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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & , 2017. "Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01169-0
    DOI: 10.1038/s41467-017-01169-0
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    Cited by:

    1. Nunzia Caporarello & Jisu Lee & Tho X. Pham & Dakota L. Jones & Jiazhen Guan & Patrick A. Link & Jeffrey A. Meridew & Grace Marden & Takashi Yamashita & Collin A. Osborne & Aditya V. Bhagwate & Steven, 2022. "Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Ahmed A. Raslan & Tho X. Pham & Jisu Lee & Konstantinos Kontodimas & Andrew Tilston-Lunel & Jillian Schmottlach & Jeongmin Hong & Taha Dinc & Andreea M. Bujor & Nunzia Caporarello & Aude Thiriot & Ulr, 2024. "Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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