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Methylguanine-DNA Methyltransferase Gene Expression by Histone Acetylation and Methyl-Cpg Binding Proteins

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Methylguanine-DNA Methyltransferase Gene Expression by Histone Acetylation and Methyl-Cpg Binding Proteins Molecular Cancer Therapeutics 61 Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins Rebecca P. Danam, Sherie R. Howell, MGMT-silenced cells. Our findings implicate specific MBD Thomas P. Brent, and Linda C. Harris proteins in methylation-mediated transcriptional silencing of MGMT. [Mol Cancer Ther 2005;4(1):61–9] Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, Tennessee Introduction Abstract The DNA repair protein, O6-methylguanine-DNA methyl- Transcriptional silencing of the DNA repair gene, O6-methyl- transferase (MGMT), removes alkyl adducts from the guanine-DNA methyltransferase (MGMT) in a proportion of O6-position of guanine in DNA and protects cells against transformed cell lines is associated with methylated CpG the mutagenic, carcinogenic and cytotoxic effects of alkyl- hotspots in the MGMT 5V flank. The goal of the study was ating agents. MGMT is expressed in all human cells, to evaluate the mechanism by which CpG methylation tissues, and most tumors, although its expression varies of the MGMT promoter region influenced silencing of widely (1). Furthermore, MGMT is silenced in a significant the gene. Analysis of histone acetylation status in two proportion (f20-30%) of malignant and transformed cell regions of the promoter using chromatin immunopre- lines and a fraction of primary tumors. Such silenced cells cipitation assay showed that a higher level of histone are hypersensitive to cancer therapeutic and carcinogenic acetylation was associated with expression in three MGMT- alkylating agents (2). expressing cell lines (HeLa CCL2, HT29, and Raji) com- MGMT gene has a CpG-rich promoter containing a CpG pared with three MGMT-silenced cell lines (HeLa S3, BE, island with no TATA or CAAT boxes. There are six puta- and TK6). To determine how the modulation of CpG tive Sp1 recognition sites, along with two glucocorticoid methylation and histone acetylation influenced MGMT ex- receptor binding elements, two activator protein-1 (AP-1), pression, we exposed the cells to 5-aza-2Vdeoxycytidine and two putative AP-2 binding sequences (3). MGMT- (5-Aza-dC), inhibitor of DNA methylation, which strongly silenced cells lack detectable levels of MGMT RNA and up-regulated MGMT expression in three MGMT-silenced protein. However, no gross rearrangements nor deletions cell lines whereas trichostatin A, inhibitor of histone of the gene have been reported suggesting that the ab- deacetylase, weakly induced MGMT. However, combined sence of RNA is due to regulation at the transcriptional treatment with 5-Aza-dC and trichostatin A significantly level. Previous reports from our lab and others have shown up-regulated MGMT RNA expression to a greater extent that MGMT suppression is strongly linked to CpG than in cells treated with either agent alone suggesting methylation in the 5V flanking region of the gene (4–7). that histone deacetylation plays a role in MGMT silenc- We also reported that in cell lines and xenografts, there ing but that CpG methylation has a dominant effect. are two hotspot regions in the 5V region of the MGMT gene Consistent with enhanced MGMT expression, 5-Aza-dC where CpG methylation is almost always associated increased the association of acetylated histone H3 and with MGMT silencing (8). Whereas methylation is clearly H4 bound to the MGMT promoter. Chromatin immuno- involved in MGMT silencing, the precise mechanism of precipitation analysis of methyl-CpG binding domain methylation-mediated transcriptional inactivation of the containing proteins detected a greater amount of MeCP2, MGMT gene is not understood. MBD1, and CAF-1 bound to the MGMT promoter in DNA methylation can repress gene transcription either by interfering with the sequence-specific binding and/or function of transcription factors due to cytosine meth- ylation of the recognition sites (9, 10) or by recruiting methyl CpG binding domain (MBD) containing family of Received 8/30/04; revised 10/20/04; accepted 11/16/04. proteins. MBD proteins mediate transcriptional repression Grant support: NIH grants CA 14799, Cancer Center CORE grant CA via corepressors and by altering the chromatin structure, 21765, and American Lebanese Syrian Associated Charities. or by blocking access to transcription machinery (11, 12). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked Based on studies demonstrating the connection between advertisement in accordance with 18 U.S.C. Section 1734 solely to DNA methylation and histone deacetylation (13, 14), a indicate this fact. model has been proposed for methylation-mediated tran- Requests for reprints: Linda C. Harris, Department of Molecular scriptional silencing. According to this model, MBD Pharmacology, St. Jude Children’s Research Hospital, 332 North Lauderdale Memphis, TN 38105. Phone: 901-495-3833; proteins bind to methylated CpGs and recruit histone Fax: 901-495-4293. E-mail: [email protected] deacetylase (HDAC) either directly or via a corepressor Copyright C 2005 American Association for Cancer Research. complex. The HDAC removes acetyl groups from the Mol Cancer Ther 2005;4(1). January 2005 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2005 American Association for Cancer Research. 62 Histone Deacetylation, MBD Proteins, and MGMT lysines on the NH2-terminal histone tails, which restores inhibitors. Equal amounts of proteins were size fractionated the positive charge on the lysine residues and promotes by 10% SDS-PAGE and transferred onto polyvinylidene the stabilization of histone-DNA interaction. This results difluoride membrane. Membranes were probed with anti- in chromatin condensation, inaccessibility of transcription bodies against MeCP2 (Upstate Biotechnology, Lake Placid, factors, and transcriptional inactivation. Conversely, his- NY), MBD1 (Santa Cruz Biotechnology, Santa Cruz, CA), tone acetylation reverses the process leading to a more MGMT (Chemicon International, Temecula, CA), and h- open chromatin, accessibility of transcription factors, and tubulin (Sigma). The proteins were detected with the transcriptional activation. enhanced chemilumiscence Western blotting detection Five methyl-CpG binding proteins, MeCP2, MBD1, system (Amersham Biosciences, Piscataway, NY). MBD2, MBD3, and MBD4 have been identified to date WesternBlotAnalysisofIsolatedHistones in mammalian systems. Four of these proteins, MeCP2, Cells were cultured as described above. After 24 hours of MBD1, MBD2, and MBD4 bind to methylated CpG through culture without or with TSA (330 nmol/L), cells were har- the conserved protein motif called the MBD (15). MeCP2, vested and washed in ice-cold PBS. Nuclei were isolated MBD1, and MBD2 have been shown to recruit HDAC by dounce homogenization of cells in 1 mL of lysis buf- and function as transcriptional repressors. MBD3 is a non- fer [10 mmol/L Tris-HCl (pH 6.5), 50 mmol/L sodium DNA binding component of the Mi-2/NuRD corepressor bisulfite, 8.6% sucrose, 1% Triton X-100, and 10 mmol/L complex, and MBD4 has uracil DNA glycosylase activity MgCl2]andcentrifugedat1,000rpmfor5minutes, and has been implicated in DNA repair (16). Another pro- washed twice in lysis buffer and later with Tris-EDTA tein, Kaiso, binds methylated DNA through a zinc finger solution [10 mmol/L Tris-HCl (pH 7.4) and 13 mmol/L motif and behaves as a transcriptional repressor (17). EDTA]. Histones were isolated from the nuclear fraction The present study was designed to first assess whether by acid extraction as described (18). Histones (25 Ag) were histone acetylation is associated with CpG methylation in separated on 15% SDS-PAGE minigels, transferred to nitro- the MGMT promoter region and evaluate the relative cellulose membranes (Bio-Rad, Hercules, CA) and probed contribution of histone acetylation to MGMT expression. with different antibodies. The following antibodies were Second, the goal was to identify the MBD proteins used: antiacetylated histone H3, anti-histone H3, anti- associated with MGMT promoter in MGMT expressing acetylated histone H4, anti-histone H4, (Upstate Biotech- and silenced cell lines and thereby understand the role of nology). The proteins were detected with the enhanced the MBD proteins in mediating MGMT transcriptional chemiluminescence Western blotting detection system repression. (Amersham Biosciences). ChromatinImmunoprecipitationAssay We used the chromatin immunoprecipitation (ChIP) assay kit from Upstate Biotechnology and followed the Materials and Methods manufacturer’s protocol with some modifications. The Cell Culture proteins were cross-linked to the DNA, by the addition of The human cervical tumor cell lines HeLa S3 and CCL2 formaldehyde to the culture medium to a final concentra- weregrowninEagle’sminimumessentialmedium tion of 1%, and were incubated at 37jC for 10 minutes. supplemented with 10% FCS. The human colon adenocar- The cross-linking reaction was quenched by adding cinoma cell lines BE and HT29, were grown in McCoy’s 125 mmol/L glycine (in PBS) for 5 minutes at room 5A medium supplemented with 10% FCS. The human B temperature. The medium was removed and the cells were lymphoblast cell lines, TK6, and Raji were cultured in suspended in 1 mL of ice-cold PBS containing protease RPMI 1640 containing 10% FCS. All cells were grown inhibitors. Cells were pelleted, resuspended in 0.2 mL of at 37jC in 95% humidified air and 5% CO2. All cells SDS lysis buffer
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