title: Fli1 acts downstream of Etv2 to govern cell survival and vascular homeostasis via positive autoregulation.
abstract: BACKGROUND
  Cardiovascular health depends on proper development and integrity of blood vessels. Ets variant 2 (Etv2), a member of the E26 transforming-specific family of transcription factors, is essential to initiate a transcriptional program leading to vascular morphogenesis in early mouse embryos. However, endothelial expression of the Etv2 gene ceases at midgestation; therefore, vascular development past this stage must continue independent of Etv2.
  
  
  OBJECTIVE
  To identify molecular mechanisms underlying transcriptional regulation of vascular morphogenesis and homeostasis in the absence of Etv2.
  
  
  RESULTS
  Using loss- and gain-of-function strategies and a series of molecular techniques, we identify Friend leukemia integration 1 (Fli1), another E26 transforming-specific family transcription factor, as a downstream target of Etv2. We demonstrate that Etv2 binds to conserved Ets-binding sites within the promoter region of the Fli1 gene and governs Fli1 expression. Importantly, in the absence of Etv2 at midgestation, binding of Etv2 at Ets-binding sites in the Fli1 promoter is replaced by Fli1 protein itself, sustaining expression of Fli1 as well as selective Etv2-regulated endothelial genes to promote endothelial cell survival and vascular integrity. Consistent with this, we report that Fli1 binds to the conserved Ets-binding sites within promoter and enhancer regions of other Etv2-regulated endothelial genes, including Tie2, to control their expression at and beyond midgestation.
  
  
  CONCLUSIONS
  We have identified a novel positive feed-forward regulatory loop in which Etv2 activates expression of genes involved in vasculogenesis, including Fli1. Once the program is activated in early embryos, Fli1 then takes over to sustain the process in the absence of Etv2.
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.).
authors.forename: Md J
authors.initials: MJ
authors.lastname: Abedin
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.).
authors.forename: Annie
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.).
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.).
authors.forename: Cameron E
authors.initials: CE
authors.lastname: Perry
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.).
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.).
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Watson
authors.affiliation: From the Department of Internal Medicine (Cardiology) (M.J.A., A.N., N.J., C.E.P., J.M.S., A.F.), University of Texas Southwestern Medical Center, Dallas; Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston (D.K.W.); and Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis (M.J.A.). anwarul.ferdous@utsouthwestern.edu.
authors.forename: Anwarul
authors.initials: A
authors.lastname: Ferdous
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology; D005260:Female; D006470:Hemorrhage / Q000209:etiology / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009024:Morphogenesis / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: C503994:ER71 protein, mouse; C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1; D014157:Transcription Factors
keywords: apoptosis; developmental biology; embryonic development; gene expression; homeostasis; transcription factors
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