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The Transcription Factor ERG Is a Gatekeeper of Endothelial Cell Homeostasis

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The Transcription Factor ERG Is a Gatekeeper of Endothelial Cell Homeostasis The Transcription Factor ERG is a Gatekeeper of Endothelial Cell Homeostasis Nicola Helen Dryden This thesis is submitted to Imperial College London for the degree of Doctor of Philosophy (PhD) Imperial College London National Heart and Lung Institute Vascular Sciences Section 1 Declaration of originality I, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract 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. 3 For My Family 4 Table of Contents The Transcription Factor ERG is a Gatekeeper of Endothelial Cell Homeostasis .................... 1 Declaration of originality ........................................................................................................... 2 Abstract ...................................................................................................................................... 3 Publications arising from this Thesis ....................................................................................... 13 Acknowledgements .................................................................................................................. 14 List of Figures .......................................................................................................................... 15 List of Tables ........................................................................................................................... 18 Chapter One: Introduction ...................................................................................................... 19 1.1. Inflammation ................................................................................................................. 20 1.1.1. Inflammation in atherosclerosis .......................................................................... 21 1.1.2. Mechanisms of inflammation in atherosclerosis ................................................ 21 1.1.3. The resting endothelium ..................................................................................... 24 1.1.4. Activation of endothelium during inflammation ................................................ 24 1.1.5. Leukocyte recruitment ........................................................................................ 25 1.2. Inflammatory stimuli involved in leukocytes recruitment and downstream targets ..... 28 1.2.1. TNF-α ................................................................................................................. 28 1.2.2. IL-1 ..................................................................................................................... 28 1.2.3. IFN-γ ................................................................................................................... 29 1.3. Role of the transcription factor NF-κB in inflammation .............................................. 29 1.3.1. NF-κB family members and structure ................................................................ 29 1.3.2. NF-κB consensus sequences and specificity ...................................................... 32 1.3.3. Regulation of NF-κB .......................................................................................... 32 1.4. The inflammatory molecule ICAM-1 ........................................................................... 35 1.4.1. Structure and mechanisms of action in EC ......................................................... 35 1.4.2. Regulation of ICAM-1 expression ..................................................................... 37 1.4.3. Transcription factors involved in the regulation of ICAM-1 expression ........... 39 5 1.4.3.1. Regulation of ICAM-1 expression by AP-1/ETS transcription factors ......... 39 1.4.3.2. Regulation of ICAM-1 expression by ETS transcription factors ................... 39 1.4.3.3. Regulation of ICAM-1 expression by STAT and ETS transcription factors . 40 1.4.3.4. Regulation of ICAM-1 expression by NF-κB ................................................ 40 1.4.3.5. Regulation of ICAM-1 expression by STAT-1 .............................................. 43 1.4.3.6. Regulation of ICAM-1 expression by AP-1 ................................................... 43 1.5. Epigenetic regulation of transcription ........................................................................... 43 1.5.1. Introduction ........................................................................................................ 43 1.5.2. Histone acetylation ............................................................................................. 46 1.5.3. Histone methylation ............................................................................................ 47 1.5.4. Other post-translational modifications of histones ............................................. 47 1.5.5. The histone code ................................................................................................. 50 1.5.6. HDAC inhibitors ................................................................................................. 50 1.5.7. HDAC inhibitors and inflammation ................................................................... 50 1.6. The ETS family of transcription factors ....................................................................... 51 1.6.1. Structure and interactions of ETS factors ........................................................... 51 1.6.2. DNA binding and specificity of ETS factors ...................................................... 55 1.6.3. Expression and function of ETS factors ............................................................. 57 1.6.4. ETS transcriptional activators ............................................................................ 57 1.6.5. ETS transcriptional repressors ............................................................................ 57 1.6.6. ETS factors with both activating and repressing properties ............................... 58 1.6.7. ETS factors and endothelial cells ....................................................................... 58 1.6.8. ETS factors and inflammation ............................................................................ 59 1.7. The ETS related gene Erg ............................................................................................. 60 1.7.1. Expression of Erg ............................................................................................... 60 1.7.2. Erg: genomic structure and isoforms .................................................................. 60 1.7.3. Domains of the Erg protein ................................................................................ 63 6 1.7.3.1. Erg ETS DNA binding domain ...................................................................... 63 1.7.3.2. Erg Pointed domain ........................................................................................ 63 1.7.3.3. Additional Erg functional domains ................................................................ 63 1.7.3.4. Erg fusion proteins and the deregulation of Erg in cancer ............................. 64 1.7.3.5. FUS(TLS)/Erg and EWS/Erg fusions in sarcoma and leukaemia.................. 64 1.7.3.6. TMPRSS2/Erg in prostate cancer .................................................................. 64 1.8. Erg binding partners ...................................................................................................... 67 1.9. Function of Erg ............................................................................................................
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