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Published ahead of print on June 12, 2008, doi:10.1165/rcmb.2007-0322OC

Am. J. Respir. Cell Mol. Biol., Volume 39, Number 5, November 2008, 610-618

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Submitted on September 2, 2007
Revised on June 12, 2008

Thy-1 Promoter Hypermethylation: A Novel Epigenetic Pathogenic Mechanism in Pulmonary Fibrosis

Yan Y Sanders1, Annie Pardo2, Moises Selman3, Gerard J Nuovo4, Trygve O Tollefsbol5, Gene P Siegal6, and James S Hagood1*

1 Department of Pediatrics, Division of Pulmonary Medicine, University of Alabama at Birmingham, Birmingham, AL, USA, 2 Facultad de Ciencias, Univerisdad Nacional Autonoma de Mexico, Mexico City, Mexico, 3 Insituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico, 4 Department of Pathology, Ohio State University, Columbus, OH, USA, 5 Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA, 6 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

* To whom correspondence should be addressed. E-mail: JHagood{at}PEDS.UAB.EDU.

Rationale: Mechanisms regulating myofibroblastic differentiation of fibroblasts within fibroblastic foci in idiopathic pulmonary fibrosis (IPF) remain unclear. Epigenetic processes, including DNA methylation, produce heritable but potentially reversible changes in DNA or its associated proteins, and are prominent in development and oncogenesis. We have shown that Thy-1 suppresses myofibroblastic differentiation of lung fibroblasts, and that fibroblasts in fibroblastic foci are Thy-1(-). Epigenetic downregulation of Thy-1 has been demonstrated in cellular transformation and clinical cancer. Objectives: We hypothesized that epigenetic regulation of Thy-1 affects the lung fibroblast fibrogenic phenotype. Methods: Reverse transcriptase polymerase chain reaction (RT-PCR), methylation-specific PCR (MSP), and bisulfite genomic sequencing (BGS) were used to determine methylation status of the Thy-1 promoter in Thy-1(+) and (-) lung fibroblasts, and MSP-in situ hybridization (MSPISH) was performed on fibrotic tissue. Measurements and Main Results: Thy-1 gene expression is absent in Thy-1(-) human and rat fibroblasts despite intact Thy-1 genomic DNA. Cytosine-guanine (CpG) islands in the Thy-1 gene promoter are hypermethylated in Thy-1(-), but not Thy-1(+), fibroblasts. RT-PCR and MSP demonstrates that in IPF samples in which Thy-1 expression is absent, the Thy-1 promoter region is methylated; while in lung samples retaining Thy-1 expression, the promoter region is unmethylated. MSPISH confirms methylation of the Thy-1 promoter in fibroblastic foci in IPF. Treatment with DNA methyltransferase inhibitors restores Thy-1 expression in Thy-1(-) fibroblasts. Conclusions: Epigenetic regulation of Thy-1 is a novel and potentially reversible mechanism in fibrosis, which may offer the possibility of new therapeutic options.






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