Dynamic regulation of canonical TGF beta signalling by endothelial transcription factor ERG protects from liver fibrogenesis
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Volume
8
DOI
10.1038/s41467-017-01169-0
Journal
NATURE COMMUNICATIONS
ISSN
2041-1723
Metadata
Show full item recordAbstract
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.