The Experts below are selected from a list of 1422 Experts worldwide ranked by ideXlab platform

Graeme M Birdsey - One of the best experts on this subject based on the ideXlab platform.

  • Author Correction: Dynamic regulation of canonical TGFβ signalling by endothelial Transcription Factor ERG protects from liver fibrogenesis
    Nature communications, 2020
    Co-Authors: Neil Dufton, Graeme M Birdsey, Viktoria Kalna, Youwen Yang, Claire Peghaire, Claudio Raimondi, Lourdes Osuna-almagro, Gwilym J. Webb, Abhishek Chauhan, Patricia F. Lalor
    Abstract:

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • Dynamic regulation of canonical TGFβ signalling by endothelial Transcription Factor ERG protects from liver fibrogenesis
    Nature communications, 2017
    Co-Authors: Neil Dufton, Graeme M Birdsey, Viktoria Kalna, Youwen Yang, Claire Peghaire, Claudio Raimondi, Lourdes Osuna-almagro, Abhishek Chuahan, Gwilym J. Webb, Patricia F. Lalor
    Abstract:

    The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial Transcription Factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ERG cEC-Het ) and inducible homozygous deficient mice (ERG iEC-KO ), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.The Transcription Factor ERG is key to endothelial lineage specification and vascular homeostasis. Here the authors show that ERG balances TGFβ signalling through the SMAD1 and SMAD3 pathways, protecting the endothelium from endothelial-to-mesenchymal transition and consequent liver fibrosis in mice via a SMAD3-dependent mechanism.

  • the endothelial Transcription Factor ERG mediates angiopoietin 1 dependent control of notch signalling and vascular stability
    Nature Communications, 2017
    Co-Authors: Graeme M Birdsey, Youwen Yang, Claire Peghaire, A V Shah, Mara E Pitulescu, Neil Dufton, I Weinberg, Osuna L Almagro
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability. Vascular maturation and stability is regulated by Notch and Angiopoietin-1/Tie2 signalling. Here, Shahet al. show that the Transcription Factor ERG coordinates the Ang1, Notch and Wnt/β-catenin pathways to promote vascular maturation and stability.

  • The endothelial Transcription Factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability.
    Nature communications, 2017
    Co-Authors: Aarti V. Shah, Graeme M Birdsey, Claire Peghaire, Mara E Pitulescu, Neil Dufton, I Weinberg, Y. Yang, L Osuna Almagro, L Payne, Justin C Mason
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.

  • regulation of endothelial homeostasis vascular development and angiogenesis by the Transcription Factor ERG
    Vascular Pharmacology, 2016
    Co-Authors: Aarti V. Shah, Graeme M Birdsey, Anna M Randi
    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.

Neil Dufton - One of the best experts on this subject based on the ideXlab platform.

  • Author Correction: Dynamic regulation of canonical TGFβ signalling by endothelial Transcription Factor ERG protects from liver fibrogenesis
    Nature communications, 2020
    Co-Authors: Neil Dufton, Graeme M Birdsey, Viktoria Kalna, Youwen Yang, Claire Peghaire, Claudio Raimondi, Lourdes Osuna-almagro, Gwilym J. Webb, Abhishek Chauhan, Patricia F. Lalor
    Abstract:

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • The Transcription Factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature.
    Nature communications, 2019
    Co-Authors: Claire Peghaire, Viktoria Kalna, Neil Dufton, Martin Lang, Isabelle I. Salles‐crawley, Josefin Ahnström, Claudio Raimondi, C. Pericleous, L. Inuabasi, Raisa Yu. Kiseleva
    Abstract:

    Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The Transcription Factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ERGiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives Transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Kruppel-like Factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ERGiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS.

  • Dynamic regulation of canonical TGFβ signalling by endothelial Transcription Factor ERG protects from liver fibrogenesis
    Nature communications, 2017
    Co-Authors: Neil Dufton, Graeme M Birdsey, Viktoria Kalna, Youwen Yang, Claire Peghaire, Claudio Raimondi, Lourdes Osuna-almagro, Abhishek Chuahan, Gwilym J. Webb, Patricia F. Lalor
    Abstract:

    The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial Transcription Factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ERG cEC-Het ) and inducible homozygous deficient mice (ERG iEC-KO ), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.The Transcription Factor ERG is key to endothelial lineage specification and vascular homeostasis. Here the authors show that ERG balances TGFβ signalling through the SMAD1 and SMAD3 pathways, protecting the endothelium from endothelial-to-mesenchymal transition and consequent liver fibrosis in mice via a SMAD3-dependent mechanism.

  • the endothelial Transcription Factor ERG mediates angiopoietin 1 dependent control of notch signalling and vascular stability
    Nature Communications, 2017
    Co-Authors: Graeme M Birdsey, Youwen Yang, Claire Peghaire, A V Shah, Mara E Pitulescu, Neil Dufton, I Weinberg, Osuna L Almagro
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability. Vascular maturation and stability is regulated by Notch and Angiopoietin-1/Tie2 signalling. Here, Shahet al. show that the Transcription Factor ERG coordinates the Ang1, Notch and Wnt/β-catenin pathways to promote vascular maturation and stability.

  • The endothelial Transcription Factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability.
    Nature communications, 2017
    Co-Authors: Aarti V. Shah, Graeme M Birdsey, Claire Peghaire, Mara E Pitulescu, Neil Dufton, I Weinberg, Y. Yang, L Osuna Almagro, L Payne, Justin C Mason
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.

Aarti V. Shah - One of the best experts on this subject based on the ideXlab platform.

  • The Transcription Factor ERG Regulates Super-Enhancers Associated With an Endothelial-Specific Gene Expression Program.
    Circulation research, 2019
    Co-Authors: Viktoria Kalna, Youwen Yang, Claire Peghaire, Karen Frudd, Rebecca Hannah, Aarti V. Shah, Lourdes Osuna Almagro, Joseph J. Boyle, Berthold Göttgens, Jorge Ferrer
    Abstract:

    Rationale: The ETS (E-26 transformation-specific) Transcription Factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflamm...

  • The endothelial Transcription Factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability.
    Nature communications, 2017
    Co-Authors: Aarti V. Shah, Graeme M Birdsey, Claire Peghaire, Mara E Pitulescu, Neil Dufton, I Weinberg, Y. Yang, L Osuna Almagro, L Payne, Justin C Mason
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.

  • regulation of endothelial homeostasis vascular development and angiogenesis by the Transcription Factor ERG
    Vascular Pharmacology, 2016
    Co-Authors: Aarti V. Shah, Graeme M Birdsey, Anna M Randi
    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.

  • the endothelial Transcription Factor ERG promotes vascular stability and growth through wnt β catenin signaling
    Developmental Cell, 2015
    Co-Authors: Graeme M Birdsey, Justin C Mason, Youwen Yang, Aarti V. Shah, Lourdes Osuna Almagro, Neil Dufton, Louise E Reynolds, Irene M Aspalter, Samia Taufiq Khan, Elisabetta Dejana
    Abstract:

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS Transcription Factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (ERGcEC-KO) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ERGiEC-KO) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in ERGcEC-KO embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.

  • The Endothelial Transcription Factor ERG Promotes Vascular Stability and Growth through Wnt/β-Catenin Signaling
    Developmental cell, 2015
    Co-Authors: Graeme M Birdsey, Justin C Mason, Youwen Yang, Aarti V. Shah, Lourdes Osuna Almagro, Neil Dufton, Louise E Reynolds, Irene M Aspalter, Samia Taufiq Khan, Elisabetta Dejana
    Abstract:

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS Transcription Factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (ERG(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ERG(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in ERG(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.

Justin C Mason - One of the best experts on this subject based on the ideXlab platform.

  • The endothelial Transcription Factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability.
    Nature communications, 2017
    Co-Authors: Aarti V. Shah, Graeme M Birdsey, Claire Peghaire, Mara E Pitulescu, Neil Dufton, I Weinberg, Y. Yang, L Osuna Almagro, L Payne, Justin C Mason
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.

  • the endothelial Transcription Factor ERG promotes vascular stability and growth through wnt β catenin signaling
    Developmental Cell, 2015
    Co-Authors: Graeme M Birdsey, Justin C Mason, Youwen Yang, Aarti V. Shah, Lourdes Osuna Almagro, Neil Dufton, Louise E Reynolds, Irene M Aspalter, Samia Taufiq Khan, Elisabetta Dejana
    Abstract:

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS Transcription Factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (ERGcEC-KO) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ERGiEC-KO) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in ERGcEC-KO embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.

  • The Endothelial Transcription Factor ERG Promotes Vascular Stability and Growth through Wnt/β-Catenin Signaling
    Developmental cell, 2015
    Co-Authors: Graeme M Birdsey, Justin C Mason, Youwen Yang, Aarti V. Shah, Lourdes Osuna Almagro, Neil Dufton, Louise E Reynolds, Irene M Aspalter, Samia Taufiq Khan, Elisabetta Dejana
    Abstract:

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS Transcription Factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (ERG(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ERG(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in ERG(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.

  • The Transcription Factor ERG Controls Endothelial Cell Quiescence by Repressing Activity of Nuclear Factor (NF)-κB p65
    The Journal of biological chemistry, 2012
    Co-Authors: Nicola H Dryden, Graeme M Birdsey, Dorian O Haskard, Justin C Mason, Rebecca Hannah, Andrea Sperone, Samia Taufiq Khan, Silvia Martin-almedina, Janice A. Layhadi, Berthold Göttgens
    Abstract:

    The interaction of Transcription Factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the Transcription Factor NF-κB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-κB in EC. The Transcription Factor ERG, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS -118 and -181) within the ICAM-1 promoter required for ERG-mediated repression. We show that ERG binds to both EBS -118 and EBS -181, the latter located within the NF-κB binding site. Interestingly, inhibition of ERG expression in quiescent EC results in increased NF-κB-dependent ICAM-1 expression, indicating that ERG represses basal NF-κB activity. ERG prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of ERG and NF-κB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for ERG as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.

  • The Transcription Factor ERG regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis
    Blood, 2011
    Co-Authors: Graeme M Birdsey, Nicola H Dryden, Dorian O Haskard, Justin C Mason, Rebecca Hannah, Aarti V. Shah, Matthew D. Hall, Madeline Parsons, Marketa Zvelebil, Berthold Göttgens
    Abstract:

    The endothelial ETS Transcription Factor ERG plays an important role in homeostasis and angiogenesis by regulating many endothelial functions including survival and junction stability. Here we show that ERG regulates endothelial cell (EC) migration. Transcriptome profiling of ERG-deficient ECs identified ∼ 80 genes involved in cell migration as candidate ERG targets, including many regulators of Rho- GTPases. Inhibition of ERG expression in HUVECs resulted in decreased migration in vitro, while ERG overexpression using adenovirus caused increased migration. Live-cell imaging of ERG-deficient HUVECs showed a reduction in lamellipodia, in line with decreased motility. Both actin and tubulin cytoskeletons were disrupted in ERG-deficient ECs, with a dramatic increase in tubulin acetylation. Among the most significant microarray hits was the cytosolic histone deacetylase 6 (HDAC6), a regulator of cell migration. Chromatin immunoprecipitation (ChIP) and transactivation studies demonstrated that ERG regulates HDAC6 expression. Rescue experiments confirmed that HDAC6 mediates the ERG-dependent regulation of tubulin acetylation and actin localization. In vivo, inhibition of ERG expression in angiogenic ECs resulted in decreased HDAC6 expression with increased tubulin acetylation. Thus, we have identified a novel function for the Transcription Factor ERG in regulating HDAC6 and multiple pathways essential for EC migration and angiogenesis.

Youwen Yang - One of the best experts on this subject based on the ideXlab platform.

  • Author Correction: Dynamic regulation of canonical TGFβ signalling by endothelial Transcription Factor ERG protects from liver fibrogenesis
    Nature communications, 2020
    Co-Authors: Neil Dufton, Graeme M Birdsey, Viktoria Kalna, Youwen Yang, Claire Peghaire, Claudio Raimondi, Lourdes Osuna-almagro, Gwilym J. Webb, Abhishek Chauhan, Patricia F. Lalor
    Abstract:

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • The Transcription Factor ERG Regulates Super-Enhancers Associated With an Endothelial-Specific Gene Expression Program.
    Circulation research, 2019
    Co-Authors: Viktoria Kalna, Youwen Yang, Claire Peghaire, Karen Frudd, Rebecca Hannah, Aarti V. Shah, Lourdes Osuna Almagro, Joseph J. Boyle, Berthold Göttgens, Jorge Ferrer
    Abstract:

    Rationale: The ETS (E-26 transformation-specific) Transcription Factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflamm...

  • Dynamic regulation of canonical TGFβ signalling by endothelial Transcription Factor ERG protects from liver fibrogenesis
    Nature communications, 2017
    Co-Authors: Neil Dufton, Graeme M Birdsey, Viktoria Kalna, Youwen Yang, Claire Peghaire, Claudio Raimondi, Lourdes Osuna-almagro, Abhishek Chuahan, Gwilym J. Webb, Patricia F. Lalor
    Abstract:

    The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial Transcription Factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ERG cEC-Het ) and inducible homozygous deficient mice (ERG iEC-KO ), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.The Transcription Factor ERG is key to endothelial lineage specification and vascular homeostasis. Here the authors show that ERG balances TGFβ signalling through the SMAD1 and SMAD3 pathways, protecting the endothelium from endothelial-to-mesenchymal transition and consequent liver fibrosis in mice via a SMAD3-dependent mechanism.

  • the endothelial Transcription Factor ERG mediates angiopoietin 1 dependent control of notch signalling and vascular stability
    Nature Communications, 2017
    Co-Authors: Graeme M Birdsey, Youwen Yang, Claire Peghaire, A V Shah, Mara E Pitulescu, Neil Dufton, I Weinberg, Osuna L Almagro
    Abstract:

    Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the Transcription Factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability. Vascular maturation and stability is regulated by Notch and Angiopoietin-1/Tie2 signalling. Here, Shahet al. show that the Transcription Factor ERG coordinates the Ang1, Notch and Wnt/β-catenin pathways to promote vascular maturation and stability.

  • the endothelial Transcription Factor ERG promotes vascular stability and growth through wnt β catenin signaling
    Developmental Cell, 2015
    Co-Authors: Graeme M Birdsey, Justin C Mason, Youwen Yang, Aarti V. Shah, Lourdes Osuna Almagro, Neil Dufton, Louise E Reynolds, Irene M Aspalter, Samia Taufiq Khan, Elisabetta Dejana
    Abstract:

    Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS Transcription Factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (ERGcEC-KO) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ERGiEC-KO) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in ERGcEC-KO embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.