| Long-term stability of demethylation after transient exposure to 5-aza-2'-deoxycytidine correlates with sustained RNA polymerase II occupancy. | |
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MedLine Citation:
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PMID: 20587535 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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DNA methyltransferase inhibitors are currently the standard of care for myelodysplastic syndrome and are in clinical trials for leukemias and solid tumors. However, the molecular basis underlying their activity remains poorly understood. Here, we studied the induction and long-term stability of gene reactivation at three methylated tumor suppressor loci in response to the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-azaCdR) in human breast cancer cells. At the TMS1/ASC locus, treatment with 5-azaCdR resulted in partial DNA demethylation, the reengagement of RNA polymerase II (Pol II), and a shift from a repressive chromatin profile marked with H3K9me2 and H4K20me3 to an active profile enriched in H3ac and H3K4me2. Using a single-molecule approach coupling chromatin immunoprecipitation with bisulfite sequencing, we show that H3ac, H3K4me2, and Pol II selectively associated with the demethylated alleles, whereas H3K9me2 preferentially marked alleles resistant to demethylation. H4K20me3 was unaffected by DNA demethylation and associated with both unmethylated and methylated alleles. After drug removal, TMS1 underwent partial remethylation, yet a subset of alleles remained stably demethylated for over 3 months. These alleles remained selectively associated with H3K4me2, H3ac, and Pol II and correlated with a sustained low level of gene expression. TMS1 alleles reacquired H3K9me2 over time, and those alleles that became remethylated retained H3ac. In contrast, CDH1 and ESR1 were remethylated and completely silenced within approximately 1 week of drug removal, and failed to maintain stably unmethylated alleles. Our data suggest that the ability to maintain Pol II occupancy is a critical factor in the long-term stability of drug-induced CpG island demethylation. |
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Authors:
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Jacob D Kagey; Priya Kapoor-Vazirani; Michael T McCabe; Doris R Powell; Paula M Vertino |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-06-29 |
Journal Detail:
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Title: Molecular cancer research : MCR Volume: 8 ISSN: 1557-3125 ISO Abbreviation: Mol. Cancer Res. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-16 Completed Date: 2010-11-01 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 101150042 Medline TA: Mol Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1048-59 Citation Subset: IM |
Affiliation:
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Graduate Program in Genetics and Molecular Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Azacitidine
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analogs & derivatives*,
pharmacology Cell Line, Tumor CpG Islands DNA Methylation / drug effects* Gene Expression Regulation, Neoplastic Gene Silencing Genes, Tumor Suppressor Humans Promoter Regions, Genetic RNA Polymerase II / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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2R01 CA077337/CA/NCI NIH HHS; R01 CA077337-10/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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2353-33-5/decitabine; 320-67-2/Azacitidine; EC 2.7.7.-/RNA Polymerase II |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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