التفاصيل البيبلوغرافية
| العنوان: |
Role for DNA Methylation in the Regulation of miR-200c and miR-141 Expression in Normal and Cancer Cells. |
| المؤلفون: |
Vrba, Lukas, Jensen, Taylor J., Garbe, James C., Heimark, Ronald L., Cress, Anne E., Dickinson, Sally, Stampfer, Martha R., Futscher, Bernard W. |
| المصدر: |
PLoS ONE; 2010, Vol. 5 Issue 1, p1-8, 8p, 6 Graphs |
| مصطلحات موضوعية: |
RNA, PHENOTYPES, CANCER, DNA, METHYLATION, CANCER cells, EPITHELIAL cells, FIBROBLASTS, CHROMATIN |
| مستخلص: |
Background: The microRNA-200 family participates in the maintenance of an epithelial phenotype and loss of its expression can result in epithelial to mesenchymal transition (EMT). Furthermore, the loss of expression of miR-200 family members is linked to an aggressive cancer phenotype. Regulation of the miR-200 family expression in normal and cancer cells is not fully understood. Methodology/Principal Findings: Epigenetic mechanisms participate in the control of miR-200c and miR-141 expression in both normal and cancer cells. A CpG island near the predicted mir-200c/mir-141 transcription start site shows a striking correlation between miR-200c and miR-141 expression and DNA methylation in both normal and cancer cells, as determined by MassARRAY technology. The CpG island is unmethylated in human miR-200/miR-141 expressing epithelial cells and in miR-200c/miR-141 positive tumor cells. The CpG island is heavily methylated in human miR-200c/miR-141 negative fibroblasts and miR-200c/miR-141 negative tumor cells. Mouse cells show a similar inverse correlation between DNA methylation and miR-200c expression. Enrichment of permissive histone modifications, H3 acetylation and H3K4 trimethylation, is seen in normal miR-200c/miR-141-positive epithelial cells, as determined by chromatin immunoprecipitation coupled to real-time PCR. In contrast, repressive H3K9 dimethylation marks are present in normal miR-200c/miR-141- negative fibroblasts and miR-200c/miR-141 negative cancer cells and the permissive histone modifications are absent. The epigenetic modifier drug, 5-aza-29-deoxycytidine, reactivates miR-200c/miR-141 expression showing that epigenetic mechanisms play a functional role in their transcriptional control. Conclusions/Significance: We report that DNA methylation plays a role in the normal cell type-specific expression of miR- 200c and miR-141 and this role appears evolutionarily conserved, since similar results were obtained in mouse. Aberrant DNA methylation of the miR-200c/141 CpG island is closely linked to their inappropriate silencing in cancer cells. Since the miR-200c cluster plays a significant role in EMT, our results suggest an important role for DNA methylation in the control of phenotypic conversions in normal cells. [ABSTRACT FROM AUTHOR] |
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