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Science DOI:10.1126/science.1179050

Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses.

Publication TypeJournal Article
Year of Publication2009
AuthorsAmit, I, Garber, M, Chevrier, N, Leite, APaula, Donner, Y, Eisenhaure, T, Guttman, M, Grenier, JK, Li, W, Zuk, O, Schubert, LA, Birditt, B, Shay, T, Goren, A, Zhang, X, Smith, Z, Deering, R, McDonald, RC, Cabili, M, Bernstein, BE, Rinn, JL, Meissner, A, Root, DE, Hacohen, N, Regev, A
Date Published2009 Oct 09
KeywordsAnimals, Bacteria, Chromatin Assembly and Disassembly, Dendritic Cells, DNA, Single-Stranded, Feedback, Physiological, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Inflammation, Lipopeptides, Lipopolysaccharides, Mice, Mice, Inbred C57BL, Poly I-C, RNA-Binding Proteins, Toll-Like Receptors, Transcription Factors, Transcription, Genetic, Viruses

Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.


Alternate JournalScience
PubMed ID19729616
PubMed Central IDPMC2879337
Grant ListDP2 OD002230-01 / OD / NIH HHS / United States
R21 AI071060-01 / AI / NIAID NIH HHS / United States
R21 AI071060 / AI / NIAID NIH HHS / United States
DP1 OD003958-01 / OD / NIH HHS / United States
DP2 OD002230 / OD / NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R21 AI71060 / AI / NIAID NIH HHS / United States
S10 RR026688 / RR / NCRR NIH HHS / United States
DP1 OD003958 / OD / NIH HHS / United States