Inhibition of DNA methylation de‐represses peroxisome proliferator‐activated receptor‐γ and attenuates pulmonary fibrosis

Abstract

Background and Purpose: Development of pulmonary fibrosis is associated with altered DNA methylation modifications of fibrogenic gene expression. However, their causal relationships and the underlying mechanisms remain unclear. This study investigates the critical role of DNA methylation aberration-associated suppression of peroxisome proliferator-activated receptor-γ (PPARγ) in pulmonary fibrosis. Experimental Approach: Expression of PPARγ and bioactive DNA methyltransferases (DNMTs) and PPARγ promoter methylation status were examined in fibrotic lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin (Blm)-treated mice. DNA demethylating agent 5-aza-2 0 -deoxycytidine (5aza) and glycyrrhizic acid (GA) derived from medicinal plant were assessed for their PPARγ de-repression and antipulmonary fibrosis activities. PPARγ knockout mice were created to determine the critical role of PPARγ in this protection. Key Results: Lung PPARγ expression was markedly suppressed in IPF patients and Blm mice, accompanied by increased DNMT 1/DNMT3a and PPARγ promoter hypermethylation. Administration of 5-aza and GA similarly demethylated PPARγ promoter, restored PPARγ loss and alleviated fibrotic lung pathologies, including structural alterations and adverse expression of fibrotic mediators and inflammatory cytokines. In cultured lung fibroblasts and alveolar epithelial cells, GA alleviated PPARγ-mediated suppression of fibrosis in a gain of DNMT-sensitive manner, and in PPARγ knockout mice, the anti-fibrotic effects of 5aza and GA were significantly reduced, suggesting that PPARγ is a critical mediator of epigenetic pulmonary fibrogenesis. Conclusion and Implications: Aberrant DNMT1/3a elevations and the resultant PPARγ suppression contribute significantly to the development of pulmonary fibrosis, and strategies targeting DNMT/PPARγ axis with synthetic or natural compounds might benefit patients with pulmonary fibrotic disorders.

Myeloid Fbxw7 Prevents Pulmonary Fibrosis by Suppressing TGF-β Production

“…The Fbxw7 promoter can be regulated through epigenetic mechanism during lung fibrosis, including histone modifications. Aberrant elevation of DNA methyltransferase 1 (Dnmt1) can mediate the hypermethylation of Fbxw7 promoter and result in decreased gene level of Fbxw7 ( 65 ), subsequently contributes significantly to the development of pulmonary fibrosis ( 66 ). Moreover, the expression of enhancer of zeste homolog 2 (Ezh2) is increased in IPF patients, increased Ezh2 recruitment and hypermethylated H3K27 at the promoter of fibrotic related genes have been demonstrated, such as Cox-2 ( 67 ) and Cxcl10 ( 68 ).…”

Myeloid DNA methyltransferase3b deficiency aggravates pulmonary fibrosis by enhancing profibrotic macrophage activation

“…Together with DNMT3B, DNMT3A also catalyzes de novo DNA methylation, while the DNMT1 maintains DNA methylation [ 16 ]. Therefore, we cannot rule out a potential role of DNMT3A and DNMT1 in regulating macrophage polarization during fibrosis, and other studies have already shown that both DNMT1 and DNMT3A play a role in the development of pulmonary fibrosis by modulating DNA methylation in lung fibroblasts and alveolar epithelial cells [ 18 ].…”

Epigenetics Approaches toward Precision Medicine for Idiopathic Pulmonary Fibrosis: Focus on DNA Methylation

“…The DNMT3A-induced silencing of SOCS3 expression stimulates TGF-β-dependent fibroblast activation in experimental systemic sclerosis (SSc) murine models [ 70 ]. A recent study found that the peroxisome proliferator-activated receptor-γ (PPARγ) expression was low, but increased DNMT 1/DNMT3a and PPARγ promoter hypermethylation in IPF patients; therefore, the inhibition of DNA methylation that restored PPARγ led to attenuated pulmonary fibrosis [ 71 ]. The aberrant expression of DNMTs patterns is associated with pulmonary fibrosis, although the exact mechanisms underlying this pathogenesis remain elusive.…”

“…In addition, 5aza reduced global DNA methylation in chemo-sensitive cancer cells [ 143 ]. Targeting DNMT 1/DNMT3a and the peroxisome proliferator-activated receptor-γ (PPAR-γ) axis with 5-aza can demethylate the PPAR-γ promoter, restore PPAR-γ loss, and alleviate fibrotic lung [ 71 ].…”