title: Yin yang 1 is a novel regulator of pulmonary fibrosis.
abstract: BACKGROUND
  The differentiation of fibroblasts into myofibroblasts is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The transcription factor Yin Yang 1 (YY1) plays a role in the proliferation and differentiation of diverse cell types, but its role in fibrotic lung diseases is not known.
  
  
  OBJECTIVE
  To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis.
  
  
  METHODS
  Lung fibroblasts were cultured with transforming growth factor (TGF)-β or tumor necrosis factor-α. Nuclear factor (NF)-κB, YY1, and α-smooth muscle actin (SMA) were determined in protein, mRNA, and promoter reporter level. Lung fibroblasts and lung fibrosis were assessed in a partial YY1-deficient mouse and a YY1(f/f) conditional knockout mouse after being exposed to silica or bleomycin.
  
  
  RESULTS
  TGF-β and tumor necrosis factor-α up-regulated YY1 expression in lung fibroblasts. TGF-β-induced YY1 expression was dramatically decreased by an inhibitor of NF-κB, which blocked I-κB degradation. YY1 is significantly overexpressed in both human IPF and murine models of lung fibrosis, including in the aggregated pulmonary fibroblasts of fibrotic foci. Furthermore, the mechanism of fibrogenesis is that YY1 can up-regulate α-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1(+/-)) mice were significantly protected from lung fibrosis, which was associated with attenuated α-SMA and collagen expression. Finally, decreasing YY1 expression through instilled adenovirus-cre in floxed-YY1(f/f) mice reduced lung fibrosis.
  
  
  CONCLUSIONS
  YY1 is overexpressed in fibroblasts in both human IPF and murine models in a NF-κB-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing α-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.
authors.affiliation: Department of Medicine, University of Rochester Medical School, Rochester, New York 14642, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Marc A
authors.initials: MA
authors.lastname: Williams
authors.forename: Larry
authors.initials: L
authors.lastname: LaRussa
authors.forename: Steve N
authors.initials: SN
authors.lastname: Georas
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D050986:YY1 Transcription Factor / Q000032:analysis / Q000502:physiology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D050986:YY1 Transcription Factor