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The diversity of expressed genes plays a critical role in cellularspecialization, adaptation to environmental changes, and overall cellfunctionality. This diversity varies dramatically across cell types and isorchestrated by intricate, dynamic, and cell type-specific gene regulatorynetworks (GRNs). Despite extensive research on GRNs, their governingprinciples, as well as the underlying forces that have shaped them, remainlargely unknown. Here, we investigated whether there is a tradeoff between thediversity of expressed genes and the intensity of GRN interactions. We havedeveloped a computational framework that evaluates GRN interaction intensityfrom scRNA-seq data and used it to analyze simulated and real scRNA-seq datacollected 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 criticallevel of complexity - a product of gene expression diversity and interactionintensity. Furthermore, we analyzed hematopoietic stem cell differentiationdata and find that the overall complexity of unstable transition states cellsis higher than that of stem cells and fully differentiated cells. Our resultssuggest that GRNs are shaped by stability constraints which limit the diversityof gene expression.

Gene regulatory interactions limit the gene expression diversity