PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells

Autor: An-Ping Zeng, Feng He, Klaus Schughart, Michael Probst-Kepper, Robert Geffers, Hairong Chen, Serge Eifes, Antonio del Sol, Rudi Balling
Přispěvatelé: 1] Department of Infection Genetics, Helmholtz Centre for Infection Research (HZI), University of Veterinary Medicine Hannover, Braunschweig, Germany [2] Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center]
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Time Factors
Cytokines/genetics/metabolism
STAT5 Transcription Factor/metabolism
Biochemistry
biophysics & molecular biology [F05] [Life sciences]
L-Selectin/metabolism
T-Lymphocytes
Regulatory
law.invention
Transcriptome
Mice
Extracellular Signal-Regulated MAP Kinases/metabolism
law
Gene Knockdown Techniques
STAT5 Transcription Factor
IL-2 receptor
L-Selectin
Biochimie
biophysique & biologie moléculaire [F05] [Sciences du vivant]
Extracellular Signal-Regulated MAP Kinases
STAT5
Genetics
Mice
Knockout
human CD4 regulatory T cell
biology
Applied Mathematics
Biowissenschaften
Biologie [570]
FOXP3
hemic and immune systems
Forkhead Transcription Factors
Transcriptome/genetics
Down-Regulation/genetics
Cell biology
Hyaluronan Receptors
Computational Theory and Mathematics
Cytokines
General Agricultural and Biological Sciences
Information Systems
Signal Transduction
MAP Kinase Signaling System
Down-Regulation
chemical and pharmacologic phenomena
T-Lymphocytes
Regulatory/enzymology/metabolism
infer key genes from undirected gene networks
Treg development and suppressor function
General Biochemistry
Genetics and Molecular Biology
Article
high time-resolution time series
ddc:570
Plau knockout mice
Animals
Humans
Antigens
CD44/metabolism
Gene
General Immunology and Microbiology
Urokinase-Type Plasminogen Activator
biology.protein
Signal Transduction/genetics
Suppressor
Urokinase-Type Plasminogen Activator/genetics/metabolism
Function (biology)
Zdroj: Molecular Systems Biology
Molecular Systems Biology, 8, 624. England (2012).
Molecular systems biology (8): art. no. 624 (2012)
ISSN: 1744-4292
Popis: Network-based analysis of transcriptome dynamics during activation in two human T-cell subpopulations identifies key regulators, and reveals that PLAU plays a critical role in both human and murine regulatory T-cell function.
We construct a Treg-specific correlation network from a high time-resolution transcriptome of human Tregs versus CD4+ T effector cells measured during their very early activation process. We propose a queen bee-surrounding principle to predict key candidate genes from the simplified undirected correlation network rather than an advanced directed transcription regulatory network. These potential key genes would have not been easily identified by a differential expression analysis. We show that the plasminogen activator urokinase (PLAU) is critical for suppressor function of both human and murine Tregs. We further demonstrate that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways.
Human FOXP3+CD25+CD4+ regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4+ T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function.
Databáze: OpenAIRE
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