title: Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses.
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.
authors.affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Manuel
authors.initials: M
authors.lastname: Garber
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chevrier
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Leite
authors.forename: Yoni
authors.initials: Y
authors.lastname: Donner
authors.forename: Thomas
authors.initials: T
authors.lastname: Eisenhaure
authors.forename: Mitchell
authors.initials: M
authors.lastname: Guttman
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Grenier
authors.forename: Weibo
authors.initials: W
authors.lastname: Li
authors.forename: Or
authors.initials: O
authors.lastname: Zuk
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Schubert
authors.forename: Brian
authors.initials: B
authors.lastname: Birditt
authors.forename: Tal
authors.initials: T
authors.lastname: Shay
authors.forename: Alon
authors.initials: A
authors.lastname: Goren
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.forename: Zachary
authors.initials: Z
authors.lastname: Smith
authors.forename: Raquel
authors.initials: R
authors.lastname: Deering
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: McDonald
authors.forename: Moran
authors.initials: M
authors.lastname: Cabili
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.forename: Alex
authors.initials: A
authors.lastname: Meissner
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
mesh_terms: D000818:Animals; D001419:Bacteria / Q000276:immunology*; D042002:Chromatin Assembly and Disassembly; D004277:DNA, Single-Stranded / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D055666:Lipopeptides / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000276:immunology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014780:Viruses / Q000276:immunology*
chemical_list: D004277:DNA, Single-Stranded; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D016601:RNA-Binding Proteins; D051193:Toll-Like Receptors; D014157:Transcription Factors; D011070:Poly I-C