The Essential Role of Histone H3 Lys9 Di-Methylation and MeCP2 Binding in MGMT Silencing with Poor DNA Methylation of the Promoter CpG Island
| Autor: | Takeshi Urano, Tsunehiro Mukai, Hidenobu Soejima, Shuzo Matsuo, Shiroh Matsukura, Shinichi Kudo, Wei Zhao, Ken Higashimoto, Tetsuji Nakagawachi, Keiichiro Joh |
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| Rok vydání: | 2005 |
| Předmět: |
Chromosomal Proteins
Non-Histone Methyl-CpG-Binding Protein 2 Gene Expression Biology Decitabine Hydroxamic Acids Polymerase Chain Reaction Biochemistry Histones O(6)-Methylguanine-DNA Methyltransferase Epigenetics of physical exercise Cell Line Tumor Histone methylation Humans Gene Silencing Cancer epigenetics Epigenetics Promoter Regions Genetic Molecular Biology RNA-Directed DNA Methylation Epigenomics Lysine General Medicine DNA Methylation Molecular biology DNA-Binding Proteins Repressor Proteins Histone methyltransferase DNA methylation Azacitidine CpG Islands Transcription Factors |
| Zdroj: | Journal of Biochemistry. 137:431-440 |
| ISSN: | 0021-924X |
| DOI: | 10.1093/jb/mvi048 |
| Popis: | Silencing of the O (6)-methylguanine-DNA methyltransferase (MGMT) gene, a key to DNA repair, is involved in carcinogenesis. Recent studies have focused on DNA hypermethylation of the promoter CpG island. However, cases showing silencing with DNA hypomethylation certainly exist, and the mechanism involved is not elucidated. To clarify this mechanism, we examined the dynamics of DNA methylation, histone acetylation, histone methylation, and binding of methyl-CpG binding proteins at the MGMT promoter region using four MGMT negative cell lines with various extents of DNA methylation. Histone H3K9 di-methylation (H3me2K9), not tri-methylation, and MeCP2 binding were commonly seen in all MGMT negative cell lines regardless of DNA methylation status. 5Aza-dC, but not TSA, restored gene expression, accompanied by a decrease in H3me2K9 and MeCP2 binding. In SaOS2 cells with the most hypomethylated CpG island, 5Aza-dC decreased H3me2K9 and MeCP2 binding with no effect on DNA methylation or histone acetylation. H3me2K9 and DNA methylation were restricted to in and around the island, indicating that epigenetic modification at the promoter CpG island is critical. We conclude that H3me2K9 and MeCP2 binding are common and more essential for MGMT silencing than DNA hypermethylation or histone deacetylation. The epigenetic mechanism leading to silent heterochromatin at the promoter CpG island may be the same in different types of cancer irrespective of the extent of DNA methylation. |
| Databáze: | OpenAIRE |
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