn stable, cyclic gene networks that vary smoothly across spatial tissue regions.

Findings

Accurately recovers piecewise constant and smooth graph structures in simulations.

Identifies spatially varying regulatory feedback loops in brain tissue.

Reveals potential cell subtypes based on regulatory mechanisms.

Abstract

Spatial transcriptomics technologies enable the measurement of gene expression with spatial context, providing opportunities to understand how gene regulatory networks vary across tissue regions. However, existing graphical models focus primarily on undirected graphs or directed acyclic graphs, limiting their ability to capture feedback loops that are prevalent in gene regulation. Moreover, ensuring the so-called stability condition of cyclic graphs, while allowing graph structures to vary continuously with spatial covariates, presents significant statistical and computational challenges. We propose BNP-DCGx, a Bayesian nonparametric approach for learning spatially varying gene regulatory networks via covariate-dependent directed cyclic graphical models. Our method introduces a covariate-dependent random partition as an intermediary layer in a hierarchical model, which discretizes the covariate space into clusters with cluster-specific stable directed cyclic graphs. Through partition averaging, we obtain smoothly varying graph structures over space while maintaining theoretical guarantees of stability. We develop an efficient parallel tempered Markov chain Monte Carlo algorithm for posterior inference and demonstrate through simulations that our method accurately recovers both piecewise constant and continuously varying graph structures. Application to spatial transcriptomics data from human dorsolateral prefrontal cortex reveals spatially varying regulatory networks with feedback loops, identifies potential cell subtypes within established cell types based on distinct regulatory mechanisms, and provides new insights into spatial organization of gene regulation in brain tissue.