title: A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation.
abstract: Much has been learned about transcriptional cascades and networks from large-scale systems analyses of high-throughput datasets. However, analysis methods that optimize statistical power through simultaneous evaluation of thousands of ChIP-seq peaks or differentially expressed genes possess substantial limitations in their ability to uncover mechanistic principles of transcriptional control. By examining nascent transcript RNA-seq, ChIP-seq, and binding motif datasets from lipid A-stimulated macrophages with increased attention to the quantitative distribution of signals, we identified unexpected relationships between the in vivo binding properties of inducible transcription factors, motif strength, and transcription. Furthermore, rather than emphasizing common features of large clusters of co-regulated genes, our results highlight the extent to which unique mechanisms regulate individual genes with key biological functions. Our findings demonstrate the mechanistic value of stringent interrogation of well-defined sets of genes as a complement to broader systems analyses of transcriptional cascades and networks.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ann-Jay
authors.initials: AJ
authors.lastname: Tong
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Thomas
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Lissner
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Mairead R
authors.initials: MR
authors.lastname: Baker
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Madhavi D
authors.initials: MD
authors.lastname: Senagolage
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Allred
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: smale@mednet.ucla.edu.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smale
mesh_terms: D000818:Animals; D053263:Gene Regulatory Networks; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D008050:Lipid A / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism
chemical_list: D008050:Lipid A; D016328:NF-kappa B; D026362:Serum Response Factor; D053633:Receptor, Interferon alpha-beta