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      Regulation of endothelial homeostasis, vascular development and angiogenesis by the transcription factor ERG

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          Abstract

          Over the last few years, the ETS transcription factor ERG has emerged as a major regulator of endothelial function. Multiple studies have shown that ERG plays a crucial role in promoting angiogenesis and vascular stability during development and after birth. In the mature vasculature ERG also functions to maintain endothelial homeostasis, by transactivating genes involved in key endothelial functions, while repressing expression of pro-inflammatory genes. Its homeostatic role is lineage-specific, since ectopic expression of ERG in non-endothelial tissues such as prostate is detrimental and contributes to oncogenesis. This review summarises the main roles and pathways controlled by ERG in the vascular endothelium, its transcriptional targets and its functional partners and the emerging evidence on the pathways regulating ERG's activity and expression.

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          ERG regulation of endothelial function and homeostasis.

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          Most cited references113

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          Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

          Ewing's sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(11;22) (q24;q12) chromosome translocation, the breakpoints of which have recently been cloned. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation. Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1.
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            The ETS-domain transcription factor family.

            ETS-domain transcription-factor networks represent a model for how combinatorial gene expression is achieved. These transcription factors interact with a multitude of co-regulatory partners to elicit gene-specific responses and drive distinct biological processes. These proteins are controlled by a complex series of inter and intramolecular interactions, and signalling pathways impinge on these proteins to further regulate their action.
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              Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo

              Members of the large ETS family of transcription factors (TFs) have highly similar DNA-binding domains (DBDs)—yet they have diverse functions and activities in physiology and oncogenesis. Some differences in DNA-binding preferences within this family have been described, but they have not been analysed systematically, and their contributions to targeting remain largely uncharacterized. We report here the DNA-binding profiles for all human and mouse ETS factors, which we generated using two different methods: a high-throughput microwell-based TF DNA-binding specificity assay, and protein-binding microarrays (PBMs). Both approaches reveal that the ETS-binding profiles cluster into four distinct classes, and that all ETS factors linked to cancer, ERG, ETV1, ETV4 and FLI1, fall into just one of these classes. We identify amino-acid residues that are critical for the differences in specificity between all the classes, and confirm the specificities in vivo using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for a member of each class. The results indicate that even relatively small differences in in vitro binding specificity of a TF contribute to site selectivity in vivo.
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                Author and article information

                Contributors
                Journal
                Vascul Pharmacol
                Vascul. Pharmacol
                Vascular Pharmacology
                Elsevier Science
                1537-1891
                1879-3649
                1 November 2016
                November 2016
                : 86
                : 3-13
                Affiliations
                Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
                Author notes
                [* ]Corresponding author at: NHLI Vascular Sciences, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom.NHLI Vascular SciencesHammersmith HospitalImperial College LondonDu Cane RoadLondonW12 0NNUnited Kingdom a.randi@ 123456imperial.ac.uk
                [1]

                Current address: Division of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, United Kingdom.

                Article
                S1537-1891(16)30045-3
                10.1016/j.vph.2016.05.003
                5404112
                27208692
                ae8dcc76-3acc-4074-ba80-b28919da0145
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 February 2016
                : 8 April 2016
                : 16 May 2016
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                ets transcription factors,gene transcription,angiogenesis,vascular development,endothelial homeostasis

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