The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages
- Bence Daniel1,8,
- Gergely Nagy1,8,
- Nasun Hah2,
- Attila Horvath1,
- Zsolt Czimmerer1,
- Szilard Poliska1,
- Tibor Gyuris1,
- Jiri Keirsse3,4,
- Conny Gysemans5,
- Jo A. Van Ginderachter3,4,
- Balint L. Balint1,
- Ronald M. Evans2,
- Endre Barta6 and
- Laszlo Nagy1,6,7,9
- 1Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
- 2The Salk Institute for Biological Studies, San Diego, California 92037, USA;
- 3Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB), Brussels B-1050, Belgium;
- 4Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels B-1050, Belgium;
- 5Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven B-3000, Belgium;
- 6MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen H-4032, Hungary
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↵8 These authors contributed equally to this work.
Abstract
RXR signaling is predicted to have a major impact in macrophages, but neither the biological consequence nor the genomic basis of its ligand activation is known. Comprehensive genome-wide studies were carried out to map liganded RXR-mediated transcriptional changes, active binding sites, and cistromic interactions in the context of the macrophage genome architecture. The macrophage RXR cistrome has 5200 genomic binding sites, which are not impacted by ligand. Active enhancers are characterized by PU.1 binding, an increase of enhancer RNA, and P300 recruitment. Using these features, 387 liganded RXR-bound enhancers were linked to 226 genes, which predominantly reside in CTCF/cohesin-limited functional domains. These findings were molecularly validated using chromosome conformation capture (3C) and 3C combined with sequencing (3C-seq), and we show that selected long-range enhancers communicate with promoters via stable or RXR-induced loops and that some of the enhancers interact with each other, forming an interchromosomal network. A set of angiogenic genes, including Vegfa, has liganded RXR-controlled enhancers and provides the macrophage with a novel inducible program.
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Footnotes
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↵9 Corresponding author
E-mail lnagy{at}sanfordburnham.org
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.242685.114.
Freely available online through the Genes & Development Open Access option.
- Received March 29, 2014.
- Accepted June 20, 2014.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0.