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Molecular and Cellular Biology, June 2009, p. 3435-3450, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01805-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7{triangledown} ,§

Pierre Génin,1 Rongtuan Lin,2 John Hiscott,2 and Ahmet Civas1*

UPR 2228-CNRS, Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques, UFR Biomédicale des Saints-Pères, Université Paris Descartes, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France,1 Lady Davis Institute for Medical Research and Departments of Microbiology & Immunology and Medicine, McGill University, Montréal, Canada H3T 1E22

Received 25 November 2008/ Returned for modification 9 January 2009/ Accepted 28 March 2009

Differential expression of the human interferon A (IFN-A) gene cluster is modulated following paramyxovirus infection by the relative amounts of active interferon regulatory factor 3 (IRF-3) and IRF-7. IRF-3 expression activates predominantly IFN-A1 and IFN-B, while IRF-7 expression induces multiple IFN-A genes. IFN-A1 gene expression is dependent on three promoter proximal IRF elements (B, C, and D modules, located at positions –98 to –45 relative to the mRNA start site). IRF-3 binds the C module of IFN-A1, while other IFN-A gene promoters are responsive to the binding of IRF-7 to the B and D modules. Maximal expression of IFN-A1 is observed with complete occupancy of the three modules in the presence of IRF-7. Nucleotide substitutions in the C modules of other IFN-A genes disrupt IRF-3-mediated transcription, whereas a G/A substitution in the D modules enhances IRF7-mediated expression. IRF-3 exerts dual effects on IFN-A gene expression, as follows: a synergistic effect with IRF-7 on IFN-A1 expression and an inhibitory effect on other IFN-A gene promoters. Chromatin immunoprecipitation experiments reveal that transient binding of both IRF-3 and IRF-7, accompanied by CBP/p300 recruitment to the endogenous IFN-A gene promoters, is associated with transcriptional activation, whereas a biphasic recruitment of IRF-3 and CBP/p300 represses IFN-A gene expression. This regulatory mechanism contributes to differential expression of IFN-A genes and may be critical for alpha interferon production in different cell types by RIG-I-dependent signals, leading to innate antiviral immune responses.

* Corresponding author. Mailing address: UPR 2228-CNRS, Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques, UFR Biomédicale des Saints-Pères, Université Paris Descartes, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France. Phone: 33-1-42-86-22-84. Fax: 33-1-42-86-20-42. E-mail: ahmet.civas{at}parisdescartes.fr

{triangledown} Published ahead of print on 6 April 2009.

§ Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2009, p. 3435-3450, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01805-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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