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Transforming growth factor beta 1 induces methylation changes in lung fibroblasts.

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-?1) as a potential modifier of the DNA methylome. Here we analyzed changes in methylation and gene transcription in normal and IPF fibroblasts following TGF-?1 treatment. We analyzed the effects of TGF-?1 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-?1 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-?1 treatment in both cell types, whereas DNMT3a was upregulated after 24h only in IPF fibroblasts. Our findings demonstrate that TGF-?1 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.

SUBMITTER: Negreros M

PROVIDER: S-EPMC6788707 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transforming growth factor beta 1 induces methylation changes in lung fibroblasts.

Negreros Miguel M Hagood James S JS Espinoza Celia R CR Balderas-Martínez Yalbi I YI Selman Moisés M Pardo Annie A

PloS one 20191011 10

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 fibr ...[more]

PMID: 31603936

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Project description:BackgroundLung fibroblasts are involved in extracellular matrix homeostasis, which is mainly regulated by transforming growth factor-beta (TGF-?), and are therefore crucial in lung tissue repair and remodeling. Abnormal repair and remodeling has been observed in lung diseases like COPD. As miRNA levels can be influenced by TGF-?, we hypothesized that TGF-? influences miRNA expression in lung fibroblasts, thereby affecting their function.Materials and methodsWe investigated TGF-?1-induced miRNA expression changes in 9 control primary parenchymal lung fibroblasts using miRNA arrays. TGF-?1-induced miRNA expression changes were validated and replicated in an independent set of lung fibroblasts composted of 10 controls and 15 COPD patients using qRT-PCR. Ago2-immunoprecipitation followed by mRNA expression profiling was used to identify the miRNA-targetomes of unstimulated and TGF-?1-stimulated primary lung fibroblasts (n = 2). The genes affected by TGF-?1-modulated miRNAs were identified by comparing the miRNA targetomes of unstimulated and TGF-?1-stimulated fibroblasts.ResultsTwenty-nine miRNAs were significantly differentially expressed after TGF-?1 stimulation (FDR<0.05). The TGF-?1-induced miR-455-3p and miR-21-3p expression changes were validated and replicated, with in addition, lower miR-455-3p levels in COPD (p<0.05). We identified 964 and 945 genes in the miRNA-targetomes of unstimulated and TGF-?1-stimulated lung fibroblasts, respectively. The TGF-? and Wnt pathways were significantly enriched among the Ago2-IP enriched and predicted targets of miR-455-3p and miR-21-3p. The miR-455-3p target genes HN1, NGF, STRADB, DLD and ANO3 and the miR-21-3p target genes HHEX, CHORDC1 and ZBTB49 were consistently more enriched after TGF-?1 stimulation.ConclusionTwo miRNAs, miR-455-3p and miR-21-3p, were induced by TGF-?1 in lung fibroblasts. The significant Ago2-IP enrichment of targets of these miRNAs related to the TGF-? and/or Wnt pathways (NGF, DLD, HHEX) in TGF-?1-stimulated fibroblasts suggest a role for these miRNAs in lung diseases by affecting lung fibroblast function.

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Transforming growth factor beta 1 induces methylation changes in lung fibroblasts.

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Transforming growth factor beta 1 induces methylation changes in lung fibroblasts.

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