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Epigenetic Regulation Mediates Thy-1 Gene Silencing and Induction of the Myofibroblast Phenotype

¹ Department of Pediatrics, University of Alabmama Birmingham, Birmingham, Alabama; ² Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico; and ³ Ohio State University, Department. of Pathology, Columbus, Ohio

Correspondence and requests for reprints should be addressed to James S. Hagood, M.D., Professor of Pediatrics, Cell Biology, Pathology and Biochemistry/Molecular Genetics, University of Alabama-Birmingham, 1670 University Blvd., 648A VH, Birmingham, AL 35294-0019. E-mail: JHagood{at}peds.uab.edu

Molecular mechanisms regulating myofibroblastic differentiation of fibroblasts within fibroblastic foci (FF) in idiopathic pulmonary fibrosis (IPF) remain unclear. Epigenetic processes, such as DNA or histone methylation and histone acetylation, produce heritable but potentially reversible changes in DNA or its associated proteins, and are prominent in developmental processes and oncogenesis (1). We showed that Thy-1 expression suppresses myofibroblastic differentiation of lung fibroblasts (2), and that fibroblasts in FF of IPF are Thy-1(–) (3). Epigenetic downregulation of Thy-1 has been demonstrated in cellular transformation and clinical cancer (4). We hypothesized that epigenetic regulation of Thy-1 affects lung fibroblast phenotypic differentiation. Thy-1 gene expression is absent in Thy-1(–) human and rat fibroblasts by RT-PCR but intact in genomic DNA. In Thy-1(–) and some IPF-derived fibroblasts, methylation-specific PCR (MSP) showed that CpG islands in the promoter region of Thy-1 are hypermethylated, but not in Thy-1(+) fibroblasts. Bisulfite genomic sequencing confirmed methylation of 6 of 14 CpG islands in the Thy-1 promoter of Thy-1(–), but not Thy-1(+), fibroblasts. RT-PCR and MSP on archived lung tissue of patients with IPF demonstrates that in samples in which Thy-1 expression is absent, the Thy-1 promoter region is methylated, whereas in samples that retain Thy-1 expression, the promoter region is unmethylated. MSP-in situ hybridization confirms methylation of the Thy-1 promoter in cells within fibroblastic foci in IPF. Treatment with a DNA methyltransferase inhibitor or histone deacetylase inhibitor restores Thy-1 expression and inhibits myosin expression in Thy-1(–) fibroblasts. Epigenetic regulation of Thy-1 is a novel and potentially reversible mechanism in fibrosis.

FOOTNOTES

Supported in part by The Rud Polhill Senior Faculty Award from the Children's Center for Research and Innovation (J.S.H.), and Research Facilities Improvement Program Grant No. C06RR 15490 from the National Center for Research Resources (to Dr. Albert LoBuglio).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form August 29, 2007; accepted in final form October 16, 2007)

REFERENCES

1. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 2006;7:21–33.[CrossRef][Medline]
2. Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. Am J Respir Cell Mol Biol 2007;36:226–235.[Abstract/Free Full Text]
3. Hagood JS, Prabhakaran P, Kumbla P, Salazar L, MacEwen MW, Barker TH, Ortiz LA, Schoeb T, Siegal GP, Alexander CB, et al. Loss of fibroblast Thy-1 expression correlates with lung fibrogenesis. Am J Pathol 2005;167:365–379.[Abstract/Free Full Text]
4. Lung HL, Bangarusamy DK, Xie D, Cheung AK, Cheng Y, Kumaran MK, Miller L, Liu ET, Guan XY, Sham JS, et al. THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene 2005;24:6525–6532.[Medline]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sanders, Y. Y. Articles by Hagood, J. S. PubMed Articles by Sanders, Y. Y. Articles by Hagood, J. S.