scTenifoldNet: A Machine Learning Workflow for Constructing and Comparing Transcriptome-wide Gene Regulatory Networks from Single-Cell Data

Abstract Constructing and comparing gene regulatory networks (GRNs) from single-cell RNA sequencing (scRNAseq) data has the potential to reveal critical components in the underlying regulatory networks regulating different cellular transcriptional activities. Here, we present a robust and powerful machine learning workflow—scTenifoldNet—for comparative GRN analysis of single cells. The scTenifoldNet workflow, consisting of principal component regression, low-rank tensor approximation, and manifold alignment, constructs and compares transcriptome-wide single-cell GRNs (scGRNs) from different samples to identify gene expression signatures shifting with cellular activity changes such as those associated with pathophysiological processes and responses to environmental perturbations. We used simulated data to benchmark scTenifoldNet’s performance, and then applied scTenifoldNet to several real data sets. In real-data applications, scTenifoldNet identified highly specific changes in gene regulation in response to acute morphine treatment, an antibody anticancer drug, gene knockout, double-stranded RNA stimulus, and amyloid-beta plaques in various types of mouse and human cells. We anticipate that scTenifoldNet can help achieve breakthroughs through constructing and comparing scGRNs in poorly characterized biological systems, by deciphering the full cellular and molecular complexity of the data. Highlights scTenifoldNet is a machine learning workflow built upon principal component regression, low-rank tensor approximation, and manifold alignment scTenifoldNet uses single-cell RNA sequencing (scRNAseq) data to construct single-cell gene regulatory networks (scGRNs) scTenifoldNet compares scGRNs of different samples to identify differentially regulated genes Real-data applications demonstrate that scTenifoldNet accurately detects specific signatures of gene expression relevant to the cellular systems tested. Short abstract We present scTenifoldNet—a machine learning workflow built upon principal component regression, low-rank tensor approximation, and manifold alignment—for constructing and comparing single-cell gene regulatory networks (scGRNs) using data from single-cell RNA sequencing (scRNAseq). scTenifoldNet reveals regulatory changes in gene expression between samples by comparing the constructed scGRNs. With real data, scTenifoldNet identifies specific gene expression programs associated with different biological processes, providing critical insights into the underlying mechanism of regulatory networks governing cellular transcriptional activities.