Yin Yang 1 Is a Novel Regulator of Pulmonary Fibrosis

Rationale: 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. Objectives: To elucidate the mechanism by which YY1 regulates fibroblast differentiation and lung fibrosis. Methods: Lung fibroblasts were cultured with transforming growth factor (TGF)-beta or tumor necrosis factor-alpha. Nuclear factor (NF)-kappa B, YY1, and alpha-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. Measurements and Main Results: TGF-beta and tumor necrosis factor-a up-regulated YY1 expression in lung fibroblasts. TGF-beta-induced YY1 expression was dramatically decreased by an inhibitor of NF-kappa B, which blocked I-kB 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 a-SMA expression in pulmonary fibroblasts. YY1-deficient (YY1(+/-)) mice weresignificantly protected from lung fibrosis, which was associated with attenuated alpha-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-kappa B-dependent manner, and YY1 regulates fibrogenesis at least in part by increasing alpha-SMA and collagen expression. Decreasing YY1 expression may provide a new therapeutic strategy for pulmonary fibrosis.