Holst-Hansen, T. | Search bioRxiv

bioRxiv2021

Spatiotemporal NF-κB dynamics encodes the position, amplitude and duration of local immune inputs

Infected cells communicate through secreted signaling molecules like cytokines, which inform nearby cells about the type, severity and location of pathogens. How differences in cytokine secretion affect inflammatory signaling over space and time, and how responding cells decode information from propagating cytokine signals are not understood. By computationally and experimentally studying NF-{kappa}B dynamics in co-cultures of signal sending cells (macrophages) and receiving cells (fibroblasts), we found that cytokine signals are transmitted by wave-like propagation of NF-{kappa}B activity and create well-defined cellular activation zones in a responding cell population. Remarkably, NF-{kappa}B dynamics in responding cells can simultaneously encode information about cytokine dose, duration, and distance to the cytokine source. Spatially-resolved transcriptional analysis revealed that responding cells transmit local cytokine information to distance specific pro-inflammatory gene expression patterns, creating "gene expression zones" in the population. Despite single-cell variability, the size and duration of the signaling zone is tightly controlled by the macrophage cytokine secretion profile. Our results highlight how macrophages tune their cytokine secretion dynamics to control signal transmission distance, and how NF-{kappa}B interprets these signals to coordinate inflammatory response in space and time.

systems biology↗

bioRxiv2016

Impact of Zygosity in Bimodal Phenotype Distributions

Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. But the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedbacks. Here we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells between donors infected with human cytomegalovirus (HCMV) with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, indicative of the presence of a positive feedback somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback with respect to the gene can all reproduce well the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, only one model (the one with the positive feedback located at the level of gene transcription) reproduces the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate structure and function of gene regulatory networks.\n\nAuthor SummaryNearly all mammalian cells, including human cells, have two copies of each chromosome, and thus possess two potentially different copies of each gene (which might be in some cases non-functional or even absent). Naiively one might expect that two identical copies of the gene would lead to the protein being expressed at twice the rate, but many factors can alter this simple calculation. One of these factors is the existence of feedback mechanisms affecting in one way or another the regulatory circuit in which our gene of interest is embedded. Here we study the relationship between the number of gene copies and the expression of a receptor protein that plays a crucial role in the recognition of pathogens by natural killer cells, which are important elements of the innate immune system. Experimental data of virus-infected donors reveals a bimodal expression profile of this receptor, typical of a positive feedback, and a clear difference between donors with one or two copies of the gene. Mathematical modeling allows us to find the likely location of the feedback loop within the genes regulatory circuit, by requiring the correct model to reproduce the expression profiles of both types of donors.

systems biology↗