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Genes Dev. 2014 Jul 15;28(14):1562-77. doi: 10.1101/gad.242685.114.

The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages.

Author information

1
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
2
The Salk Institute for Biological Studies, San Diego, California 92037, USA;
3
Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB), Brussels B-1050, Belgium; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels B-1050, Belgium;
4
Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven B-3000, Belgium;
5
MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen H-4032, Hungary.
6
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary; MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen H-4032, Hungary.

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.

KEYWORDS:

RXR; angiogenesis; enhancer; macrophage; transcription

PMID:
25030696
PMCID:
PMC4102764
DOI:
10.1101/gad.242685.114
[Indexed for MEDLINE]
Free PMC Article

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