title: Transcriptional network dynamics in macrophage activation.
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.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roland
authors.initials: R
authors.lastname: Nilsson
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Bajic
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Diego
authors.initials: D
authors.lastname: di Bernardo
authors.forename: Johan
authors.initials: J
authors.lastname: Björkegren
authors.forename: Shintaro
authors.initials: S
authors.lastname: Katayama
authors.forename: James F
authors.initials: JF
authors.lastname: Reid
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.forename: Manuela
authors.initials: M
authors.lastname: Gariboldi
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Yosihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegner
authors.forename: Timothy
authors.initials: T
authors.lastname: Ravasi
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D024363:Transcription Initiation Site / Q000187:drug effects; D014158:Transcription, Genetic
chemical_list: D008070:Lipopolysaccharides