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Title: The transcription factor ERG is a gatekeeper of endothelial cell homeostasis
Author: Dryden, Nicola Helen
ISNI:       0000 0004 2729 1020
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Endothelial cells (EC) maintain homeostasis through the tightly controlled balance between expression of protective genes and repression of pro-inflammatory genes, and loss of this balance can cause endothelial dysfunction, leading to inflammatory diseases including atherosclerosis. We have previously shown that the ETS transcription factor Erg is involved in maintaining EC homeostasis through transactivation of genes involved in key functions including angiogenesis, migration and survival. In addition to the role for Erg as a transcriptional activator, recent genome wide gene expression analysis has also highlighted a role for Erg in the repression of multiple pro-inflammatory genes. In this Thesis I describe a novel mechanism for Erg-mediated repression of these pro-inflammatory genes using ICAM-1 as a model. We identify two ETS binding sites (EBS) within the ICAM-1 promoter (EBS-118 and -181) which are required for Erg mediated repression. One of these EBS is within a functional NF-κB binding site. We show that the increase in ICAM-1 expression upon Erg inhibition is NF-κB dependent, and that Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene Set Enrichment Analysis (GSEA) of transcriptome profiles of Erg and NF-κB dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other pro-inflammatory genes, including cIAP2 and IL8. We investigate the role of chromatin modifying enzymes and histone modifications in Erg-mediated repression and show that in quiescent EC the ICAM-1 promoter is also bound by the histone methyltransferase ESET, and by HDAC1, both indicators of a repressed chromatin structure. Moreover, in silico data on histone modifications suggest that in quiescent EC the ICAM-1 promoter is in a repressed conformation. The results from this Thesis suggest that Erg acts as a gatekeeper to inhibit transactivation of pro-inflammatory genes in quiescent EC, providing an important barrier to protect against inappropriate endothelial activation.
Supervisor: Randi, Anna ; Birdsey, Graeme ; Mason, Justin Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral