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Journal of Virology, December 2004, p. 12762-12772, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12762-12772.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Conserved Methylation Patterns of Human Papillomavirus Type 16 DNA in Asymptomatic Infection and Cervical Neoplasia

Mina Kalantari,1 Itzel E. Calleja-Macias,1,2 Devansu Tewari,3 Bjørn Hagmar,4 Kathrine Lie,5 Hugo A. Barrera-Saldana,2 Dorothy J. Wiley,6 and Hans-Ulrich Bernard1*

Department of Molecular Biology and Biochemistry, University of California—Irvine, Irvine,1 Department of Obstetrics and Gynecology, University of California—Irvine, Orange,3 School of Nursing, University of California—Los Angeles, Los Angeles,California,6 Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, México,2 Department of Pathology, National Hospital,4 Department of Pathology, the Norwegian Radium Hospital, Oslo, Norway5

Received 3 June 2004/ Accepted 29 July 2004

DNA methylation contributes to the chromatin conformation that represses transcription of human papillomavirus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In an effort to clarify the role of this phenomenon in the regulation and carcinogenicity of HPV-16, 115 clinical samples were studied to establish the methylation patterns of the 19 CpG dinucleotides within the long control region and part of the L1 gene by bisulfite modification, PCR amplification, DNA cloning, and sequencing. We observed major heterogeneities between clones from different samples as well as between clones from individual samples. The methylation frequency of CpGs was measured at 14.5%. In addition, 0.21 and 0.23%, respectively, of the CpA and CpT sites, indicators of de novo methylation, were methylated. Methylation frequencies exceeded 30% in the CpGs overlapping with the L1 gene and were about 10% for most other positions. A CpG site located in the linker between two nucleosomes positioned over the enhancer and promoter of HPV-16 had minimal methylation. This region forms part of the HPV replication origin and is close to binding sites of master-regulators of transcription during epithelial differentiation. Methylation of most sites was highest in carcinomas, possibly due to tandem repetition and chromosomal integration of HPV-16 DNA. Methylation was lowest in dysplasia, likely reflecting the transcriptional activity in these infections. Our data document the efficient targeting of HPV genomes by the epithelial methylation machinery, possibly as a cellular defense mechanism, and suggest involvement of methylation in HPV oncogene expression and the early-late switch.

* Corresponding author. Mailing address: Department of Molecular Biology and Biochemistry, 114 Sprague Hall, University of California, Irvine, Irvine, CA 92697-3900. Phone: (949) 824-5162. Fax: (949) 824-8551. E-mail: hbernard{at}uci.edu.

Journal of Virology, December 2004, p. 12762-12772, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.12762-12772.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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