title: The active enhancer network operated by liganded RXR supports angiogenic activity in macrophages.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Bence
authors.initials: B
authors.lastname: Daniel
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Gergely
authors.initials: G
authors.lastname: Nagy
authors.affiliation: The Salk Institute for Biological Studies, San Diego, California 92037, USA;
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Attila
authors.initials: A
authors.lastname: Horvath
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Czimmerer
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Szilard
authors.initials: S
authors.lastname: Poliska
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Tibor
authors.initials: T
authors.lastname: Gyuris
authors.affiliation: 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;
authors.forename: Jiri
authors.initials: J
authors.lastname: Keirsse
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven B-3000, Belgium;
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.affiliation: 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;
authors.forename: Jo A
authors.initials: JA
authors.lastname: Van Ginderachter
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen H-4032, Hungary;
authors.forename: Balint L
authors.initials: BL
authors.lastname: Balint
authors.affiliation: The Salk Institute for Biological Studies, San Diego, California 92037, USA;
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen H-4032, Hungary.
authors.forename: Endre
authors.initials: E
authors.lastname: Barta
authors.affiliation: 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.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009930:Organic Chemicals / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D006657:Histones; C423914:LG 268; D008024:Ligands; D009930:Organic Chemicals; D047488:Retinoid X Receptors; D012313:RNA
keywords: RXR; angiogenesis; enhancer; macrophage; transcription