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Urologic Cancer Research Laboratory, Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center and Hospital, University of Southern California, Keck School of Medicine, Los Angeles, California 90089
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ABSTRACT |
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Introduction |
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There is growing evidence that an interplay exists between cytosine methylation and histone modification. For example, the methyl-CpG binding protein, MeCP2, has been found to be associated with HDAC3 activity, providing a pathway by which histone modification can be induced by DNA methylation changes (11 , 12) . It has also been shown that histone modification is crucial to the process of DNA methylation in some organisms; abrogation of H3-K9 methylation in Neurospora results in the loss of DNA methylation (13) . These data suggest a functional linkage between DNA methylation and H3-K9 methylation in gene repression and the establishment of a heterochromatic state.
To better understand the relationship between cytosine methylation and histone modification in cancer-associated gene silencing, we have performed ChIP analyses of the patterns of H3-K4 methylation and H3-K9 methylation at the p14ARF/p16INK4a locus in a variety of normal and tumor cell lines, each of which display unique cytosine methylation patterns at the three CpG islands contained within the locus. We also treated the T24 bladder cancer cell line with the cytosine methylation inhibitor, 5-Aza-CdR, to determine whether or not modulation of DNA methylation could affect histone modification.
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Materials and Methods |
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5-Aza-CdR Treatment.
Cells were plated at 1 x 106 cells/150-mm dish and treated the next day with freshly prepared 3 x 10-6 M 5-Aza-CdR (Sigma Chemical Co., St. Louis, MO). The medium was changed 24 h after treatment, and ChIPs were performed and DNA/RNA extracted on days 1, 2, and 3 after drug treatment from exponentially growing cultures. Two independent 5-Aza-CdR treatment experiments were performed.
ChIP Assays.
ChIP assays were performed as previously described (4)
with 10 µl of anti-MeCP2, 10 µl of anti-K9-dimethylated H3, 10 µl of anti-acetylated H3 (lysine 9 and lysine 14 residues), or 5 µl of anti-K4-dimethylated H3. All of the antibodies were obtained from Upstate Biotechnology, Lake Placid, NY.
PCR Analysis of Immunoprecipitated DNA.
PCR amplification of immunoprecipitated DNA was performed as previously described (4)
. PCR products were electrophoresed on 2% agarose gels and quantitated with the Bio-Rad Gel Doc 1000 system and Molecular Analyst software. Fold enrichment in each immunoprecipitation was determined by quantifying the intensities of the PCR product in immunoprecipitated DNA versus input DNA (total chromatin).
RT-PCR Analysis of p14 and p16 Expression.
RT-PCR and subsequent PCR reactions were carried out with 100 ng of the cDNA product, dNTPs (Roche Molecular Biochemicals) and TaqDNA polymerase (Sigma) as described previously (4)
. The p14 and p16 primers used have been described previously (4)
.
Western Blot Analysis.
T24 cell pellets were lysed in 10 mM HEPES (pH 7.9), 1.5 mM MgCl2, 10 mM KCl, 0.5 mM DTT, and 1.5 mM phenylmethylsulfonyl fluoride and HCl were added to a concentration of 0.2 M. After incubation on ice for 30 min and centrifugation at 11,000 x g for 10 min at 4°C, the supernatant was dialyzed against 0.1 M acetic acid twice for 1 h and then dialyzed three times against H2O for 1 h, 3 h, and overnight at 4°C. The protein electrophoresis, transfer, and detection were performed as described previously (4)
. Membranes were hybridized with antibodies (Upstate) against H3 (1:500), acetylated H3 (1:20,000), K9-dimethylated H3 (1:5,000), and K4-dimethylated H3 (1:5,000). Secondary antibodies were antimouse-IgG-horseradish peroxidase (1:1,000 dilution for H3; Santa Cruz Biotechnology, Santa Cruz, CA), and antirabbit-IgG-horseradish peroxidase (1:1,000 dilution for acetylated and methylated histones; Santa Cruz Biotechnology).
Hemimethylation Assay.
Hemimethylation analysis was performed as described previously (14)
. Undigested or HpaII-digested DNA from T24 cells was subjected to bisulfite modification. HpaII digests unmethylated DNA but does not cut a fully or hemimethylated configuration of its CCGG target sequence. Bisulfite-treated DNA was then amplified by PCR using primers that flanked the first HpaII site in p16 exon 2. The PCR primers used to amplify this locus are as follows: sense 5'-GGA AAT TGG AAA TTG GAA GTA AAT G-3', antisense 5'-TAA AAC AAC AAC AAC TC-3'. Methylation-sensitive single-nucleotide primer extension assay (Ms-SNuPE) analysis was performed on the purified PCR product using the following primer: 5' ATA AGT TTT TTT TT(C/T) GTT ATG T-3', and the equations used to determine hemimethylation levels used were as described previously (14)
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Results |
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Previous work has demonstrated that CpG islands in either promoter or exonic regions within the p14/p16 locus can become de novo methylated at CpG dinucleotides in cancer, resulting in binding by MeCP2, H3 hypoacetylation, and inaccessibility to endonucleases (4)
. ChIP analysis using antibodies against dimethylated histones demonstrated that such islands are characterized by high levels of H3-K9 methylation (Fig. 1A)
. In fact, cytosine and H3-K9 methylation of CpG islands correlated very well in the three cancer cell lines studied (Fig. 1A)
. For example, in J82 bladder cancer cells, the shared exon 2, which has high levels of cytosine methylation and MeCP2 occupancy, displayed higher levels of H3-K9 methylation than either of the two promoter regions, both of which have very little cytosine methylation and are sites of transcriptional initiation. Heterochromatic domains present at CpG islands with high cytosine and H3-K9 methylation also do not prevent transcriptional elongation. The two bladder cancer cell lines, J82 and T24, both have heterochromatic regions (the shared exon 2 in J82 and the p16 promoter/shared exon 2 in T24) which are situated downstream of active promoters (Fig. 1B
; Ref. 4
).
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; Ref. 4
). H3-K4 methylation was lowest at CpG islands with high cytosine and H3-K9 methylation. For example, the p16 promoter and shared exon 2 of T24, both of which have high levels of cytosine and H3-K9 methylation, exhibited very little H3-K4 methylation. However, it was observed that the p16 promoter and shared exon 2 in LD419 cells displayed less H3-K4 methylation than predicted for CpG islands that have negligible cytosine or H3-K9 methylation. Furthermore, there appeared to be no significant difference in the levels of H3-K4 methylation at the p14 promoter of T24 and HCT15 cells, even though the CpG islands are differentially methylated in the two cell lines (Fig. 1B)
. This suggests that the positive correlation between H3-K4 methylation and euchromatin may not be absolute.
5-Aza-CdR Induces Rapid Reduction of MeCP2 and K9-methylated H3 and Enhancement of Acetylated H3 and K4-methylated H3 at Silenced Loci.
Previous work has shown that the treatment of the T24 bladder cancer cell line with 5-Aza-CdR caused substantial demethylation of the p16 promoter and shared exon 2 and strong reactivation of p16 expression (15
, 16)
, although no change was induced in the level of expression of the p14 gene, which is unmethylated in these cells (Fig. 2
; Ref. 4
). Reactivation of the p16 gene was preceded by a rapid chromatin remodeling of the promoter and shared exon 2 regions in which the heterochromatic imprint was reversed and replaced by a euchromatic one. The levels of MeCP2 and methylated H3-K9 at the p16 promoter and shared exon 2 decreased dramatically just 24 h after treatment with 5-Aza-CdR, reaching their lowest points by 48 h after drug treatment and were maintained at low levels after 72 h (Fig. 3, A and B)
. In contrast, H3 acetylation and H3-K4 methylation increased at the same two CpG islands compared with untreated T24 cells (day 0), reaching their highest levels by 48–72 h after drug treatment (Fig. 3, C and D)
.
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. The p14 gene was expressed relatively strongly, and its levels did not change over the time course of 5-Aza-CdR treatment (Fig. 2)
. This promoter region was also occupied by high levels of acetylated H3 and H3-K4 methylation (relative to the p16 promoter and shared exon 2) that were substantially augmented after treatment with 5-Aza-CdR, with increases observed as early as 24 h after treatment (Fig. 3, C and D)
. Therefore, these results suggest that 5-Aza-CdR can induce chromatin remodeling independently of its effects on cytosine methylation.
5-Aza-CdR Induces High Levels of DNA Hemimethylation but Does Not Dramatically Inhibit Overall Histone Modification.
MeCP2 is known to specifically bind to symmetrically methylated CpG sequences, and has a poor affinity for unmethylated and hemimethylated DNA (17)
. We determined the levels of hemimethylated, fully methylated, and unmethylated DNA at the p16 exon2 CpG island after treatment of T24 cells with 5-Aza-CdR using a novel assay that we recently developed (14)
. The levels of hemimethylation dramatically increased within the first 24 h of treatment, suggesting that the precipitous decrease of MeCP2-binding after 5-Aza-CdR treatment (Fig. 4A)
may be attributable to its inability to bind to a hemimethylated DNA substrate. Whereas the levels of hemimethylation decreased at 48 h and 72 h after treatment, the levels of unmethylated DNA increased at this time, which may further prevent MeCP2 binding. Western blot analysis showed that the overall levels of K9-methylated H3, K4-methylated H3, and acetylated H3, however, did not dramatically change after 5-Aza-CdR treatment of T24 cells (Fig. 4B)
, suggesting that the chromatin alterations detected by ChIP analysis were region-specific rather than global.
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Discussion |
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In addition, our study is consistent with previous work that has linked H3-K4 methylation with active euchromatin (5) . However, the data show that the inverse correlation between H3-K4 methylation and heterochromatin may not be absolute, suggesting that H3-K4 methylation may be more of a permissive rather than an exclusive marker of euchromatin. The lack of a complete correlation may also be explained by the limitations of our PCR-based assay, which does not allow precise quantitation. However, such a limitation does not influence the major findings of our study, and it should be noted that the data are internally consistent and reproducible (based on two independent experiments).
The mechanisms by which heterochromatic domains are established at CpG islands are poorly understood. However, data from this study, in conjunction with previous work from our laboratory, suggest that certain regions of a gene are more vulnerable than others to heterochromatinization and may serve as foci for the seeding of aberrant cytosine and H3-K9 methylation (18) . It has been postulated that transcription through a gene region may facilitate de novo cytosine methylation, and we have previously demonstrated that downstream/exonic regions of a gene become aberrantly methylated more easily than promoter regions in normal and cancer cells (18 , 19) . The data in this study indicate that CpG islands are more heterochromatic when they are located downstream of an active promoter. For example, the p16 promoter and shared exon 2 of LD419 exhibit little cytosine or H3-K9 methylation, and yet both show relatively lower K9-acetylation and K4-methylation than would be predicted for CpG islands that are devoid of methylation (compared with the p14 promoter in LD419). Indeed, these two CpG islands displayed far less accessibility to endonuclease than did the equally unmethylated p14 promoter (4) . The low level of H3 acetylation in downstream regions of a gene could predispose them to heterochromatic change by providing more sites for K9 histone-methyltransferase activity. Decreased levels of acetylation also imply higher occupancy by HDACs, which may recruit DNA-methyltransferase activity to a region as suggested by data demonstrating in vivo interactions between HDAC and DNMT1 (20, 21, 22) . These data may explain why there is a greater prevalence of aberrant cytosine methylation and inactivation of p16 than than there is of p14 in numerous tumor cell types (3) .
The colocalization of aberrant cytosine and H3-K9 methylation to the heterochromatic microdomains of the p14/p16 locus in the various cancer cell lines raises another intriguing question: how do these two epigenetic marks interact to stably repress a gene, or, even more interesting, which epigenetic modification is dominant in abnormal gene silencing? It is entirely conceivable that cytosine methylation can facilitate H3-K9 methylation. For example, it is known that the DNA methylation signal is translated by methyl-CpG binding proteins, such as MeCP2 or MBD2; MeCP2 is able to recruit HDAC activity and induce deacetylation of K9 residues on H3, thus allowing methylation of K9 by histone methyltransferases (11 , 12) . The opposite pathway, in which H3-K9 methylation might regulate cytosine methylation, is supported by work done in Neurospora, in which it was shown that abrogation of H3-K9 methylation led to a loss of DNA methylation, as well as data from kinetic analyses of X inactivation demonstrating that H3-K9 methylation is the earliest epigenetic mark during inactivation, preceding even cytosine methylation (7 , 13) .
5-Aza-CdR treatment induced a precipitous remodeling of chromatin structure, drastically reducing MeCP2-binding and H3-K9 methylation while enhancing H3 acetylation and H3-K4 methylation. A recent study has also demonstrated a similar decrease in MeCP2 occupancy and increase in histone H3 acetylation at the promotor of the MDRI gene following 5-Aza-CdR treatment (23) . These changes appeared to be regional, because no changes in the overall levels of modified histones were detected by Western blot analysis. Given that MeCP2 does not have a high affinity for hemimethylated DNA (17) , the dramatic decrease in MeCP2-binding at methylated CpG islands might be explained by an increase in the levels of hemimethylated DNA after drug treatment. A substantial increase in hemimethylation immediately after 5-Aza-CdR treatment has been previously predicted because of the inhibition of maintenance DNA methylation machinery (16) . As a result, DNA replication is not accompanied by DNA methylation. This work represents the first experimental evidence of 5-Aza-CdR-induced hemimethylation in the context of a hypermethylated CpG island. The presence of a hemimethylated DNA substrate may prevent MeCP2 binding at these sequences after drug treatment.
Furthermore, the inhibition of H3-K9 methylation by 5-Aza-CdR seemed to be more powerful than its inhibition of cytosine methylation. Previous work has shown that significant cytosine demethylation (an 
30% decrease) is achieved between 36 and 48 h after treatment with 5-Aza-CdR (16)
. The data from this study show that H3-K9 methylation levels precipitously decreased by almost two-thirds (a 66% reduction) a mere 24 h after treatment with 5-Aza-CdR.
Drug-induced remodeling of chromatin was also observed at the p14 promoter that was enriched for H3 acetylation and H3-K4 methylation and showed little, if any, MeCP2 binding or H3-K9 methylation before drug treatment. The levels of the two euchromatic markers were substantially increased after drug treatment, showing that the drug could induce chromatin remodeling in the absence of DNA methylation.
Taken together, these data suggest that 5-Aza-CdR is able to cause a regional remodeling of chromatin, by diminishing H3-K9 methylation and augmenting H3 acetylation and H3-K4 methylation, independently of its effects on DNA methylation or gene expression. Substantial enhancement of the two euchromatic markers at the p14 promoter was not accompanied by a concomitant increase in p14 expression, and chromatin remodeling preceded changes in expression of p16, suggesting that the observed changes in the levels of the chromatin markers after 5-Aza-CdR treatment are not secondary to transcriptional effects. Our data are supported by previous work showing that 5-Aza-CdR can induce hyperacetylation of pericentric heterochromatin (which is transcriptionally inert) in mice independently of its cytosine demethylation activity (24) .
How does 5-Aza-CdR induce chromatin remodeling and modulate histone methylation? Drug-induced up-regulation of genes encoding chromatin-modifying proteins, such as SWI-SNF or HAT (histone acetyltransferase) enzymes, represent a possible mechanism by which 5-Aza-CdR could modulate histone methylation by inducing nucleosomal remodeling and turnover. Also, extensive data show that DNMT1 interacts with HDAC activity in complexes bound to DNA, suggesting that it can recruit histone modifiers to DNA (20, 21, 22) . Conceivably, the trapping of DNA-methyltransferase by 5-Aza-CdR would prevent DNMT1 from targeting HDAC activity to certain regions of DNA, thereby affecting chromatin structure. Furthermore, it is still possible that histone methylation is dependent on cytosine methylation despite our observation that H3-K9 methylation diminished more rapidly than cytosine methylation after 5-Aza-CdR treatment. Methyl-CpG binding proteins, such as MeCP2 and MBD2, are known to interact with HDAC activity in vivo and may also interact with other unidentified chromatin modifiers (11 , 12 , 25) . A loss of cytosine methylation because of sequestration of functional DNA-methyltransferase would eliminate binding sites for methyl-CpG binding proteins, subsequently decreasing recruitment of HDACs to DNA.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by USPHS Grant RO1 CA82422 from the National Cancer Institute (to P. A. J.). M. V. was supported by a NIH Training Grant T32 DE07211-11. D. J. W. was supported by NIH Training Grant in Basic Research in Oncology T32 CA09659. 
2 To whom requests for reprints should be addressed, at University of Southern California/Norris Comprehensive Cancer Center and Hospital, 1441 Eastlake Ave., Room 8302L, Mail Stop 83, Los Angeles, CA 90089-9181. Phone: (323) 865-0816; Fax: (323) 865-0102; E-mail: jones_p{at}ccnt.hsc.usc.edu
3 The abbreviations used are: HDAC, histone deacetylase; 5-Aza-CdR, 5-aza-2'-deoxycytidine; ChIP, chromatin immunoprecipitation; DNMT, DNA methyltransferase; H3, histone H3; H3-K9, lysine 9 amino acid residue of H3; H3-K4, lysine 4 amino acid residue of H3; MeCP2, methyl-CpG binding protein 2; RT-PCR, reverse transcription-PCR.
Received 8/21/02. Accepted 9/24/02.
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J. Fan, E.-i. Kodama, Y. Koh, M. Nakao, and M. Matsuoka Halogenated Thymidine Analogues Restore the Expression of Silenced Genes without Demethylation Cancer Res., August 1, 2005; 65(15): 6927 - 6933. [Abstract] [Full Text] [PDF]
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 K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF]
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 A. M. Bode and Z. Dong Inducible Covalent Posttranslational Modification of Histone H3 Sci. Signal., April 26, 2005; 2005(281): re4 - re4. [Abstract] [Full Text] [PDF]
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 P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF]
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S.-i. Kumakura, T. W. Tsutsui, J. Yagisawa, J. C. Barrett, and T. Tsutsui Reversible Conversion of Immortal Human Cells from Telomerase-Positive to Telomerase-Negative Cells Cancer Res., April 1, 2005; 65(7): 2778 - 2786. [Abstract] [Full Text] [PDF]
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 D. D. Edberg, J. N. Adkins, D. L. Springer, and R. Reeves Dynamic and Differential in Vivo Modifications of the Isoform HMGA1a and HMGA1b Chromatin Proteins J. Biol. Chem., March 11, 2005; 280(10): 8961 - 8973. [Abstract] [Full Text] [PDF]
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 W. Zhao, H. Soejima, K. Higashimoto, T. Nakagawachi, T. Urano, S. Kudo, S. Matsukura, S. Matsuo, K. Joh, and T. Mukai The Essential Role of Histone H3 Lys9 Di-Methylation and MeCP2 Binding in MGMT Silencing with Poor DNA Methylation of the Promoter CpG Island J. Biochem., March 1, 2005; 137(3): 431 - 440. [Abstract] [Full Text] [PDF]
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 P.-O. Esteve, H. G. Chin, and S. Pradhan Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters PNAS, January 25, 2005; 102(4): 1000 - 1005. [Abstract] [Full Text] [PDF]
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 S.B. BAYLIN and W.Y. CHEN Aberrant Gene Silencing in Tumor Progression: Implications for Control of Cancer Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 427 - 433. [Abstract] [PDF]
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G. Liang, J. C. Y. Lin, V. Wei, C. Yoo, J. C. Cheng, C. T. Nguyen, D. J. Weisenberger, G. Egger, D. Takai, F. A. Gonzales, et al. Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome PNAS, May 11, 2004; 101(19): 7357 - 7362. [Abstract] [Full Text] [PDF]
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Y. Kondo, L. Shen, P. S. Yan, T. H.-M. Huang, and J.-P. J. Issa Chromatin immunoprecipitation microarrays for identification of genes silenced by histone H3 lysine 9 methylation PNAS, May 11, 2004; 101(19): 7398 - 7403. [Abstract] [Full Text] [PDF]
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L. J. Rush, A. Raval, P. Funchain, A. J. Johnson, L. Smith, D. M. Lucas, M. Bembea, T.-H. Liu, N. A. Heerema, L. Rassenti, et al. Epigenetic Profiling in Chronic Lymphocytic Leukemia Reveals Novel Methylation Targets Cancer Res., April 1, 2004; 64(7): 2424 - 2433. [Abstract] [Full Text] [PDF]
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A. P. Kimura, S. A. Liebhaber, and N. E. Cooke Epigenetic Modifications at the Human Growth Hormone Locus Predict Distinct Roles for Histone Acetylation and Methylation in Placental Gene Activation Mol. Endocrinol., April 1, 2004; 18(4): 1018 - 1032. [Abstract] [Full Text] [PDF]
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J. C. Cheng, D. J. Weisenberger, F. A. Gonzales, G. Liang, G.-L. Xu, Y.-G. Hu, V. E. Marquez, and P. A. Jones Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells Mol. Cell. Biol., February 1, 2004; 24(3): 1270 - 1278. [Abstract] [Full Text] [PDF]
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Q. Yan, E. Cho, S. Lockett, and K. Muegge Association of Lsh, a Regulator of DNA Methylation, with Pericentromeric Heterochromatin Is Dependent on Intact Heterochromatin Mol. Cell. Biol., December 1, 2003; 23(23): 8416 - 8428. [Abstract] [Full Text] [PDF]
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 J. G. Herman and S. B. Baylin Gene Silencing in Cancer in Association with Promoter Hypermethylation N. Engl. J. Med., November 20, 2003; 349(21): 2042 - 2054. [Full Text] [PDF]
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H. Siddiqui, D. A. Solomon, R. W. Gunawardena, Y. Wang, and E. S. Knudsen Histone Deacetylation of RB-Responsive Promoters: Requisite for Specific Gene Repression but Dispensable for Cell Cycle Inhibition Mol. Cell. Biol., November 1, 2003; 23(21): 7719 - 7731. [Abstract] [Full Text] [PDF]
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J. A. Fahrner and S. B. Baylin Heterochromatin: stable and unstable invasions at home and abroad Genes & Dev., August 1, 2003; 17(15): 1805 - 1812. [Full Text] [PDF]
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Y. Kondo and J.-P. J. Issa Enrichment for Histone H3 Lysine 9 Methylation at Alu Repeats in Human Cells J. Biol. Chem., July 18, 2003; 278(30): 27658 - 27662. [Abstract] [Full Text] [PDF]
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 M. Lachner, R. J. O'Sullivan, and T. Jenuwein An epigenetic road map for histone lysine methylation J. Cell Sci., June 1, 2003; 116(11): 2117 - 2124. [Full Text] [PDF]
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