Journal article
Antiviral Response Dictated by Choreographed Cascade of Transcription Factors
The Journal of immunology (1950), v 184(6), pp 2908-2917
15 Mar 2010
PMID: 20164420
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response. To isolate and identify this network, we studied DCs infected with Newcastle disease virus, which is able to stimulate innate immunity and DC maturation through activation of RIG-I signaling, but lacks the ability to evade the human IFN response. To analyze this experimental model, we developed a new approach integrating genome-wide expression kinetics and time-dependent promoter analysis. We found that the genetic program underlying the antiviral cell-state transition during the first 18 h postinfection could be explained by a single convergent regulatory network. Gene expression changes were driven by a stepwise multifactor cascading control mechanism, where the specific transcription factors controlling expression changed over time. Within this network, most individual genes were regulated by multiple factors, indicating robustness against virus-encoded immune evasion genes. In addition to effectively recapitulating current biological knowledge, we predicted, and validated experimentally, antiviral roles for several novel transcription factors. More generally, our results show how a genetic program can be temporally controlled through a single regulatory network to achieve the large-scale genetic reprogramming characteristic of cell-state transitions. The Journal of Immunology, 2010, 184: 2908-2917.
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Details
- Title
- Antiviral Response Dictated by Choreographed Cascade of Transcription Factors
- Creators
- Elena Zaslavsky - Icahn School of Medicine at Mount SinaiUri Hershberg - Yale UniversityJeremy Seto - Center for Systems BiologyAlissa M. Pham - Icahn School of Medicine at Mount SinaiSusanna Marquez - Yale UniversityJamie L. Duke - Yale UniversityJames G. Wetmur - Icahn School of Medicine at Mount SinaiBenjamin R. tenOever - Icahn School of Medicine at Mount SinaiStuart C. Sealfon - Center for Systems BiologySteven H. Kleinstein - Yale University
- Publication Details
- The Journal of immunology (1950), v 184(6), pp 2908-2917
- Publisher
- American Association of Immunologists
- Number of pages
- 10
- Grant note
- T15 LM07056 / National Library of Medicine; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM) HHSN266200500021C / National Institutes of Health, National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T15LM007056 / NATIONAL LIBRARY OF MEDICINE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Library of Medicine (NLM)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000275389000019
- Scopus ID
- 2-s2.0-77951916659
- Other Identifier
- 991019280182604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology