The transcription factor Erg controls endothelial cell quiescence by repressing the activity of nuclear factor (NF)-κB p65.

Dryden NH, Sperone A, Martin-Almedina S, Hannah RL, Birdsey GM, Taufiq Khan S, Layhadi JA, Mason JC, Haskard DO, Göttgens B, Randi AM

The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programmes. In endothelial cells (EC), the transcription factor NFκB 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 NFκB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing pro-inflammatory gene expression. Focussing on ICAM1 as a model, we identify two ETS binding sites (EBS-118 and -181) within the ICAM1 promoter required for Erg mediated repression. We show that Erg binds to both EBS-118 and EBS-181, the latter located within the NFκB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NFκB-dependent ICAM1 expression, indicating that Erg represses basal NFκB activity. Erg prevents NFκB p65 from binding to the ICAM1 promoter, suggesting a direct mechanism of interference. Gene Set Enrichment Analysis (GSEA) of transcriptome profiles of Erg and NFκB dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other pro-inflammatory genes, including cIAP2 and IL8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.

Chromatin Shearing

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February, 2012



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