Environment Tunes Propagation of Cell-to-Cell Variation in the Human Macrophage Gene Network

Cell-to-cell variation in gene expression and the propagation of such variation (PoV or “noise propagation”) from one gene to another in the gene network, as reflected by gene-gene correlation across single cells, are commonly observed in single-cell transcriptomic studies and can shape the phenotypic diversity of cell populations. While gene network “rewiring” is known to accompany cellular adaptation to different environments, how PoV changes between environments and its underlying regulatory mechanisms are less understood. Here, we systematically explored context-dependent PoV among genes in human macrophages, utilizing different cytokines as natural perturbations of multiple molecular parameters that may influence PoV. Our single-cell, epigenomic, computational, and stochastic simulation analyses reveal that environmental adaptation can tune PoV to potentially shape cellular heterogeneity by changing parameters such as the degree of phosphorylation and transcription factor-chromatin interactions. This quantitative tuning of PoV may be a widespread, yet underexplored, property of cellular adaptation to distinct environments. [Display omitted] •Propagation of variation (PoV) in gene expression depends on biochemical parameters•Different cytokine environments can tune system parameters to affect PoV•Transcription factor activity and interaction with target enhancers can tune PoV•Natural perturbation of cellular and biochemical parameters can reveal PoV regulators Martins and Narayanan et al. use single-cell analysis of human macrophages exposed to distinct cytokines combined with flow cytometry, imaging, epigenomic, and in silico stochastic simulation analyses to reveal how cell-to-cell expression variation in one gene can propagate to other genes in an environment-dependent manner to potentially shape cellular heterogeneity.