title: The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear factor (NF)-κB p65.
abstract: The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-κB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-κB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS -118 and -181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS -118 and EBS -181, the latter located within the NF-κB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-κB-dependent ICAM-1 expression, indicating that Erg represses basal NF-κB activity. Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-κB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.
authors.affiliation: National Heart and Lung Institute Cardiovascular Sciences Unit, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors.forename: Nicola H
authors.initials: NH
authors.lastname: Dryden
authors.forename: Andrea
authors.initials: A
authors.lastname: Sperone
authors.forename: Silvia
authors.initials: S
authors.lastname: Martin-Almedina
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hannah
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Birdsey
authors.forename: Samia Taufiq
authors.initials: ST
authors.lastname: Khan
authors.forename: Janice A
authors.initials: JA
authors.lastname: Layhadi
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.forename: Anna M
authors.initials: AM
authors.lastname: Randi
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016192:Resting Phase, Cell Cycle; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000071230:Transcriptional Regulator ERG; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; D049410:Luciferases, Renilla