Abstract
Idiopathic pulmonary fibrosis is a complex disease of unknown etiology. Environmental factors can affect disease susceptibility via epigenetic effects. Few studies explore global DNA methylation in lung fibroblasts, but none have focused on transforming growth factor beta-1 (TGF-β1) as a potential modifier of the DNA methylome. Here we analyzed changes in methylation and gene transcription in normal and IPF fibroblasts following TGF-β1 treatment. We analyzed the effects of TGF-β1 on primary fibroblasts derived from normal or IPF lungs treated for 24 hours and 5 days using the Illumina 450k Human Methylation array and the Prime View Human Gene Expression Array. TGF-β1 induced an increased number of gene expression changes after short term treatment in normal fibroblasts, whereas greater methylation changes were observed following long term stimulation mainly in IPF fibroblasts. DNA methyltransferase 3 alpha (DMNT3a) and tet methylcytosine dioxygenase 3 (TET3) were upregulated after 5-days TGF-β1 treatment in both cell types, whereas DNMT3a was upregulated after 24h only in IPF fibroblasts. Our findings demonstrate that TGF-β1 induced the upregulation of DNMT3a and TET3 expression and profound changes in the DNA methylation pattern of fibroblasts, mainly in those derived from IPF lungs.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is an irreversible, chronic, progressive and lethal disease of unknown etiology, characterized by excessive extracellular matrix (ECM) deposition [1]
After 5 days of TGF-β1 treatment IPF fibroblasts showed a higher expression of actin alpha 2 smooth muscle (ACTA2), and fibronectin containing extra domain A (FnEDA) and a lower increase of COL1A1 and A2 compared with the normal ones
When we focused on the distribution of these changes in relation to the CpG Island distance, we found that in the normal fibroblasts most methylation changes induced by TGF-β1 occurred directly in the islands (67–80%), whereas in the IPF fibroblasts, the Island and Open sea were the best represented groups
Summary
Idiopathic Pulmonary Fibrosis (IPF) is an irreversible, chronic, progressive and lethal disease of unknown etiology, characterized by excessive extracellular matrix (ECM) deposition [1]. Among them, transforming growth factor-beta 1(TGF-β1) is considered one of the most potent mediators of tissue remodeling and fibrosis [3, 4]. TGF-β1 promotes fibroblast proliferation, and their differentiation to myofibroblasts, highly synthetic cells producing multiple ECM components (mainly collagens) with increased contractility and apoptosis resistance [5,6,7,8]. This phenotypic change is the result of the strong effect of TGF-β1 on global gene
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