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

作者：Dufton Neil P; Peghaire Claire R; Osuna Almagro Lourdes; Raimondi Claudio; Kalna Viktoria; Chuahan Abhishek; Webb Gwilym; Yang Youwen; Birdsey Graeme M; Lalor Patricia; Mason Justin C; Adams David H; Randi Anna M

来源：Nature Communications, 2017, 8(1): 895.

DOI：10.1038/s41467-017-01169-0

The role of the endothelium in protecting from chronic liver disease and TGF beta-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGF beta-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-alpha 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.

• 出版日期2017-10-12