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• W2023688724 abstract "Methylation of mammalian DNA by the DNA methyltransferase enzyme (dnmt-1) at CpG dinucleotide sequences has been recognized as an important epigenetic control mechanism in regulating the expression of cellular genes (Yen, R. W., Vertino, P. M., Nelkin, B. D., Yu, J. J., el-Deiry, W., Cumaraswamy, A., Lennon, G. G., Trask, B. J., Celano, P., and Baylin, S. B. (1992) Nucleic Acids Res. 20, 2287–2291; Ramchandani, S., Bigey, P., and Szyf, M. (1998) Biol. Chem. 379, 535–5401). Here we show that interleukin (IL)-6 regulates the methyltransferase promoter and resulting enzyme activity, which requires transcriptional activation by theFli-1 transcription factor (Spyropoulos, D. D., Pharr, P. N., Lavenburg, K. R., Jackers, P., Papas, T. S., Ogawa, M., and Watson, D. K. (1998) Mol. Cell. Biol.15, 5643–5652). The data suggest that inflammatory cytokines such as IL-6 may exert many epigenetic changes in cells via the regulation of the methyltransferase gene. Furthermore, IL-6 regulation of transcription factors like Fli-1, which can help to direct cells along opposing differentiation pathways, may in fact be reflected in part by their ability to regulate the methylation of cellular genes. Methylation of mammalian DNA by the DNA methyltransferase enzyme (dnmt-1) at CpG dinucleotide sequences has been recognized as an important epigenetic control mechanism in regulating the expression of cellular genes (Yen, R. W., Vertino, P. M., Nelkin, B. D., Yu, J. J., el-Deiry, W., Cumaraswamy, A., Lennon, G. G., Trask, B. J., Celano, P., and Baylin, S. B. (1992) Nucleic Acids Res. 20, 2287–2291; Ramchandani, S., Bigey, P., and Szyf, M. (1998) Biol. Chem. 379, 535–5401). Here we show that interleukin (IL)-6 regulates the methyltransferase promoter and resulting enzyme activity, which requires transcriptional activation by theFli-1 transcription factor (Spyropoulos, D. D., Pharr, P. N., Lavenburg, K. R., Jackers, P., Papas, T. S., Ogawa, M., and Watson, D. K. (1998) Mol. Cell. Biol.15, 5643–5652). The data suggest that inflammatory cytokines such as IL-6 may exert many epigenetic changes in cells via the regulation of the methyltransferase gene. Furthermore, IL-6 regulation of transcription factors like Fli-1, which can help to direct cells along opposing differentiation pathways, may in fact be reflected in part by their ability to regulate the methylation of cellular genes. interleukin fetal bovine serum glyceraldehyde-3-phosphate dehydrogenase nucleotide(s) base pair(s) The transfer of a methyl group to the cytosine portion of the CpG dinucleotide by dnmt-1 permits or enables the binding of methyl-specific DNA-binding proteins to the methylated CpG site (1Yen R.W. Vertino P.M. Nelkin B.D., Yu, J.J. el-Deiry W. Cumaraswamy A. Lennon G.G. Trask B.J. Celano P. Baylin S.B. Nucleic Acids Res. 1992; 20: 2287-2291Crossref PubMed Scopus (217) Google Scholar, 2Ramchandani S. Bigey P. Szyf M. Biol. Chem. 1998; 379: 535-540Crossref PubMed Scopus (19) Google Scholar, 4Lewis J.D. Meehan R.R. Henzel W.J. Maurer-Fogy I. Jeppesen P. Klein F. Bird A. Cell. 1992; 69: 905-914Abstract Full Text PDF PubMed Scopus (1091) Google Scholar, 5Meehan R.R. Lewis J.D. Bird A.P. Nucleic Acids Res. 1992; 20: 5085-5092Crossref PubMed Scopus (419) Google Scholar). The binding of methyl-specific proteins such as MeCP1 and MeCP2 to genetic regulatory elements represses transcription by blocking the binding of other positive acting transactivation factors (6Nan X. Ng H.H. Johnson C.A. Laherty C.D. Turner B.M. Eisenman R.N. Bird A. Nature. 1998; 393: 386-389Crossref PubMed Scopus (2804) Google Scholar). Methylcytosine-DNA-binding proteins can attract histone deacetylases to the site, which remodel chromatin into highly repressed states (7Robertson K.D. Ait-Si-Ali S. Yokochi T. Wade P.A. Jones P.L. Wolffe A.P. Nat. Genet. 2000; 3: 338-342Crossref Scopus (809) Google Scholar). Thus, DNA methylation can result in permanent epigenetic alteration of genes and is important in promoting or guiding the differentiation of cells and the establishment of tissue-specific gene expression patterns (8Storb U. Arp B. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 6642-6646Crossref PubMed Scopus (76) Google Scholar). The inflammatory cytokine IL-61 is able to induce the maturation and differentiation of cells (9Tosato G. Seamon K.B. Goldman N.D. Sehgal P.B. May L.T. Washington G.C. Jones K.D. Pike S.E. Science. 1988; 239: 502-504Crossref PubMed Scopus (226) Google Scholar). Treatment of the human erythroleukemia cell line K562 with IL-6 induces the expression of megakaryocytic markers and the silencing of certain globin genes (10Ferry A.E. Baliga S.B. Monteiro C. Pace B.S. J. Biol. Chem. 1997; 272: 20030-20037Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Derived from an acute erythroblastic leukemia, K562 cells are multipotent in that they can be directed into two separate differentiation pathways (11Andersson L.C. Jokinen M. Gahmberg C.G. Nature. 1979; 278: 364-365Crossref PubMed Scopus (331) Google Scholar). K562 cells express low levels of both erythrocytic- and megakaryocytic-specific genetic markers and can be induced to differentiate along one of these two major pathways depending upon the external stimuli applied to the cells (12Navarro S. Mitjavila M.T. Katz A. Doly J. Vainchenker W. Exp. Hematol. 1991; 19: 11-17PubMed Google Scholar, 13Athanasiou M. Clausen P.A. Mavrothalassitis G.J. Zhang X.K. Watson D.K. Blair D.G. Cell Growth Differ. 1996; 7: 1525-1534PubMed Google Scholar). This ability suggests some form of epigenetic control over the differentiation process. The ETS family of transcription factors represent a large family of differentially expressed, positive and negative regulators of transcription and are involved in cell differentiation (3Spyropoulos D.D. Pharr P.N. Lavenburg K.R. Jackers P. Papas T.S. Ogawa M. Watson D.K. Mol. Cell. Biol. 1998; 15: 5643-5652Google Scholar). Here we show that when K562 cells are induced to enter the megakaryocytic differentiation pathway by IL-6, an increase in Fli-1 expression occurs, which results in the transactivation of the human methyltransferase-1 gene expression. COS-1 cells were obtained from the American Type Culture Collection (CRL-1650) and maintained in Dulbecco's modified Eagle's medium high glucose supplemented with 10% FBS, glutamine, and penicillin-streptomycin solutions. Human erythroleukemia K562 cells (ATCC CCL-243) were maintained in RPMI 1640 medium supplemented with 10% FBS, glutamine, and penicillin-streptomycin solutions. Recombinant interleukin-6 (catalog number 200-06) was purchased from Pepro-Tech Inc. (Rocky Hill, NJ). For IL-6 stimulation, K562 cells were collected by centrifugation, rinsed twice in phosphate-buffered saline, pH 7.4, then resuspended in RPMI 1640 medium supplemented with glutamine, penicillin-streptomycin, and 0.05% FBS for 48 h, then treated with IL-6. Cell nuclear pellets were freeze-thawed three times and centrifuged to remove debris. Clarified lysates were mixed with an equal volume of Chelex-100 resin (50%v/v) to remove DNA and RNA from the sample. For each replicate, 5 µg of the protein lysate was added to 200 µl of an assay mixture consisting of 20 mm Tris-HCl, pH 7.4, 5 mm EDTA, 25% glycerol, 0.5% Triton X-100, 1 mm dithiothreitol, 0.2 mm phenylmethylsulfonyl fluoride, 5 µCi ofS-adenosyl-l-[methyl-3H]methionine (12 Ci/mmol), 4 µg of poly(dI-dC), and 200 µg/ml bovine serum albumin and incubated at 37 °C for 2 h. Incorporated label was assessed by scintillation counting. cDNAs for each gene were prepared from TriZOL (Life Technologies, Inc.) extracted total RNAs. reverse transcription reactions were run on 2 µg of total RNA. Following reverse transcription reactions, PCR reactions were run to the midpoint of each PCR fragment's linear synthesis curve. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) bands on agarose gels were scanned on aSTORM TM Scanner (Molecular Dynamics) to ensure equalization of expression levels at each time point. Primers for the HDNMT-1 gene (GenBankTM accession number X63692) were 5′-AAGTGAAGCCCGTAGAGTG-3′, nt 579–598 (sense) and 5′-TTCTCATCCTGGTCTTTGT-3′, nt 827–846 (antisense), which yielded a 267-bp fragment, while primers specific for the Fli-1 gene (GenBankTM accession number M98833) were 5′-CGCCACCACCCTCTACAACACGGAA-3′, nt 703–728 (sense), and 5′-CGGGCCCAGGATCTGATACGGATCT-3′, nt 952–977 (antisense), which yielded a 274-bp fragment. Amplification primers specific for the GAPDH gene (sense 5′-AGGTGAAGGTCGGAGTCAACGG-3′ and antisense 5′-CCCAGCCTTCTCCATGGTGGTG-3′) were utilized to amplify a constitutively expressed internal control fragment of 319 bp. Cells were incubated for 36 h and then harvested, lysed in 1× luciferase lysis buffer (20 mmTris-Cl, pH 7.8, 1% Triton X-100 (v/v), 0.1 mm EDTA, 1 mm dithiothreitol added just prior to use), and 200 µl of medium was removed for a normalization assay using theCLONTECH pSEAP positive control vector and CSPDTM chemiluminescent substrate kit (CSPDTMdisodium 3-(4-methoxyspiro[1,2-dioxetane-3,2′-(5-chloro)tricyclo[3.3.1.1-3,7]-decan]-4-yl)phenyl phosphate catalog number K-2041-1) prior to lysis. Experiments to determine luciferase activity for each condition were run in triplicate and normalized against CSPDTM substrate assay values per microgram of protein to ensure consistent transfection levels between experiments. hdnmt-1 promoter constructs in pGL-3 basic luciferase reporter vector were generated by PCR utilizing the following primer sets: wild-type ΔMT1 construct, 5′-CGGCTAGCCGGAATTCGCCCTTTGGTGTAA-3′ (MT1), 5′-CCAAGCTTGGAAGACCCTGCCTCACTCTGT-3′ (MT2); ΔMT2 (−1214 to +71 bp), 5′-CGGCTAGCCGGTGACAGAGTGAGGCAGGGT-3′(MT3), 5′-CCAAGCTTGGGGAAGATCACTTGAACCGGA-3′ (MT4); ΔMT3 (−815 to +71 bp), 5′-CGGCTAGCCGCTCAACCTCTGGAGTAGTTT-3′ (MT5), 5′-CCAAGCTTGGTTGCCACCTACTCTAGAAAA-3′ (MT6); ΔMT4 (−474 to +71), 5′-CGGCTAGCCGGAGTAGGTGGCAATTACCCC-3′ (MT7), 5′-CCAAGCTTGGTCCAAGCTCCACGTTTCCTG-3′ (MT8); and ΔMT5 (−243 to +71 bp), 5′-CGGCTAGCCGGAGCTTGGACGAGCCCACTC-3′ (MT9), 5′-CCAAGCTTGGATTCGCCCTTACATCGTCGG-3′ (MT10). We examined the effect of IL-6 treatment on methyltransferase activity by using K562 cells in a rested state in RPMI 1640 medium supplemented with 0.05% FBS for ∼48 h. The cells were rinsed twice in serum-free RPMI 1640 and then treated with IL-6 (at 100 ng/ml). After 8-h incubation, the cells were harvested, and methylation activity assays were performed as described previously (14Belinsky S.A. Nikula K.J. Baylin S.B. Issa J.P. Toxicol. Lett. 1995; 82–83: 335-340Crossref PubMed Scopus (9) Google Scholar) to determine the relative levels of activity following IL-6 treatment.Lanes 1 and 2 in Fig.1show the results obtained from control reactions utilizing only cell lysates with no poly(dI-dC)·poly(dI-dC) substrate added and poly(dI-dC)·poly(dI-dC) substrate with no cell lysates added, respectively. Lane 3 represents the basal level of methylation activity obtained from rested K562 cells, while lane 4 shows a 3.2-fold increase in activity following treatment with IL-6. Based on these observations, treatment with IL-6 appears to increase overall methylation activity. To determine whether treatment with IL-6 activates thehdnmt-1 promoter, we generated a series of deletion constructs as shown in Fig.2A. The constructs were sequenced and used to transfect K562 cells, which were rested prior to stimulation with IL-6 as described above. Gradual deletion of increasing amounts of the wild-type promoter as shown inlane 1 (ΔMT1), lane 2 (ΔMT2) (−1214 to +71 bp), lane 3 (ΔMT3) (-815 to +71 bp), and lane 4(ΔMT4) (−474 to +71) did not abrogate the IL-6-induced activity. The results shown in Fig. 2 B, lane 5, indicate that IL-6-induced promoter activity is localized to the ΔMT5 segment (−243 to +71 bp), which encodes several potential ETS family recognition sites. Fig. 2 C, lane 1, shows the results of transfecting wild-type ΔMT5 and then stimulating with IL-6. Unstimulated wild-type ΔMT5 reporter levels are represented inlane 2. Fig. 2 C, lanes 3 and4, show the activity levels of a ΔMT5 triple-mutant reporter stimulated with IL-6 and unstimulated, respectively. The ETS site-mutated ΔMT5 reporter shows a markedly suppressed response, as the loss of the three Fli-1 binding sites in ΔMT5 abrogated the IL-6-mediated response. To determine whether IL-6 induced increased expression ofhdnmt-1 and Fli-1 mRNA, K562 cells were incubated in RPMI 1640 medium supplemented with 0.05% FBS for ∼48 h. The cells were rinsed twice in serum-free RPMI 1640 and then treated with IL-6 at a concentration of 100 ng/ml. Treated cells were collected at 0, 1, 2, 4, 6, 8, 12, and 24 h post-treatment with IL-6. Total cellular RNA was prepared at each time point and stored at −70 °C. Ultraviolet spectroscopy was used to quantitate equally each RNA sample, and final working dilutions for each time point were rechecked following initial dilution to a concentration of 100 ng/µl. The adjusted total RNA preparations were then used to create cDNA, on which PCR reactions were performed. Using primers specific for hdnmt-1 and Fli-1, PCR was performed for each time point to determine the relative expression level of each gene. The temporal expression pattern of hdnmt-1 is shown in Fig. 3A. The expression ofhdnmt-1 begins to appear at 6 h post-treatment, reaching a peak between 8 and 12 h. At 24 h,hdnmt-1 mRNA is still expressed, but the level is considerably diminished. The double-banded PCR product seen for thehdnmt-1 is due to an intronic insertion, and the PCR primers were chosen to amplify this region to determine whether both possible gene products are affected equally by IL-6 (15Hsu D.W. Lin M.J. Lee T.L. Wen S.C. Chen X. Shen C.K. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 9751-9756Crossref PubMed Scopus (49) Google Scholar). In K562 cells, no difference in expression levels between the two possiblehdnmt-1 mRNA products were noted. The ETS family transcription factor, Fli-1, which is known to be expressed in megakaryocytic lineages as a mediator of differentiation (16Bastian L.S. Kwiatkowski B.A. Breininger J. Danner S. Roth G. Blood. 1999; 93: 2637-2644Crossref PubMed Google Scholar), begins to be expressed at ∼4 h post-treatment (Fig. 3 B) and continues to increase throughout the sampling period. The expression pattern of the prototypic ETS family member, Ets-1, did not show a response to IL-6 when cDNA from the rested K562 cells was analyzed in parallel reactions withhdnmt-1 and Fli-1, and Ets-1 did not produce a discernable band when the reactions were analyzed at the midpoint of the amplification curve (data not shown.) Fig.3 C shows equivalent expression levels of the GAPDH gene cDNA control at each time point. Analysis of the ΔMT5 promoter elements reveals three potentialFli-1 binding sites at −194, −170, and −60 base pairs (17Bigey P. Ramchandani S. Theberge J. Araujo F.D. Szyf M. Gene (Amst.). 2000; 242: 407-418Crossref PubMed Scopus (108) Google Scholar). A series of singular and multiple point mutations of the ΔMT5 constructs, shown in Fig. 4a, were co-transfected into COS-1 cells with pSG5Fli-1expression plasmid to determine the authenticity of each potential ETS binding site. Fig. 4 b shows the strongest activation with all three potential Fli-1 binding sites left intact. The intact promoter construct ΔMT5-WT (lane 1) is transactivated nearly 29-fold over the triple mutant ΔMT5–25 (lane 8), which shows merely 2-fold activation over background. The other point-mutated ΔMT5 constructs showed varying degrees of activity, which suggests an additive effect for each site, with the constructs containing only single site mutations (ΔMT5–20 (lane 3), ΔMT5–22 (lane 5), and ΔMT5–23 (lane 6), showing the most activity when compared with those constructs receiving two combined site mutations ΔMT5–19 (lane 2), ΔMT5–21 (lane 4), and ΔMT5–24 (lane 7)). The mutation of the double ETS binding sites (−194 and −170) in the ΔMT5–24 construct (lane 7) produced nearly the same effect as the triple mutant, with a 5-fold increase in activity compared with 2-fold for the triple mutant. These results provide evidence of a novel mechanism of IL-6 cytokine-mediated alteration, via the Fli-1 transcription factor, of methyltransferase gene expression. Previously, it was shown that IL-6 activation of the immediate-early gene junB occurred through an ETS family protein, in cooperation with a CREB-ATF factor (18Nakajima K. Kusafuka T. Takeda T. Fujitani Y. Nakae K. Hirano T. Mol. Cell. Biol. 1993; 13: 3027-3041Crossref PubMed Scopus (114) Google Scholar). An analogous situation exists in fos-transformed cells, in which the expression of DNA methyltransferase is three times that of normal levels (19Bakin A.V. Curran T. Science. 1999; 283: 387-390Crossref PubMed Scopus (216) Google Scholar). Thus, it has been proposed that fostransformation is mediated by increased methyltranferase expression. Therefore, by analogy, even slight alterations in methyltransferase expression resulting from chronic exposure to IL-6 could, over time, result in abnormal patterns of cellular DNA methylation, similar to those caused by transformation of fos. Indeed, the importance of dnmt-1 activity in the establishment and propagation of neoplastic growth has emerged as an important diagnostic factor (20Petrangeli E. Lubrano C. Ravenna L. Vacca A. Cardillo M.R. Salvatori L. Sciarra F. Frati L. Gulino A. Br. J. Cancer. 1995; 72: 973-975Crossref PubMed Scopus (17) Google Scholar). Methylated CpG dinucleotides are susceptible to spontaneous deamination of 5-methylcytosine to uracil and are believed to be responsible for approximately one-third of C-T transition mutations found in human genetic diseases and tumors (21Malik K. Brown K.W. Br. J. Cancer. 2000; 83: 1583-1588Crossref PubMed Scopus (31) Google Scholar). Hypermethylation of tumor suppressor genes such as p53 (22Yebra M.J. Bhagwat A.S. Biochemistry. 1995; 34: 14752-14757Crossref PubMed Scopus (78) Google Scholar), retinoblastoma (Rb) (23Denissenko M.F. Chen J.X. Tang M.S. Pfeifer G.P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3893-3898Crossref PubMed Scopus (305) Google Scholar), and p16ink (24Stirzaker C. Millar D.S. Paul C.L. Warnecke P.M. Harrison J. Vincent P.C. Frommer M. Clark S.J. Cancer Res. 1997; 57: 2229-2237PubMed Google Scholar) occur in many different tumors types, serving to promote tumor growth by rendering these genes inactive. The effects of promiscuous methylation of important tumor suppressor and cell cycle regulatory genes potentially resulting from prolonged exposure to inflammatory cytokines are probably cumulative in nature, remaining latent until sufficient insult to the cell permits it to transform into a neoplastic growth (25Nuovo G.J. Plaia T.W. Belinsky S.A. Baylin S.B. Herman J.G. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12754-12759Crossref PubMed Scopus (308) Google Scholar). We demonstrate here that IL-6, an inflammatory cytokine capable of mediating cellular differentiation, is capable of increasing DNA methytransferase expression and activity. The data suggest that one of the normal molecular consequences of the biological activity of IL-6 may be mediated by DNA methyltransferase activity modifying gene expression. Additionally, IL-6 has been implicated in numerous cancer models, including multiple myeloma and prostate carcinoma (26Goldberg D.M. Diamandis E.P. Clin. Chem. 1993; 39: 2360-2374Crossref PubMed Scopus (19) Google Scholar,27Wierzbowska A. Urbanska-Rys H. Robak T. Br. J. Haematol. 1999; 105: 412-419Crossref PubMed Scopus (46) Google Scholar). However, in a few cell lines, IL-6 has shown inhibitory effects on tumorigenesis (28Chung T.D., Yu, J.J. Spiotto M.T. Bartkowski M. Simons J.W. Prostate. 1999; 38: 199-207Crossref PubMed Scopus (196) Google Scholar) and anti-inflammatory capacity (29Spiotto M.T. Chung T.D. Prostate. 2000; 42: 88-98Crossref PubMed Scopus (119) Google Scholar). Notwithstanding these pleiotropic characteristics, chronic exposure of cells to inflammatory cytokines such as IL-6 may have serious consequences by altering the normal levels, or time of expression of many genes, by up-regulating methyltransferase, whose expression is normally tightly controlled in a cell cycle-dependent manner (30Tilg H. Trehu E. Atkins M.B. Dinarello C.A. Mier J.W. Blood. 1994; 83: 113-118Crossref PubMed Google Scholar, 31Vogel M.C. Papadopoulos T. Muller-Hermelink H.K. Drahovsky D. Pfeifer G.P. FEBS Lett. 1988; 236: 9-13Crossref PubMed Scopus (15) Google Scholar). Dysregulation of DNA methyltransferase may result in the methylation of important tumor suppressor and cell cycle regulatory genes eventually initiating or enhancing neoplastic growth (32Mizuno Si S. Chijiwa T. Okamura T. Akashi K. Fukumaki Y. Niho Y. Sasaki H. Blood. 2001; 97: 1172-1179Crossref PubMed Scopus (384) Google Scholar, 33De Marzo A.M. Marchi V.L. Yang E.S. Veeraswamy R. Lin X. Nelson W.G. Cancer Res. 1999; 59: 3855-3860PubMed Google Scholar). We are very grateful to Dr. Joost Oppenheim for his critical review of the manuscript." @default.
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• W2023688724 title "Interleukin-6 Regulation of the Human DNA Methyltransferase (HDNMT) Gene in Human Erythroleukemia Cells" @default.
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