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

Andrew J Martins,Manikandan Narayanan,Thorsten Prüstel,Bethany Fixsen,Kyemyung Park,Rachel A Gottschalk,Yong Lu,Cynthia Andrews-Pfannkoch,William W Lau,Katherine V Wendelsdorf,John S Tsang

doi:10.1016/j.cels.2017.03.002

Abstract

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 suchas 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.

Highlights

Single-cell expression data have revealed pervasive cell-to-cell variability in mRNA and protein expression, even within isogenic cell populations exposed to identical environments (Altschuler and Wu, 2010; Eldar and Elowitz, 2010; Raj and van Oudenaarden, 2008)
While observing single cell gene-gene correlation (scGGC) is often expected when a gene X is capable of regulating another gene Y, it is possible that cells may tune propagation of variation (PoV), for example to attenuate PoV when buffering of stochastic fluctuation in gene expression level is beneficial, or to enhance PoV when robust transmission of upstream signals is desired (Figure 1A)
As certain ‘‘hub’’ genes may regulate many partners, changes in PoV involving hubs may lead to modules of genes showing differential scGGC between different environments (Figure 1C)

Summary

Introduction

Single-cell expression data have revealed pervasive cell-to-cell variability in mRNA and protein expression, even within isogenic cell populations exposed to identical environments (Altschuler and Wu, 2010; Eldar and Elowitz, 2010; Raj and van Oudenaarden, 2008). Such cell-to-cell differences in gene expression can arise due to a combination of ‘‘intrinsic’’ (e.g., inherent stochasticity in biochemical reactions underlying gene and protein expression) and ‘‘extrinsic’’ (e.g., differences in the micro-environment or ribosome concentration of individual cells) factors. The environmental, cellular, and biochemical conditions affecting the extent of PoV remain poorly understood, in mammalian cells that often exhibit complex signaling and gene-regulatory mechanisms

Methods

Results

Discussion

Conclusion