Dataset Information

Definition of a Family of Tissue-Protective Cytokines Using Functional Cluster Analysis: A Proof-of-Concept Study.

ABSTRACT: The discovery of the tissue-protective activities of erythropoietin (EPO) has underlined the importance of some cytokines in tissue-protection, repair, and remodeling. As such activities have been reported for other cytokines, we asked whether we could define a class of tissue-protective cytokines. We therefore explored a novel approach based on functional clustering. In this pilot study, we started by analyzing a small number of cytokines (30). We functionally classified the 30 cytokines according to their interactions by using the bioinformatics tool STRING (Search Tool for the Retrieval of Interacting Genes), followed by hierarchical cluster analysis. The results of this functional clustering were different from those obtained by clustering cytokines simply according to their sequence. We previously reported that the protective activity of EPO in a model of cerebral ischemia was paralleled by an upregulation of synaptic plasticity genes, particularly early growth response 2 (EGR2). To assess the predictivity of functional clustering, we tested some of the cytokines clustering close to EPO (interleukin-11, IL-11; kit ligand, KITLG; leukemia inhibitory factor, LIF; thrombopoietin, THPO) in an in vitro model of human neuronal cells for their ability to induce EGR2. Two of these, LIF and IL-11, induced EGR2 expression. Although these data would need to be extended to a larger number of cytokines and the biological validation should be done using more robust in vivo models, rather then just one cell line, this study shows the feasibility of this approach. This type of functional cluster analysis could be extended to other fields of cytokine research and help design biological experiments.

SUBMITTER: Mengozzi M

PROVIDER: S-EPMC3955874 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Definition of a Family of Tissue-Protective Cytokines Using Functional Cluster Analysis: A Proof-of-Concept Study.

Mengozzi Manuela M Ermilov Peter P Annenkov Alexander A Ghezzi Pietro P Pearl Frances F

Frontiers in immunology 20140317

The discovery of the tissue-protective activities of erythropoietin (EPO) has underlined the importance of some cytokines in tissue-protection, repair, and remodeling. As such activities have been reported for other cytokines, we asked whether we could define a class of tissue-protective cytokines. We therefore explored a novel approach based on functional clustering. In this pilot study, we started by analyzing a small number of cytokines (30). We functionally classified the 30 cytokines accord ...[more]

PMID: 24672526

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Project description:Identifying the complete set of functional elements within the human genome would be a windfall for multiple areas of biological research including medicine, molecular biology, and evolution. Complete knowledge of function would aid in the prioritization of loci when searching for the genetic bases of disease or adaptive phenotypes. Because mutations that disrupt function are disfavored by natural selection, purifying selection leaves a detectable signature within functional elements; accordingly, this signal has been exploited for over a decade through the use of genomic comparisons of distantly related species. While this is so, the functional complement of the genome changes extensively across time and between lineages; therefore, evidence of the current action of purifying selection in humans is essential. Because the removal of deleterious mutations by natural selection also reduces within-species genetic diversity within functional loci, dense population genetic data have the potential to reveal genomic elements that are currently functional. Here, we assess the potential of this approach by examining an ultradeep sample of human mitochondrial genomes (n = 16,411). We show that the high density of polymorphism in this data set precisely delineates regions experiencing purifying selection. Furthermore, we show that the number of segregating alleles at a site is strongly correlated with its divergence across species after accounting for known mutational biases in human mitochondrial DNA (ρ = 0.51; P < 2.2 × 10(-16)). These two measures track one another at a remarkably fine scale across many loci-a correlation that is purely the result of natural selection. Our results demonstrate that genetic variation has the potential to reveal with surprising precision which regions in the genome are currently performing important functions and likely to have deleterious fitness effects when mutated. As more complete human genomes are sequenced, similar power to reveal purifying selection may be achievable in the human nuclear genome.

Dataset Information

Definition of a Family of Tissue-Protective Cytokines Using Functional Cluster Analysis: A Proof-of-Concept Study.

Publications

Definition of a Family of Tissue-Protective Cytokines Using Functional Cluster Analysis: A Proof-of-Concept Study.

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