IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages

IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages

Interferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated w...

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Main Authors: David G. Saliba, Andreas Heger, Hayley L. Eames, Spyros Oikonomopoulos, Ana Teixeira, Katrina Blazek, Ariadne Androulidaki, Daniel Wong, Fui G. Goh, Miriam Weiss, Adam Byrne, Manolis Pasparakis, Jiannis Ragoussis, Irina A. Udalova
Format: Article
Language:English
Published: Elsevier 2014-09-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124714006184
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spelling doaj-62176b6cba9e405491e69a22de5b11c82020-11-24T21:14:45ZengElsevierCell Reports2211-12472014-09-01851308131710.1016/j.celrep.2014.07.034IRF5:RelA Interaction Targets Inflammatory Genes in MacrophagesDavid G. Saliba0Andreas Heger1Hayley L. Eames2Spyros Oikonomopoulos3Ana Teixeira4Katrina Blazek5Ariadne Androulidaki6Daniel Wong7Fui G. Goh8Miriam Weiss9Adam Byrne10Manolis Pasparakis11Jiannis Ragoussis12Irina A. Udalova13Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKCGAT, MRC Functional Genomics Unit, University of Oxford, South Parks Road, Oxford OX13PT, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKInstitute for Genetics, University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne 50931, GermanyWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKInstitute for Genetics, University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne 50931, GermanyWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKKennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX37FY, UKInterferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated with bacterial lipopolysaccharide and discover that IRF5 binds to regulatory elements of highly transcribed genes. Analysis of protein:DNA microarrays demonstrates that IRF5 recognizes the canonical IRF-binding (interferon-stimulated response element [ISRE]) motif in vitro. However, IRF5 binding in vivo appears to rely on its interactions with other proteins. IRF5 binds to a noncanonical composite PU.1:ISRE motif, and its recruitment is aided by RelA. Global gene expression analysis in macrophages deficient in IRF5 and RelA highlights the direct role of the RelA:IRF5 cistrome in regulation of a subset of key inflammatory genes. We map the RelA:IRF5 interaction domain and suggest that interfering with it would offer selective targeting of macrophage inflammatory activities.http://www.sciencedirect.com/science/article/pii/S2211124714006184
collection DOAJ
language English
format Article
sources DOAJ
author David G. Saliba
Andreas Heger
Hayley L. Eames
Spyros Oikonomopoulos
Ana Teixeira
Katrina Blazek
Ariadne Androulidaki
Daniel Wong
Fui G. Goh
Miriam Weiss
Adam Byrne
Manolis Pasparakis
Jiannis Ragoussis
Irina A. Udalova
spellingShingle David G. Saliba
Andreas Heger
Hayley L. Eames
Spyros Oikonomopoulos
Ana Teixeira
Katrina Blazek
Ariadne Androulidaki
Daniel Wong
Fui G. Goh
Miriam Weiss
Adam Byrne
Manolis Pasparakis
Jiannis Ragoussis
Irina A. Udalova
IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages
Cell Reports
author_facet David G. Saliba
Andreas Heger
Hayley L. Eames
Spyros Oikonomopoulos
Ana Teixeira
Katrina Blazek
Ariadne Androulidaki
Daniel Wong
Fui G. Goh
Miriam Weiss
Adam Byrne
Manolis Pasparakis
Jiannis Ragoussis
Irina A. Udalova
author_sort David G. Saliba
title IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages
title_short IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages
title_full IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages
title_fullStr IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages
title_full_unstemmed IRF5:RelA Interaction Targets Inflammatory Genes in Macrophages
title_sort irf5:rela interaction targets inflammatory genes in macrophages
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2014-09-01
description Interferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated with bacterial lipopolysaccharide and discover that IRF5 binds to regulatory elements of highly transcribed genes. Analysis of protein:DNA microarrays demonstrates that IRF5 recognizes the canonical IRF-binding (interferon-stimulated response element [ISRE]) motif in vitro. However, IRF5 binding in vivo appears to rely on its interactions with other proteins. IRF5 binds to a noncanonical composite PU.1:ISRE motif, and its recruitment is aided by RelA. Global gene expression analysis in macrophages deficient in IRF5 and RelA highlights the direct role of the RelA:IRF5 cistrome in regulation of a subset of key inflammatory genes. We map the RelA:IRF5 interaction domain and suggest that interfering with it would offer selective targeting of macrophage inflammatory activities.
url http://www.sciencedirect.com/science/article/pii/S2211124714006184
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