A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation

Ann Jay Tong, Xin Liu, Brandon J. Thomas, Michelle M. Lissner, Mairead R. Baker, Madhavi D. Senagolage, Amanda L. Allred, Grant D. Barish, Stephen T. Smale*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)165-179
Number of pages15
JournalCell
Volume165
Issue number1
DOIs
StatePublished - Mar 24 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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