Gene expression variability across cells and species shapes innate immunity

Abstract

Summary As the first line of defence against pathogens, cells mount an innate immune response, which is highly variable from cell to cell. The response must be potent yet carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here, we characterise this programme’s transcriptional divergence between species and expression variability across cells. Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, we reveal a striking architecture of the innate immune response. Transcriptionally diverging genes, including cytokines and chemokines, vary across cells and have distinct promoter structures. Conversely, genes involved in response regulation, such as transcription factors and kinases, are conserved between species and display low cell-to-cell expression variability. We suggest that this unique expression pattern, observed across species and conditions, has evolved as a mechanism for fine-tuned regulation, achieving an effective but balanced response.

Neutrophil‐endothelial interactions of murine cells is not a good predictor of their interactions in human cells

“…[26][27][28][29][30] In support of this concept, one recent study employing bulk and single cell transcriptomics to map the innate immune response demonstrated significant species differences in cytokines, chemokines, and their respective receptors. 31 Recently, an international panel of experts emphasized the continuing need for mouse models in sepsis research but outlined significant limitations and the need for models that better represent human disease. 32 Thus, there is a significant need for an "in vitro reconstitution of disease-related cell types or tissues" to study human inflammatory diseases.…”

Dynamic rewiring of the human interactome by interferon signalling

“…A combination of unbiased transcriptome profiling [2,[7][8][9] and biochemical approaches [10][11][12][13] , have identified hundreds of ISGs and, in some cases, elucidated their mechanism of action. Yet the functional roles of most ISGs as effectors of the innate immune response remain to be fully characterized.…”

Extent, heritability, and functional relevance of single cell expression variability in highly homogeneous populations of human cells

“…This data has been deposited in the NCBI GEO database (Accession number GSE126321, Data Availability). For the other two cell types, LAEC and DF, we obtained the scRNA-seq data for 3,863 and 2,553 cells from the studies of (Habiel et al 2018) and (Hagai et al 2018), respectively (Materials and Methods). All scRNA-seq data sets of the three cell types were produced using 10X Genomics droplet-based solution and made use of unique molecular identifiers (UMIs) (Kivioja et al 2011).…”

“…Third, DFs are responsible for generating connective tissue and play a critical role in normal wound healing (Tracy et al 2016). DFs are also commonly used in immunological studies (Zhao et al 2012;Ivashkiv and Donlin 2014;Hagai et al 2018). HVGs identified in DFs again accurately reflect these primary aspects of DF functions, including extracellular matrix organization, keratinization, and regulation of signaling receptor activity.…”

“…We used the data generated from the CCR10 -cells with the sample identifier GSM3204305. The scRNA-seq data for primary dermal fibroblasts (DFs) was generated in the study of (Hagai et al 2018). We downloaded the data for unstimulated DFs from the ArrayExpress database using accession number E-MTAB-5988.…”