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09.08.2015 | Research Article | Ausgabe 1/2016

Tumor Biology 1/2016

Genome-wide profiling of DNA methylation reveals preferred sequences of DNMTs in hepatocellular carcinoma cells

Tumor Biology > Ausgabe 1/2016
Hong Fan, Zhujiang Zhao, Yuchao Cheng, He Cui, Fengchang Qiao, Ling Wang, Jiaojiao Hu, Huzhang Wu, Wei Song
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The online version of this article (doi:10.​1007/​s13277-015-3202-z) contains supplementary material, which is available to authorized users.
Hong Fan and Zhujiang Zhao contributed equally to this work.


Aberrant DNA methylation of CpG site is among the earliest and most frequent alterations in developmental process and diseases including cancer. To elucidate the functional preferred site of DNMTs, we analyzed the feature of distinct methylated sequences and established the defined relationship between DNMTs and preference genomic DNA sequences. Small interfering RNA (siRNA) construct of DNTM1, DNMT3A, and DNMT3B was transfected into the human hepatocellular carcinoma cell line SMMC-7721, respectively. Distinguishing methylated fragments pool was enriched by SHH method in cells which is knocked down DNMT1, DNMT3A, DNMT3B, separately. The defined binding transcription factors (TFs) containing of 5′CpG islands were obtained with bioinformatics software and website. In SMMC-7721 hepatocellular carcinoma (HCC) cell line, DNMT1, DNMT3A, and DNMT3B were specific suppressed by their corresponding siRNA construct, separately. A 46, 42, 67 distinctive methylated fragments from three different DNMTs were evaluated according to genomic DNA database. Those separated fragments were distributed among genomic DNA regions of all chromosome complements, including coding genes, repeat sequences, and genes with unknown function. The majority of coding genes contain CpG islands in their promoter region. Cluster analysis demonstrated all of preference sequences identified by three DNMTs shares their own conserved sequences. In depleting of different DNMTs cells, 80 % of 103 upregulation genes induced by DNMT1 knock-down contain CpG sites; 76 % of 25 upregulation genes induced by DNMT3A knock-down contain CpG sites; 63 % of 126 upregulation genes induced by DNMT3B knock-down contain CpG sites. Our findings suggested that distinctive DNMTs targeted DNA methylation site to their preference sequences, and this targeting might be associated with diverse roles of DNMTs in tumorigenesis. Meanwhile, the analysis of preference sequences provides an alternative way to find out the individual function of DNMTs.

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Table 1 The information of sequences recognized by DNMT1 (DOC 74 kb)
Table 2 The information of sequences recognized by DNMT3A (DOC 71 kb)
Table 3 The information of sequences recognized by DNMT3B (DOC 101 kb)
Table 4 Genes altered ≥ 2-fold after DNMT1 knocked down treatment in hepatocellular carcinoma cell line SMMC-7721 (DOC 110 kb)
Table 5 Genes altered ≥ 2-fold after DNMT3A knocked-down treatment in hepatocellular carcinoma cell line SMMC-7721 (DOC 49 kb)
Table 6 Genes altered ≥ 2-fold after DNMT3B knocked-down treatment in hepatocellular carcinoma cell line SMMC-7721 (DOC 154 kb)
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