Fli1 acts downstream of etv2 to govern cell survival and vascular homeostasis via positive autoregulation

Md J. Abedin, Annie Nguyen, Nan Jiang, Cameron E. Perry, John M. Shelton, Dennis K. Watson, Anwarul Ferdous

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

RATIONALE:: 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. METHODS AND 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.

Original languageEnglish (US)
Pages (from-to)1690-1699
Number of pages10
JournalCirculation Research
Volume114
Issue number11
DOIs
StatePublished - May 23 2014

Fingerprint

Blood Vessels
Cell Survival
Leukemia
Homeostasis
Binding Sites
Morphogenesis
Genetic Promoter Regions
Genes
Transcription Factors
Embryonic Structures
Endothelial Cells
Gene Expression
Health
Proteins

Keywords

  • apoptosis
  • developmental biology
  • embryonic development
  • gene expression
  • homeostasis
  • transcription factors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Fli1 acts downstream of etv2 to govern cell survival and vascular homeostasis via positive autoregulation. / Abedin, Md J.; Nguyen, Annie; Jiang, Nan; Perry, Cameron E.; Shelton, John M.; Watson, Dennis K.; Ferdous, Anwarul.

In: Circulation Research, Vol. 114, No. 11, 23.05.2014, p. 1690-1699.

Research output: Contribution to journalArticle

Abedin, Md J. ; Nguyen, Annie ; Jiang, Nan ; Perry, Cameron E. ; Shelton, John M. ; Watson, Dennis K. ; Ferdous, Anwarul. / Fli1 acts downstream of etv2 to govern cell survival and vascular homeostasis via positive autoregulation. In: Circulation Research. 2014 ; Vol. 114, No. 11. pp. 1690-1699.
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abstract = "RATIONALE:: 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. METHODS AND 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.",
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T1 - Fli1 acts downstream of etv2 to govern cell survival and vascular homeostasis via positive autoregulation

AU - Abedin, Md J.

AU - Nguyen, Annie

AU - Jiang, Nan

AU - Perry, Cameron E.

AU - Shelton, John M.

AU - Watson, Dennis K.

AU - Ferdous, Anwarul

PY - 2014/5/23

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N2 - RATIONALE:: 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. METHODS AND 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.

AB - RATIONALE:: 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. METHODS AND 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.

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KW - developmental biology

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KW - gene expression

KW - homeostasis

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