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Mol Cell Biol
2002 Mar 01;226:1844-57. doi: 10.1128/MCB.22.6.1844-1857.2002.
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Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation.
El-Osta A
,
Kantharidis P
,
Zalcberg JR
,
Wolffe AP
.
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Overexpression of the human multidrug resistance gene 1 (MDR1) is a negative prognostic factor in leukemia. Despite intense efforts to characterize the gene at the molecular level, little is known about the genetic events that switch on gene expression in P-glycoprotein-negative cells. Recent studies have shown that the transcriptional competence of MDR1 is often closely associated with DNA methylation. Chromatin remodeling and modification targeted by the recognition of methylated DNA provide a dominant mechanism for transcriptional repression. Consistent with this epigenetic model, interference with DNA methyltransferase and histone deacetylase activity alone or in combination can reactivate silent genes. In the present study, we used chromatin immunoprecipitation to monitor the molecular events involved in the activation and repression of MDR1. Inhibitors of DNA methyltransferase (5-azacytidine [5aC]) and histone deacetylase (trichostatin A [TSA]) were used to examine gene transcription, promoter methylation status, and the chromatin determinants associated with the MDR1 promoter. We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones H3 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression. MDR1 expression was significantly increased following combined 5aC and TSA treatments. Inhibition of histone deacetylase is not an overriding mechanism in the reactivation of methylated MDR1. Our results provide us with a clearer understanding of the molecular mechanism necessary for repression of MDR1.
Bannister,
Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.
2001, Pubmed
Bannister,
Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.
2001,
Pubmed
Bauer,
Nucleosome structural changes due to acetylation.
1994,
Pubmed
,
Xenbase
Bestor,
Gene silencing. Methylation meets acetylation.
1998,
Pubmed
Boyes,
Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein.
1992,
Pubmed
Boyes,
DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein.
1991,
Pubmed
Cameron,
Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer.
1999,
Pubmed
Clark,
High sensitivity mapping of methylated cytosines.
1994,
Pubmed
Coffee,
Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells.
1999,
Pubmed
Cosma,
Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle- and developmentally regulated promoter.
1999,
Pubmed
Cross,
A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins.
1997,
Pubmed
Csankovszki,
Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation.
2001,
Pubmed
Desiderato,
Demethylation of the human MDR1 5' region accompanies activation of P-glycoprotein expression in a HL60 multidrug resistant subline.
1997,
Pubmed
Eden,
DNA methylation models histone acetylation.
1998,
Pubmed
Forsberg,
Developmentally dynamic histone acetylation pattern of a tissue-specific chromatin domain.
2000,
Pubmed
Fuks,
DNA methyltransferase Dnmt1 associates with histone deacetylase activity.
2000,
Pubmed
Gregory,
DNA methylation is linked to deacetylation of histone H3, but not H4, on the imprinted genes Snrpn and U2af1-rs1.
2001,
Pubmed
Hendrich,
Identification and characterization of a family of mammalian methyl-CpG binding proteins.
1998,
Pubmed
Hendrich,
The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites.
1999,
Pubmed
Herman,
Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B.
1996,
Pubmed
Jeppesen,
The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression.
1993,
Pubmed
Jin,
Transcriptional regulation of the MDR1 gene by histone acetyltransferase and deacetylase is mediated by NF-Y.
1998,
Pubmed
Jones,
Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.
1998,
Pubmed
,
Xenbase
Jones,
Cancer epigenetics comes of age.
1999,
Pubmed
Kaludov,
MeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery.
2000,
Pubmed
Kantharidis,
Regulation of MDR1 gene expression: emerging concepts.
2000,
Pubmed
Kantharidis,
Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance.
1997,
Pubmed
Keohane,
Histone acetylation and X inactivation.
1998,
Pubmed
Leegwater,
Analysis of DNA methylation of the 5' region of the deoxycytidine kinase gene in CCRF-CEM-sensitive and cladribine (CdA)- and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA)-resistant cells.
1998,
Pubmed
Lewis,
Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA.
1992,
Pubmed
Lorincz,
Methylation-mediated proviral silencing is associated with MeCP2 recruitment and localized histone H3 deacetylation.
2001,
Pubmed
Luger,
Crystal structure of the nucleosome core particle at 2.8 A resolution.
1997,
Pubmed
Magdinier,
Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia.
2001,
Pubmed
McQueen,
Chicken microchromosomes are hyperacetylated, early replicating, and gene rich.
1998,
Pubmed
Meehan,
Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs.
1989,
Pubmed
Meehan,
Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA.
1992,
Pubmed
Muscat,
The corepressor N-CoR and its variants RIP13a and RIP13Delta1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70.
1998,
Pubmed
Nakayama,
Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias.
1998,
Pubmed
Nan,
DNA methylation specifies chromosomal localization of MeCP2.
1996,
Pubmed
Nan,
Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2.
1993,
Pubmed
Nan,
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.
1998,
Pubmed
Nan,
MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.
1997,
Pubmed
Ng,
Active repression of methylated genes by the chromosomal protein MBD1.
2000,
Pubmed
Ng,
MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex.
1999,
Pubmed
Ng,
DNA methylation and chromatin modification.
1999,
Pubmed
Peterson,
ATP-dependent chromatin remodeling: going mobile.
2000,
Pubmed
Petronzelli,
Investigation of the substrate spectrum of the human mismatch-specific DNA N-glycosylase MED1 (MBD4): fundamental role of the catalytic domain.
2000,
Pubmed
Pérez-Martín,
The C-terminal domain of Sin1 interacts with the SWI-SNF complex in yeast.
1998,
Pubmed
Reinke,
A transient histone hyperacetylation signal marks nucleosomes for remodeling at the PHO8 promoter in vivo.
2001,
Pubmed
Robertson,
DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters.
2000,
Pubmed
Rountree,
DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.
2000,
Pubmed
Schübeler,
Genomic targeting of methylated DNA: influence of methylation on transcription, replication, chromatin structure, and histone acetylation.
2000,
Pubmed
Sif,
Purification and characterization of mSin3A-containing Brg1 and hBrm chromatin remodeling complexes.
2001,
Pubmed
Tatematsu,
MBD2-MBD3 complex binds to hemi-methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase.
2000,
Pubmed
Ueda,
Recent progress in P-glycoprotein research.
1999,
Pubmed
Ura,
Histone acetylation: influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression.
1997,
Pubmed
,
Xenbase
Wade,
Histone deacetylase directs the dominant silencing of transcription in chromatin: association with MeCP2 and the Mi-2 chromodomain SWI/SNF ATPase.
1998,
Pubmed
Wade,
Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation.
1999,
Pubmed
,
Xenbase
Wade,
A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase.
1998,
Pubmed
,
Xenbase
Wakefield,
Histone underacetylation is an ancient component of mammalian X chromosome inactivation.
1997,
Pubmed
Wall,
Expression of mdr1 and mrp in the normal B-cell homologue of B-cell chronic lymphocytic leukaemia.
1997,
Pubmed
Wang,
Purification and biochemical heterogeneity of the mammalian SWI-SNF complex.
1996,
Pubmed
Wang,
Diversity and specialization of mammalian SWI/SNF complexes.
1996,
Pubmed
Weitzel,
Chicken MAR-binding protein ARBP is homologous to rat methyl-CpG-binding protein MeCP2.
1997,
Pubmed
Wong,
Transcriptional repression by the SMRT-mSin3 corepressor: multiple interactions, multiple mechanisms, and a potential role for TFIIB.
1998,
Pubmed
Zalcberg,
Cellular and karyotypic characterization of two doxorubicin resistant cell lines isolated from the same parental human leukemia cell line.
1994,
Pubmed
el-Osta,
Absolute quantitation of MDR1 transcripts using heterologous DNA standards--validation of the competitive RT-PCR (CRT-PCR) approach.
1999,
Pubmed
