Transcriptional network dynamics in macrophage activation

Roland Nilsson, Vladimir Bajic, Harukazu Suzuki, Diego di Bernardo, Johan Björkegren, Shintaro Katayama, James F. Reid, Matthew J. Sweet, Manuela Gariboldi, Piero Carninci, Yosihide Hayashizaki, David A. Hume*, Jesper Tegner, Timothy Ravasi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Transcriptional regulatory networks govern cell differentiation and the cellular response to external stimuli. However, mammalian model systems have not yet been accessible for network analysis. Here, we present a genome-wide network analysis of the transcriptional regulation underlying the mouse macrophage response to bacterial lipopolysaccharide (LPS). Key to uncovering the network structure is our combination of time-series cap analysis of gene expression with in silico prediction of transcription factor binding sites. By integrating microarray and qPCR time-series expression data with a promoter analysis, we find dynamic subnetworks that describe how signaling pathways change dynamically during the progress of the macrophage LPS response, thus defining regulatory modules characteristic of the inflammatory response. In particular, our integrative analysis enabled us to suggest novel roles for the transcription factors ATF-3 and NRF-2 during the inflammatory response. We believe that our system approach presented here is applicable to understanding cellular differentiation in higher eukaryotes.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalGenomics
Volume88
Issue number2
DOIs
StatePublished - Aug 1 2006

Keywords

  • Complex systems
  • Genome
  • Innate immunity
  • Macrophages
  • Network dynamics
  • Regulatory networks
  • System biology
  • Transcriptional regulation
  • inflammation

ASJC Scopus subject areas

  • Genetics

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