Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses

Ido Arnit; 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 A. Hacohen; Aviv Regev

doi:10.1126/science.1179050

Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses

Ido Arnit, 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. BernsteinJohn L. Rinn, Alex Meissner, David E. Root, Nir Hacohen A. Hacohen, Aviv Regev

Research output: Contribution to journal › Article › peer-review

409 Scopus citations

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.

Original language	English
Pages (from-to)	257-263
Number of pages	7
Journal	Science
Volume	326
Issue number	5950
DOIs	https://doi.org/10.1126/science.1179050
State	Published - 9 Oct 2009
Externally published	Yes

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Arnit, I., Garber, M., Chevrier, N., Leite, A. P., Donner, Y., Eisenhaure, T., Guttman, M., Grenier, J. K., Li, W., Zuk, O., Schubert, L. A., Birditt, B., Shay, T., Goren, A., Zhang, X., Smith, Z., Deering, R., McDonald, R. C., Cabili, M., ... Regev, A. (2009). Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science, 326(5950), 257-263. https://doi.org/10.1126/science.1179050

@article{55cf56e848af4eab990b20d42174e4bd,

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.",

author = "Ido Arnit and Manuel Garber and Nicolas Chevrier and Leite, {Ana Paula} and Yoni Donner and Thomas Eisenhaure and Mitchell Guttman and Grenier, {Jennifer K.} and Weibo Li and Or Zuk and Schubert, {Lisa A.} and Brian Birditt and Tal Shay and Alon Goren and Xiaolan Zhang and Zachary Smith and Raquel Deering and McDonald, {Rebecca C.} and Moran Cabili and Bernstein, {Bradley E.} and Rinn, {John L.} and Alex Meissner and Root, {David E.} and Hacohen, {Nir Hacohen A.} and Aviv Regev",

year = "2009",

month = oct,

day = "9",

doi = "10.1126/science.1179050",

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publisher = "American Association for the Advancement of Science",

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Arnit, I, Garber, M, Chevrier, N, Leite, AP, 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, NHA & Regev, A 2009, 'Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses', Science, vol. 326, no. 5950, pp. 257-263. https://doi.org/10.1126/science.1179050

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AU - Arnit, Ido

AU - Garber, Manuel

AU - Chevrier, Nicolas

AU - Leite, Ana Paula

AU - Donner, Yoni

AU - Eisenhaure, Thomas

AU - Guttman, Mitchell

AU - Grenier, Jennifer K.

AU - Li, Weibo

AU - Zuk, Or

AU - Schubert, Lisa A.

AU - Birditt, Brian

AU - Shay, Tal

AU - Goren, Alon

AU - Zhang, Xiaolan

AU - Smith, Zachary

AU - Deering, Raquel

AU - McDonald, Rebecca C.

AU - Cabili, Moran

AU - Bernstein, Bradley E.

AU - Rinn, John L.

AU - Meissner, Alex

AU - Root, David E.

AU - Hacohen, Nir Hacohen A.

AU - Regev, Aviv

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AB - 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.

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Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses

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