DNA demethylation-dependent enhancement of toll-like receptor-2 gene expression in cystic fibrosis epithelial cells involves SP1-activated transcription
| Autor: | Mary Ann Suico, Yuko Ohira, Takashi Furuta, Shogo Shimasaki, Hirofumi Kai, Dieter C. Gruenert, Tsuyoshi Shuto |
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| Rok vydání: | 2008 |
| Předmět: |
lcsh:QH426-470
Cystic Fibrosis Transcription Genetic Sp1 Transcription Factor Biology Models Biological Cell Line Transcription (biology) Gene expression Humans lcsh:QH573-671 Promoter Regions Genetic Molecular Biology Reporter gene Toll-like receptor Binding Sites lcsh:Cytology Epithelial Cells Methylation DNA Methylation Molecular biology Toll-Like Receptor 2 Cell biology lcsh:Genetics DNA demethylation Gene Expression Regulation CpG site DNA methylation CpG Islands Research Article Protein Binding |
| Zdroj: | BMC Molecular Biology BMC Molecular Biology, Vol 9, Iss 1, p 39 (2008) |
| ISSN: | 1471-2199 |
| DOI: | 10.1186/1471-2199-9-39 |
| Popis: | Background The clinical course of cystic fibrosis (CF) is characterized by recurrent pulmonary infections and chronic inflammation. We have recently shown that decreased methylation of the toll-like receptor-2 (TLR2) promoter leads to an apparent CF-related up-regulation of TLR2. This up-regulation could be responsible, in part, for the CF-associated enhanced proinflammatory responses to various bacterial products in epithelial cells. However, the molecular mechanisms underlying DNA hypomethylation-dependent enhancement of TLR2 expression in CF cells remain unknown. Results The present study indicates that there is a specific CpG region (CpG#18-20), adjacent to the SP1 binding site that is significantly hypomethylated in several CF epithelial cell lines. These CpGs encompass a minimal promoter region required for basal TLR2 expression, and suggests that CpG#18-20 methylation regulates TLR2 expression in epithelial cells. Furthermore, reporter gene analysis indicated that the SP1 binding site is involved in the methylation-dependent regulation of the TLR2 promoter. Inhibition of SP1 with mithramycin A decreased TLR2 expression in both CF and 5-azacytidine-treated non-CF epithelial cells. Moreover, even though SP1 binding was not affected by CpG methylation, SP1-dependent transcription was abolished by CpG methylation. Conclusion This report implicates SP1 as a critical component of DNA demethylation-dependent up-regulation of TLR2 expression in CF epithelial cells. |
| Databáze: | OpenAIRE |
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