Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses
- Creators
- Amit, Ido
- Garber, Manuel
- Chevrier, Nicolas
- Leite, Ana Paula
- Donner, Yoni
- Eisenhaure, Thomas
- Guttman, Mitchell
- Grenier, Jennifer K.
- Li, Weibo
- Zuk, Or
- Schubert, Lisa A.
- Birditt, Brian
- Shay, Tal
- Goren, Alon
- Zhang, Xiaolan
- Smith, Zachary
- Deering, Raquel
- McDonald, Rebecca C.
- Cabili, Moran
- Bernstein, Bradley E.
- Rinn, John L.
- Meissner, Alex
- Root, David E.
- Hacohen, Nir
- Regev, Aviv
Abstract
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.
Additional Information
© 2016 American Association for the Advancement of Science. 14 July 2009; accepted 26 August 2009. Published online 3 September 2009. We thank E. Lander, I. Wapinski, D. Pe'er, N. Friedman, J. Kagan, A. Luster, V. Kuchroo, and A. Citri for discussions and comments; L. Gaffney for assistance with artwork; S. Gupta and the Broad Genetic Analysis Platform for microarray processing; and T. Mikkelsen and the Broad Sequencing Platform for help with the ChIP-seq experiments. Supported by the Human Frontier Science Program Organization and a Claire and Emanuel G. Rosenblatt Award from the American Physicians Fellowship for Medicine in Israel (I.A.); NIH grant R21 AI71060 and the NIH New Innovator Award (N.H.); and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, an NIH Pioneer Award, and the Sloan Foundation (A.R.). A.R. is an Early Career Scientist of the Howard Hughes Medical Institute and an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. Complete microarray data sets are available at the Gene Expression Omnibus (accession no. GSE17721).Attached Files
Accepted Version - nihms200312.pdf
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Additional details
- PMCID
- PMC2879337
- Eprint ID
- 72203
- Resolver ID
- CaltechAUTHORS:20161121-130217653
- Human Frontier Science Program
- American Physicians Fellowship for Medicine in Israel
- R21 AI71060
- NIH
- Richard Merkin Foundation for Stem Cell Research
- Burroughs Wellcome Fund
- Alfred P. Sloan Foundation
- Howard Hughes Medical Institute (HHMI)
- Broad Institute of MIT and Harvard
- Created
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2016-11-21Created from EPrint's datestamp field
- Updated
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2021-11-11Created from EPrint's last_modified field