Jane Anne Nohl Division of Hematology, Norris Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
Nucleic Acids Res. 2011 Jan;39(1):104-18. doi: 10.1093/nar/gkq774. Epub 2010 Sep 13.
DNA methyltransferases (DNMTs) play an important role in establishing and maintaining DNA methylation. Aberrant expression of DNMTs and their isoforms has been found in many types of cancer, and their contribution to aberrant DNA methylation has been proposed. Here, we generated HEK 293T cells stably transfected with each of 13 different DNMTs (DNMT1, two DNMT3A isoforms, nine DNMT3B isoforms and DNMT3L) and assessed the DNA methylation changes induced by each DNMT. We obtained DNA methylation profiles of DNA repetitive elements and 1505 CpG sites from 808 cancer-related genes. We found that DNMTs have specific and overlapping target sites and their DNA methylation target profiles are a reflection of the DNMT domains. By examining H3K4me3 and H3K27me3 modifications in the 808 gene promoter regions using promoter ChIP-on-chip analysis, we found that specific de novo DNA methylation target sites of DNMT3A1 are associated with H3K4me3 modification that are transcriptionally active, whereas the specific target sites of DNMT3B1 are associated with H3K27me3 modification that are transcriptionally inactive. Our data suggest that different DNMT domains are responsible for targeting DNA methylation to specific regions of the genome, and this targeting might be associated with histone modifications.
DNA 甲基转移酶 (DNMTs) 在建立和维持 DNA 甲基化方面发挥着重要作用。在许多类型的癌症中发现了 DNMTs 及其同工型的异常表达，并且已经提出它们对异常 DNA 甲基化的贡献。在这里，我们生成了稳定转染了 13 种不同的 DNMTs（DNMT1、两种 DNMT3A 同工型、9 种 DNMT3B 同工型和 DNMT3L）的 HEK 293T 细胞，并评估了每个 DNMT 诱导的 DNA 甲基化变化。我们从 808 个与癌症相关的基因中获得了 DNA 重复元件和 1505 个 CpG 位点的 DNA 甲基化图谱。我们发现 DNMTs 具有特定和重叠的靶标位点，并且它们的 DNA 甲基化靶标图谱反映了 DNMT 结构域。通过使用启动子 ChIP-on-chip 分析检查 808 个基因启动子区域中的 H3K4me3 和 H3K27me3 修饰，我们发现 DNMT3A1 的特定从头 DNA 甲基化靶标位点与转录活跃的 H3K4me3 修饰相关，而 DNMT3B1 的特定靶标位点与转录不活跃的 H3K27me3 修饰相关。我们的数据表明，不同的 DNMT 结构域负责将 DNA 甲基化靶向基因组的特定区域，并且这种靶向可能与组蛋白修饰相关。
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