Noise propagation through extracellular signaling leads to fluctuations in gene expression

Abstract

BackgroundCell-to-cell variability in mRNA and proteins has been observed in many biological systems, including the human innate immune response to viral infection. Most of these studies have focused on variability that arises from (a) intrinsic stochastic fluctuations in gene expression and (b) extrinsic sources (e.g. fluctuations in transcription factors). The main focus of our study is the effect of extracellular signaling on enhancing intrinsic stochastic fluctuations. As a new source of noise, the communication between cells with fluctuating numbers of components has received little attention. We use agent-based modeling to study this contribution to noise in a system of human dendritic cells responding to viral infection.ResultsOur results, validated by single-cell experiments, show that in the transient state cell-to-cell variability in an interferon-stimulated gene (DDX58) arises from the interplay between the spatial randomness of the cellular sources of the interferon and the temporal stochasticity of its own production. The numerical simulations give insight into the time scales on which autocrine and paracrine signaling act in a heterogeneous population of dendritic cells upon viral infection. We study the effect of different factors that influence the magnitude of the cell-to-cell-variability of the induced gene, including the cell density, multiplicity of infection, and the time scale over which the cellular sources begin producing the cytokine.ConclusionsWe propose a mechanism of noise propagation through extracellular communication and establish conditions under which the mechanism is operative. The cellular stochasticity of gene induction, which we investigate, is not limited to the specific interferon-induced gene we have studied; a broad distribution of copy numbers across cells is to be expected for other interferon-stimulated genes. This can lead to functional consequences for the system-level response to a viral challenge.

The Transcription Factor ThPOK Orchestrates Stochastic Interchromosomal Interactions Required for IFNB1 Virus-Inducible Gene Expression

“…When infected by viruses, individual cells variably respond in an ''all-or-none'' fashion to activate the IFNB1 gene due, at least in part, to the stochastic assembly of the IFNB1 enhanceosome in a fraction of infected cells only (Hu et al, 2007;Apostolou and Thanos, 2008;Tabbaa et al, 2013;Zhao et al, 2012). In addition, positive and negative feedback loops manifested by the autocrine and paracrine action of the secreted IFNB1 protein further contribute to the stochastic IFNB1 gene expression (Rand et al, 2012;Zhang et al, 2015).…”

“…These interactions, which are stochastic in nature, occur only in the fraction of the cell population that expresses the IFNB1 gene and involve one IFNB1 allele and one allele of a single NRC. Enhancer-bound NF-kB nucleates the assembly of the IFNB1 enhanceosome causing early mono-allelic IFNB1 gene expression (Apostolou and Thanos, 2008;Tabbaa et al, 2013).…”

Ageing and sources of transcriptional heterogeneity

“…This phenomenon was initially observed in the stochastic inactivation of one X chromosome in the somatic cells of female mammals (Lyon, 1961). In autosomal genes, the inactivation of one allele was observed firstly in olfactory receptors (Chess et al, 1994) and cytokine genes IL-2 (Holländer et al, 1998), IL-4 (Rivière et al, 1998) and IFNB1 (Tabbaa et al, 2013), among others. The mechanism of DNA looping, in the form of interchromosomal interactions, has also been shown to play a role in the regulation of stochastic monoallelic expression of the olfactory receptor genes in neurons (Lomvardas et al, 2006) and in response to viral infection for the IFNB1 gene (Apostolou and Thanos, 2008).…”

Single-cell analysis shows that paracrine signaling by first responder cells shapes the interferon-β response to viral infection

“…To study the full innate immune response, we infected DCs with NDV, a virus that lacks effective immune antagonists for human cells. Multiscale agent-based modeling has shown that the single-cell variation in the secretion of IFN is predicted to generate a spatially heterogeneous response of IFN-inducible genes (46). The propagation of noise within one cell type and in complex organs, such as the lung, is an important area for investigation.…”