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Cell. 2016 Mar 24;165(1):165-179. doi: 10.1016/j.cell.2016.01.020. Epub 2016 Feb 25.

A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating Inflammation.

Author information

1
Department of Microbiology, Immunology, and Molecular Genetics, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
3
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.

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.

PMID:
26924576
PMCID:
PMC4808443
DOI:
10.1016/j.cell.2016.01.020
[Indexed for MEDLINE]
Free PMC Article

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