Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide

Abstract

Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that a small molecule, butylidenephthalide (BP), reduces type I collagen (COL1) expression in Transforming Growth Factor beta (TGF-β)-induced lung fibroblast without altering downstream pathways of TGF-β, such as Smad phosphorylation. Treatment of BP also reduces the expression of transcription factor Sex Determining Region Y-box 2 (SOX2), and the ectopic expression of SOX2 overcomes the inhibitory actions of BP on COL1 expression. We also found that serial deletion of the SOX2 binding site on 3′COL1 promoter results in a marked reduction in luciferase activity. Moreover, chromatin immunoprecipitation, which was found on the SOX2 binding site of the COL1 promoter, decreases in BP-treated cells. In an in vivo study using a bleomycin-induced pulmonary fibrosis C57BL/6 mice model, mice treated with BP displayed reduced lung fibrosis and collagen deposition, recovering in their pulmonary ventilation function. The reduction of SOX2 expression in BP-treated lung tissues is consistent with our findings in the fibroblast. This is the first report that reveals a non-canonical regulation of COL1 promoter via SOX2 binding, and contributes to the amelioration of pulmonary fibrosis by BP treatment.

Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging

“…Further supporting this, we find here a significant increase of differentiating SOX2-positive club cells with aging, which again was anticipated in the telomerase-deficient mice. Sox2 has been previously shown a marker of differentiation of club cells ( Tompkins et al, 2009 ), which is increased in bleomycin-induced pulmonary fibrosis in mice ( Chuang et al, 2018 ), as well as in patients suffering from IPF ( Plantier et al, 2011 ).…”

Mathematical Modeling Approaches to Understanding Severe Acute Respiratory Syn-drome Coronavirus 2 (SARSCoV-2) DNA Sequences Linked Coronavirus Disease (COVID-19) for Discovery of Potential New Drugs

“…The There are examples shows the crucial role of these peptides in human genes. In 2019 Szpiech and colleagues suggested that Runs of homozygosity (ROH) 'are associated with an inflation of deleterious homozygous variation [20]. They have suggested that ' African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases [21].…”

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“…Among them, ZNF678 , which is involved in transcriptional regulation, interacted with EPB41L3 in the STRING protein–protein interaction network analysis ( Figure S8 ). Among the 99 proteins interacting with ZNF687, 33 proteins, including MYC [ 29 ], CSNK2A1 [ 30 ], CDKN2A [ 31 ], HDAC2 [ 32 ], MI1 [ 33 ], SOX2 [ 34 ], and RNF2 [ 35 ], have been revealed to be associated with fibrosis. These data indicate that EPB41L3 may be regulated through interactions with ZNF687 and interacting genes.…”