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Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses

Amit, Ido and Garber, Manuel and Chevrier, Nicolas and Leite, Ana Paula and Donner, Yoni and Eisenhaure, Thomas and Guttman, Mitchell and Grenier, Jennifer K. and Li, Weibo and Zuk, Or and Schubert, Lisa A. and Birditt, Brian and Shay, Tal and Goren, Alon and Zhang, Xiaolan and Smith, Zachary and Deering, Raquel and McDonald, Rebecca C. and Cabili, Moran and Bernstein, Bradley E. and Rinn, John L. and Meissner, Alex and Root, David E. and Hacohen, Nir and Regev, Aviv (2009) Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses. Science, 326 (5950). pp. 257-263. ISSN 0036-8075. PMCID PMC2879337.

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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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Guttman, Mitchell0000-0003-4748-9352
Regev, Aviv0000-0003-3293-3158
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).
Funding AgencyGrant Number
Human Frontier Science ProgramUNSPECIFIED
American Physicians Fellowship for Medicine in IsraelUNSPECIFIED
NIHR21 AI71060
Richard Merkin Foundation for Stem Cell ResearchUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Broad Institute of MIT and HarvardUNSPECIFIED
Issue or Number:5950
PubMed Central ID:PMC2879337
Record Number:CaltechAUTHORS:20161121-130217653
Persistent URL:
Official Citation:Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses By Ido Amit, Manuel Garber, Nicolas Chevrier, Ana Paula Leite, Yoni Donner, Thomas Eisenhaure, Mitchell Guttman, Jennifer K. Grenier, Weibo Li, Or Zuk, Lisa A. Schubert, Brian Birditt, Tal Shay, Alon Goren, Xiaolan Zhang, Zachary Smith, Raquel Deering, Rebecca C. McDonald, Moran Cabili, Bradley E. Bernstein, John L. Rinn, Alex Meissner, David E. Root, Nir Hacohen, Aviv Regev Science 09 Oct 2009: Vol. 326, Issue 5950, pp. 257-263 DOI: 10.1126/science.1179050
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72203
Deposited By: Ruth Sustaita
Deposited On:21 Nov 2016 23:29
Last Modified:09 Mar 2020 13:19

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