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PredictMethylationCPGHumanBrain_06bioinfo - BIOINFORMATICS...

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Vol. 22 no. 18 2006, pages 2204–2209 doi:10.1093/bioinformatics/btl377 BIOINFORMATICS ORIGINAL PAPER Sequence analysis Predicting methylation status of CpG islands in the human brain Fang Fang 1 , Shicai Fan 1 , Xuegong Zhang 1 and Michael Q. Zhang 2,1, Ã 1 Bioinformatics Division, TNLIST, Department of Automation, Tsinghua University, 100084 China and 2 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11274, USA Received on May 29, 2006; revised on June 24, 2006; accepted on July 5, 2006 Advance Access publication July 12, 2006 Associate Editor: Keith A Crandall ABSTRACT Motivation: Over 50% of human genes contain CpG islands in their 5 0 -regions. Methylation patterns of CpG islands are involved in tissue- specific gene expression and regulation. Mis-epigenetic silencing asso- ciated with aberrant CpG island methylation is one mechanism leading to the loss of tumor suppressor functions in cancer cells. Large-scale experimental detection of DNA methylation is still both labor-intensive and time-consuming. Therefore, it is necessary to develop in silico approaches for predicting methylation status of CpG islands. Results: Based on a recent genome-scale dataset of DNA methylation in human brain tissues, we developed a classifier called MethCGI for predicting methylation status of CpG islands using a support vector machine (SVM). Nucleotide sequence contents as well as transcription factor binding sites (TFBSs) are used as features for the classification. The method achieves specificity of 84.65% and sensitivity of 84.32% on the brain data, and can also correctly predict about two-third of the data from other tissues reported in the MethDB database. Availability: An online predictor based on MethCGI is available at Contact: [email protected] Supplementary Information: Supplementary data available at Bioinformatics online and 1 INTRODUCTION DNA methylation is involved in various biological phenomena including gene silencing, stabilization of chromosomal structure and suppressing the mobility of retrotransposons (Bird and Wolffe, 1999; Walsh and Bestor, 1999). In vertebrates, DNA methylation mainly occurs at the fifth carbon position of the cyto- sine residue in a 5 0 -CG-3 0 dinucleotide (called CpG, and the methyl- ated CpG can be denoted as m 5 CpG), and this biochemical modification is owing to the enzymatic activity of DNA methyl- transferases (DNMTs) (Bird, 1978; Gruenbaum et al ., 1981). DNA methylation, together with histone modification, are commonly regarded as major epigenetic phenomena, which are responsible for heritable alteration of gene expression pattern without changes in primary DNA sequences (Singal and Ginder, 1999). The dinucleotide CpG is notably under-represented in the human genome. Its frequency is only ± 20% of the expected frequency on the basis of the genomic G + C content. This is owing to the spon- taneous deamination of methylated cytosines to yield thymine and generate a T:G mismatch that will be fixed as TpG (or CpA on the complementary strand) if the thymine is not repaired by cytosine
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