title: Environment Tunes Propagation of Cell-to-Cell Variation in the Human Macrophage Gene Network.
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 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.
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Martins
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Narayanan
authors.affiliation: Computational Biology Section, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Prüstel
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Fixsen
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA; Biophysics Program, University of Maryland-NIH Graduate Partnership Program, University of Maryland, College Park, MD 20742, USA.
authors.forename: Kyemyung
authors.initials: K
authors.lastname: Park
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gottschalk
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Andrews-Pfannkoch
authors.affiliation: Office of Intramural Research, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Lau
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Wendelsdorf
authors.affiliation: Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institutes of Health, Bethesda, MD 20892, USA; Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: john.tsang@nih.gov.
authors.forename: John S
authors.initials: JS
authors.lastname: Tsang
mesh_terms: D003198:Computer Simulation; D015870:Gene Expression; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D014644:Genetic Variation; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D013269:Stochastic Processes
chemical_list: D016753:Interleukin-10
keywords: IL-10; environmental perturbations; gene-gene correlations across single cells; macrophage activation; network rewiring and differential gene network analysis; noise propagation; propagation of cell-to-cell variation; single-cell genomics; stochastic modeling; transcription factor activity