Transforming growth factor beta 1 induces methylation changes in lung fibroblasts


Autoři: Miguel Negreros aff001;  James S. Hagood aff002;  Celia R. Espinoza aff002;  Yalbi I. Balderas-Martínez aff004;  Moisés Selman aff004;  Annie Pardo aff001
Působiště autorů: Facultad de Ciencias Universidad Nacional Autónoma de México, Mexico City, Mexico aff001;  Department of Pediatrics, Division of Respiratory Medicine, University of California-San Diego, La Jolla, California, United States of America aff002;  Department of Pediatrics, Pulmonology Division, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff003;  Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico aff004;  Cátedra CONACyT-INER, Mexico City, Mexico aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223512

Souhrn

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.

Klíčová slova:

DNA methylation – Fibroblasts – Fibrosis – Gene expression – Gene regulation – Pulmonary fibrosis – TGF-beta signaling cascade – Cultured fibroblasts


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