Gene regulatory interactions limit the gene expression diversity

The diversity of expressed genes plays a critical role in cellular specialization, adaptation to environmental changes, and overall cell functionality. This diversity varies dramatically across cell types and is orchestrated by intricate, dynamic, and cell type-specific gene regulatory networks (GRNs). Despite extensive research on GRNs, their governing principles, as well as the underlying forces that have shaped them, remain largely unknown. Here, we investigated whether there is a tradeoff between the diversity of expressed genes and the intensity of GRN interactions. We have developed a computational framework that evaluates GRN interaction intensity from scRNA-seq data and used it to analyze simulated and real scRNA-seq data collected from different tissues in humans, mice, fruit flies, and C. elegans. We find a significant tradeoff between diversity and interaction intensity, driven by stability constraints, where the GRN could be stable up to a critical level of complexity - a product of gene expression diversity and interaction intensity. Furthermore, we analyzed hematopoietic stem cell differentiation data and find that the overall complexity of unstable transition states cells is higher than that of stem cells and fully differentiated cells. Our results suggest that GRNs are shaped by stability constraints which limit the diversity of gene expression.