Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis

Neil P. Dufton, Claire R. Peghaire, Lourdes Osuna-Almagro, Claudio Raimondi, Viktoria Kalna, Abhishek Chauhan, Gwilym Webb, Youwen Yang, Graeme M. Birdsey, Patricia Lalor, Justin C. Mason, David H. Adams and Anna M. Randi ()
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Neil P. Dufton: Imperial College London
Claire R. Peghaire: Imperial College London
Lourdes Osuna-Almagro: Imperial College London
Claudio Raimondi: Imperial College London
Viktoria Kalna: Imperial College London
Abhishek Chauhan: University of Birmingham
Gwilym Webb: University of Birmingham
Youwen Yang: Imperial College London
Graeme M. Birdsey: Imperial College London
Patricia Lalor: University of Birmingham
Justin C. Mason: Imperial College London
David H. Adams: University of Birmingham
Anna M. Randi: Imperial College London

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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 (ErgcEC-Het) and inducible homozygous deficient mice (ErgiEC-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.

Date: 2017
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DOI: 10.1038/s41467-017-01169-0

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