Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 45, Issue 1, Pages 16-23Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2010-0154OC
Keywords
lung fibroblasts; Thy-1 expression; HDAC inhibitor; histone modification; DNA methylation
Funding
- National Heart, Lung and Blood Institute [R01 HL082818]
- American Heart Association [09SDG2260095]
- National Center for Research Resources [C06RR 15,490]
- University of Alabama-Birmingham
- DHHS
- NIH
- Kaul Pediatric Research Institute
- American Heart Association
- American Thoracic Society
Ask authors/readers for more resources
Thy-1 is a cell surface glycoprotein present on normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis. Thy-1 correlates inversely with fibrogenic phenotypic characteristics and functions as a fibrosis suppressor. Promoter region hypermethylation can silence Thy-1 expression in fibroblastic foci, suggesting that epigenetic regulation is important in programming the fibrotic phenotype. We examined whether histone modifications are important in regulating Thy-1 expression in lung fibroblasts. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) restored Thy-1 expression in Thy-1(-) cells in a time-dependent and concentration-dependent fashion and was associated with enrichment of histone acetylation. Chromatin immunoprecipitation demonstrated Thy-1 depletion of trimethylated H3K27 after 24 hours of TSA treatment, concurrent with enrichment of trimethylated H3K4 and acetylated H4. Bisulfite sequencing of the Thy-1 promoter region revealed demethylation of the previously hypermethylated CpG sites after treatment with TSA. Although Thy-1 was hypermethylated in Thy-1(-) lung fibroblasts, we observed that Thy-1(-) cells have lower global DNA methylation compared with Thy-1(+) lung fibroblasts, which was partially reversed by TSA treatment. TSA treatment up-regulates total methyltransferase activity in these cells. Our data indicate that Thy-1 silencing is regulated by histone modifications in addition to promoter hypermethylation in lung fibroblasts. Additionally, our findings indicate that alteration of histone modifications alters DNA methylation. Understanding the molecular hierarchy of events with respect to reactivation of transcription and reversal of histone modification will be critical to understand and modify the regulated expression of Thy-1, a tumor-supressor and fibrosis-suppressor gene.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available