Skip to main content

Advertisement

Log in

Age and gender affect DNMT3a and DNMT3b expression in human liver

  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs) including the maintenance enzyme DNMT 1 and de novo methyltransferases DNMT 3a and DNMT 3b. Elevated levels of DNMTs have been found in cancer cells and in several types of human tumors. A polymorphism found in DNMT3b has been associated with increased risk for several cancers. The factors influencing DNMT expression in human tissues have not been clearly determined. he present study examined TDNMT3a and DNMT3b levels in human liver tissue samples and compared the effect of ageing, cigarette smoking, and gender. DNMT3a and DNMT3b expression levels in the samples from older individuals (56–78 years, n = 28) were both significantly higher than those of the younger group (16–48 years, n = 27) (73.2 ± 3.4 vs 8.3 ± 2.8 and 56.1 ± 1.9 vs 17.5 ± 5.7, respectively; p < 0.05). Levels of DNMT3b in females were significantly higher than those in males (75.4 ± 2.2 vs 16.3 ± 4.7; p < 0.05); however, DNMT3a levels were similar for females and males (52.7 ± 2.7 vs 48.4 ± 2.0). Expression levels of DNMT3a and DNMT3b were similar in smokers and nonsmokers (58.1 ± 3.5 vs 60.8 ± 3.1 and 54.5 ± 2.3 vs 48.3 ± 1.8, respectively). Genotyping for DNMT3b (C→T) variant in this sample pool showed a frequency distribution of CC (41%), CT (50%), and TT (9%). The findings from this study suggest that ageing and gender may be important factors influencing DNA methylation status.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abdelrahim M, Samudio I, Smith R, et al. Small inhibitory RNA duplexes for Sp1 mRNA block basal and estrogen-induced gene expression and cell cycle progression in MCF-7 breast cancer cells. J Biol Chem 2002;277:28815–22.

    Article  PubMed  CAS  Google Scholar 

  • Bachmann KE, Rountree MR, Baylin SB. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J Biol Chem 2001;276:32282–7.

    Article  Google Scholar 

  • Bakin AV, Curran T. Role of DNA 5-methylcytosine transferase in cell transformation by fos. Science 1999;283:387–90.

    Article  PubMed  CAS  Google Scholar 

  • Belinsky SA, Nikula KJ, Baylin SB, Issa J-PJ. Increased cytosine DNA- methyltransferase activity is target-cell-specific and an early event in lung cancer. Proc Natl Acad Sci 1996;93:4045–50.

    Article  PubMed  CAS  Google Scholar 

  • Bestor TH. The DNA methyltransferases of mammals. Hum Mol Genet 2000;9:2395–402.

    Article  PubMed  CAS  Google Scholar 

  • Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6–21.

    Article  PubMed  CAS  Google Scholar 

  • Boivin AJ, Momparler, LF, Hurtubise A, Momparler RL. Antineoplastic actionof 5-aza-2′-deoxycytidine and phenylbutyrate on human lung carcinoma cells. Anticancer Drugs 2002;13:869–74.

    Article  PubMed  CAS  Google Scholar 

  • Casillas MA, Lopatina N, Andrews LG, Tollefsbol TO. Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem 2003;252:33–43.

    Article  PubMed  CAS  Google Scholar 

  • Chuang LS, Ian HI, Koh TW, et al. Human DNA-(cytosine-5) methyltransferase–PCNA complex as a target for p21WAF1. Science 1997;277:1996–2000.

    Article  PubMed  CAS  Google Scholar 

  • Cui X, Wakai T, Shirai Y, et al. Arsenic trioxide inhibits DNA methyltransferase and restores methylation-silenced genes in human liver cancer cells. Human Pathol 2006;37:298–311.

    Article  CAS  Google Scholar 

  • Dawson-Saunders B, Trapp RG. Basic and clinical biostatistics. Norwalk, CT: Appleton and Lange; 1994.

    Google Scholar 

  • Egger G, Aparicio AM, Escobar SG, Jones PA. Inhibition of histone deacetylation does not block resilencing of p16 after 5-aza-2’-deoxycytidine treatment. Cancer Res 2007;67:346–53.

    Article  PubMed  CAS  Google Scholar 

  • Eng C, Herman JG, Baylin SB. A bird’s eye view of global methylation. Nat Genet 2000;24:101–2.

    Article  PubMed  CAS  Google Scholar 

  • Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 2002;21:5427–40.

    Article  PubMed  CAS  Google Scholar 

  • Esteve PO, Chin HG, Pradhan. Human maintenance DNA (cytosine-5)- methyltransferase and p53 modulate expression of p53-repressed promoters. Proc Natl Acad Sci 2005;102:1000–5.

    Article  PubMed  CAS  Google Scholar 

  • Fiala ES, Staretz ME, Pandya GA, et al. Inhibition of DNA cytosine methyltransferase by chemopreventive selenium compounds, determined by an improved assay of DNA cytosine methyltransferase and DNA cytosine methylation. Carcinogenesis 1998;19:597–604.

    Article  PubMed  CAS  Google Scholar 

  • Fuks F, Burgers WA, Godin N, et al. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J 2001;20:2536–3544.

    Article  PubMed  CAS  Google Scholar 

  • Hammons GJ, Yan Y, Lopatina NG, et al. Increased expression of hepatic DNA methyltransferase in smokers. Cell Biol Toxicol 1999:15:389–94.

    Article  PubMed  CAS  Google Scholar 

  • Jinawath A, Miyake S, Yanagisawa Y, et al. Transcriptional regulation of the human DNA methyltransferase 3A and 3B genes by Sp3 and Sp1 zinc finger proteins. Biochem J 2005;385:557–64.

    Article  PubMed  CAS  Google Scholar 

  • Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–28.

    Article  PubMed  CAS  Google Scholar 

  • Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science (Wash. DC) 2001;293:1068–70.

    Article  CAS  Google Scholar 

  • Jue K, Benoit G, Alcivar-Warren AA, Trasler JM. Developmental and hormonal regulation of DNA methyltransferase in the rat testis. Biol Reproduction 1995;52:1361–71.

    Article  Google Scholar 

  • Kim YI. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer? Cancer Epidemiol Biomarkers Prev 2004;13:511–9.

    PubMed  CAS  Google Scholar 

  • Kishikawa S, Murata T, Kimura H, et al. Regulation of transcription of the Dnmt1 gene by Sp1 and Sp3 zinc finger proteins. Eur J Biochem 2002;269:2961–70.

    Article  PubMed  CAS  Google Scholar 

  • Laird PW, Jaenisch R. The role of DNA methylation in cancer genetic and epigenetics. Annu Rev Genet 1996;30:441–64.

    Article  PubMed  CAS  Google Scholar 

  • Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 1992;69:915–26.

    Article  PubMed  CAS  Google Scholar 

  • Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature 1993;366:362–5.

    Article  PubMed  CAS  Google Scholar 

  • Liang G, Chan MF, Tomigahara Y, et al. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol 2002;22:480–91.

    Article  PubMed  CAS  Google Scholar 

  • Lopatina N, Haskell JF, Andrews LG, et al. Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J Cell Biochem 2002;84:324–34.

    Article  PubMed  CAS  Google Scholar 

  • MacLeod AR, Rouleau J, Szyf M. Regulation of DNA methylation by the Ras signaling pathway. J Biol Chem 1995;270:11327–37.

    Article  PubMed  CAS  Google Scholar 

  • Nagai M, Nakamura A, Makino R, Mitamura K. Expression of DNA (5-cytosin)-methyltransferases (DNMTs) in hepatocellular carcinomas. Hepatol Res 2003;26:186–91.

    Article  PubMed  CAS  Google Scholar 

  • Nan X, Coampoy FJ, Bird A. MeCP2 is a transcription repressor with abundant binding sites in genomic chromatin. Cell 1997;88:471–81.

    Article  PubMed  CAS  Google Scholar 

  • Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998;19:219–20.

    Article  PubMed  CAS  Google Scholar 

  • Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247–57.

    Article  PubMed  CAS  Google Scholar 

  • Oue N, Kuraoka K, Kuniyasu H, et al. DNA methylation status of hMLH1, p16(INK4a), and CDH1 is not associated with mRNA expression levels of DNA methyltransferase and DNA demethylase in gastric carcinomas. Oncol Rep 2001;8:1085–9.

    PubMed  CAS  Google Scholar 

  • Pradhan S, Bacolla A, Wells RD, Roberts RJ. Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem 1999;274:33002–10.

    Article  PubMed  CAS  Google Scholar 

  • Raiche J, Rodriguez-Juarez R, Pogribny I, Kovalchuk O. Sex- and tissue-specific expression of maintenance and de novo DNA methyltransferases upon low dose X-irradiation in mice. Biochem Biophys Res Commun 2004;325:39–47.

    Article  PubMed  CAS  Google Scholar 

  • Reddy PMS, Reddy PRK. Regulation of DNA methyltransferase in the testis of rats. Biochem Int 1988;16:543–7.

    PubMed  CAS  Google Scholar 

  • Reu FJ, Leaman DW, Maitra RR, et al. Expression of RASSF1A, an epigenetically silenced tumor suppressor, overcomes resistance to apoptosis induction by interferons. Cancer Res 2006;66:2785–93.

    Article  PubMed  CAS  Google Scholar 

  • Rhee I, Bachman KE, Park BH, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002;416:552–6.

    Article  PubMed  CAS  Google Scholar 

  • Richardson B. Impact of aging on DNA methylation. Ageing Res Rev 2003;2:245–61.

    Article  PubMed  CAS  Google Scholar 

  • Robertson, KD, Uzvolgyi E, Liang G, et al. The human DNA methyltransferases (DNMTs) 1, 3a, and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 1999;27:2292–8.

    Article  Google Scholar 

  • Rouleau J, MacLeod AR, Szyf M. Regulation of the DNA methyltransferase by the Ras-AP-1 signaling pathway. J Biol Chem 1995;270:1595–601.

    Article  PubMed  CAS  Google Scholar 

  • Saito Y, Kanai Y, Nakagawa T, et al. Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer 2003;105:527–32.

    Article  PubMed  CAS  Google Scholar 

  • Shen H, Wang L, Spitz MR, et al. A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 2002;62:4994–5.

    Google Scholar 

  • Slack A, Cervone N, Pinared M, Szyf M. DNA methyltransferase is a downstream effector of cellular transformation triggered by simian virus 40 large T antigen. J Biol Chem 1999a;274:10105–12.

    Article  PubMed  CAS  Google Scholar 

  • Slack A, Cervoni N, Pinard M, Szyf M. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem 1999b;264:191–9.

    Article  PubMed  CAS  Google Scholar 

  • Stewart CL, Stuhlmann H, Jahner D, Jaenisch R. De novo methylation, expression, and infectivity of retroviral genomes introduced into embryonal carcinoma cells. Proc Natl Acad Sci 1982;79:4098–102.

    Article  PubMed  CAS  Google Scholar 

  • Sun L, Hui AM, Kanai Y, et al. Increased DNA methyltransferase expression is associated with an early stage of human hepatocarcinogenesis. Jpn J Cancer Res 1997;88:1165–70.

    PubMed  CAS  Google Scholar 

  • Sun J-M, Spencer VA, Li L, et al. Estrogen regulation of trefoil factor 1 expression by estrogen receptor α and Sp proteins. Exper Cell Res 2005;302:96–107.

    Article  CAS  Google Scholar 

  • Szyf M. DNA methylation properties: consequences for pharmacology. Trends Pharmacol Sci 1994;15:233–8.

    Article  PubMed  CAS  Google Scholar 

  • Tsai C-L, Li H-P, Lu Y-J, et al. Activation of DNA methyltransferase 1 by EBV LMP1 involves c-Jun NH2-terminal kinase signaling. Cancer Res 2006;66:11668–76.

    Article  PubMed  CAS  Google Scholar 

  • Vertino PM, Issa J-P, Pereira-Smith OM, Baylin SB. Stabilization of DNA methyltransferase levels and CpG island hypermethylation precede SV40-induced immortization of human fibroblasts. Cell Growth Differ 1994;5:1395–402.

    PubMed  CAS  Google Scholar 

  • Vertino PM, Yen RW, Gao J, Baylin SB. De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Mol Cell Biol 1996;16:4555–65.

    PubMed  CAS  Google Scholar 

  • Wang L, Rodriguez M, Kim ES, et al. A novel C/T polymorphism in the core promoter of human de novo cytosine DNA methyltransferase 3B6 is associated with prognosis in head and neck cancer. Int J Oncol 2004;25:993–9.

    PubMed  CAS  Google Scholar 

  • Wang R, Zhang Q-G, Han D, et al. Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-inducted neuroprotection against transient global cerebral ischema by non-genomic mechanism in male rats. J Neurochem 2006;99:1543–54.

    Article  PubMed  CAS  Google Scholar 

  • Xie S, Wang Z, Okano M, et al. Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 1999;236:87–95.

    Article  PubMed  CAS  Google Scholar 

  • Xiong Y, Dowdy SC, Xue A, et al. Opposite alterations of DNA methyltransferase gene expression in endometrioid and serous endometrial cancers. Gynecol Oncol 2005;96:601–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclaimer

The views presented in this article do not necessarily reflect those of the Food and Drug Administration.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George Hammons.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiao, Y., Word, B., Starlard-Davenport, A. et al. Age and gender affect DNMT3a and DNMT3b expression in human liver. Cell Biol Toxicol 24, 265–272 (2008). https://doi.org/10.1007/s10565-007-9035-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-007-9035-9

Keywords

Navigation