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Design principles of cell circuits with paradoxical components.

ABSTRACT: Biological systems display complex networks of interactions both at the level of molecules inside the cell and at the level of interactions between cells. Networks of interacting molecules, such as transcription networks, have been shown to be composed of recurring circuits called network motifs, each with specific dynamical functions. Much less is known about the possibility of such circuit analysis in networks made of communicating cells. Here, we study models of circuits in which a few cell types interact by means of signaling molecules. We consider circuits of cells with architectures that seem to recur in immunology. An intriguing feature of these circuits is their use of signaling molecules with a pleiotropic or paradoxical role, such as cytokines that increase both cell growth and cell death. We find that pleiotropic signaling molecules can provide cell circuits with systems-level functions. These functions include for different circuits maintenance of homeostatic cell concentrations, robust regulation of differentiation processes, and robust pulses of cells or cytokines.

SUBMITTER: Hart Y

PROVIDER: S-EPMC3361385 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Design principles of cell circuits with paradoxical components.

Hart Yuval Y Antebi Yaron E YE Mayo Avraham E AE Friedman Nir N Alon Uri U

Proceedings of the National Academy of Sciences of the United States of America 20120504 21

Biological systems display complex networks of interactions both at the level of molecules inside the cell and at the level of interactions between cells. Networks of interacting molecules, such as transcription networks, have been shown to be composed of recurring circuits called network motifs, each with specific dynamical functions. Much less is known about the possibility of such circuit analysis in networks made of communicating cells. Here, we study models of circuits in which a few cell t ...[more]

PMID: 22562798

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Project description:For the vast majority of genes in sequenced genomes, there is limited understanding of how they are regulated. Without such knowledge, it is not possible to perform a quantitative theory-experiment dialogue on how such genes give rise to physiological and evolutionary adaptation. One category of high-throughput experiments used to understand the sequence-phenotype relationship of the transcriptome is massively parallel reporter assays (MPRAs). However, to improve the versatility and scalability of MPRA pipelines, we need a "theory of the experiment" to help us better understand the impact of various biological and experimental parameters on the interpretation of experimental data. These parameters include binding site copy number, where a large number of specific binding sites may titrate away transcription factors, as well as the presence of overlapping binding sites, which may affect analysis of the degree of mutual dependence between mutations in the regulatory region and expression levels. Here, we develop a computational pipeline that makes it possible to systematically explore how each biological and experimental parameter controls measured MPRA data. Specifically, we use equilibrium statistical mechanics in conjunction with predictive base-pair resolution energy matrices to predict expression levels of genes with mutated regulatory sequences and subsequently use mutual information to interpret synthetic MPRA data including recovering the expected binding sites. Our simulations reveal important effects of the parameters on MPRA data and we demonstrate our ability to optimize MPRA experimental designs with the goal of generating thermodynamic models of the transcriptome with base-pair specificity. Further, this approach makes it possible to carefully examine the mapping between mutations in binding sites and their corresponding expression profiles, a tool useful not only for better designing MPRAs, but also for exploring regulatory evolution.

Dataset Information

Design principles of cell circuits with paradoxical components.

Publications

Design principles of cell circuits with paradoxical components.

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