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Bioinformatics Advance Access published online on June 6, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn256
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© The Author (2008). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Enriched Transcription Factor Binding Sites in Hypermethylated Gene Promoters in Drug Resistant Cancer Cells

Meng Li 1,2,3, Hyun-il Henry Paik 1, Curt Balch 1,7, Yoosung Kim 4, Lang Li 5,7, Tim H-M. Huang 8, Kenneth P. Nephew 1,2,6,7 and Sun Kim 3,9

1Medical Sciences, School of Medicine, Indiana University, Bloomington, IN 47404, USA 2Interdisciplinary Biochemistry Program, Indiana University, Bloomington, IN 47405, USA 3School of Informatics, Indiana University, Bloomington, IN 47408, USA 4School of Information and Communication Engineering, Inha University, Incheon 402-751, Korea 5Department of Biostatistics, 6Department of Cellular and Integrative Physiology, 7IU Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, IN 46202, USA 8Human Cancer Genetics, The Ohio State University, Columbus, OH 43210, USA 9Center for Genomics and Bioinformatics, Indiana University, Bloomington, IN 47404, USA

To whom correspondence should be addressed. Prof. Sun Kim, E-mail: sunkim2{at}indiana.edu


  Abstract

Motivation: In the human genome, "CpG islands", CG-rich region located in or near gene promoters, are normally unmethylated. However, in cancer cells, CpG islands frequently gain methylation, resulting in silencing of growth-limiting tumor suppressor genes. To our knowledge, the potential relationship between CpG island hypermethylation, transcription factor (TF) binding in local promoter regions, and transcriptional control has not been previously explored in a genome-wide context.

Results: In this study, we utilized bioinformatics tools and TF binding site databases to globally analyze sequences methylated in a laboratory model for the development of drug-resistant cancer. Our results demonstrated that four transcription factor binding sites (TFBS) were enriched in hyper-methylated sequences. More interestingly, over-representation of these TFBS was observed in hyper-/hypo-methylated sequences where significant changes in methylation levels were observed in drug-resistant cancer cells. In summary, we believe that these findings offer a means to further explore the relationship between DNA methylation and gene expression in drug resistance and tumorigenesis.

Contact: sunkim2{at}indiana.edu, knephew{at}indiana.edu

Associate Editor: Prof. Alfonso Valencia

Received on July 3, 2007; revised on May 20, 2008; accepted on June 2, 2008

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