GENESIS AND CONSEQUENCES OF ABERRANT DNA METHYLATION

描述：Vertino博士的整体研究计划主要集中在 理解改变建立的分子机制 DNA甲基化模式及其在人类癌症发生中的作用。这个 正常非甲基化CpG岛基因的异常甲基化 发起人就是这样一种变化，最近被卷入 人类癌症中Tumo抑制基因和其他基因的失活。在人类中 乳腺癌中，CpG岛甲基化参与失活 已知的几个基因是肿瘤细胞生长和生长的重要介质 临床结果，包括雌激素受体基因，E-钙粘附素基因， 和p16/Ink4a基因。此外，DNA的表达增加 (胞嘧啶-5)甲基转移酶(DNA MTase)，负责DNA的酶 哺乳动物细胞中的甲基化，与更具侵略性的 雌激素受体阴性的肿瘤表型虽然有很多 研究异常的CpG岛甲基化与基因不活跃之间的关系， 很少有研究讨论以前未甲基化的CpG岛序列是如何 在成体细胞中变得重新甲基化以及这一事件 在基因沉默中起着直接作用。我们最近证明了 设计成过表达DNA MTase的细胞可以用来模拟 CpG岛甲基化早期可能发生的进展 肿瘤发生的各个阶段。为了解决潜在的分子机制 启动子区异常甲基化及其在人类中的作用 乳腺癌的发生，我们建议建立一种体外的乳腺癌模型。 人类乳腺上皮细胞中的甲基化。具体来说，我们将 确定DNA MTase表达增加是否可以推动 与CpG岛相关的已知沉默基因的甲基化 人类呼吸道肿瘤中的甲基化。其次，我们将确定是否 基因座特异性信号引导CpG岛从头开始甲基化 乳腺上皮细胞中的启动子。最后，我们将确定是否会 CpG岛序列的新甲基化足以启动该基因 确定DNA MTase驱动的下游效应的沉默过程 CpG岛甲基化对基因表达的影响。对中国传统文化的再认识 异常甲基化的发生及其后果 癌症的发生将为小说的未来发展提供基础 去甲基化策略在人类乳腺癌和其他疾病治疗中的应用 肿瘤疾病。

DESCRIPTION: Dr. Vertino's overall research initiative is focused on understanding the molecular mechanisms underlying establishment of altered DNA methylation patterns and its contribution to human carcinogenesis. The aberran methylation of normally unmethylated CpG island-containing gene promoters is one such alteration that has recently been implicated in the inactivation tumo suppresser and other genes in human cancer. In human breast cancer, CpG island methylation is involved in the inactivation of several genes known to be important mediators of tumor cell growth and clinical outcome, including the estrogen receptor gene, the E-cadherin gene, and the p16/INK4A gene. Furthermore, increased expression of DNA (cytosine-5)-methyltransferase (DNA MTase), the enzyme responsible for DNA methylation in mammalian cells, is associated with the more aggressive estrogen receptor negative tumor phenotype Although there have been numerous studies correlating aberrant CpG island methylation with gene inactivity, few studies have addressed how previously unmethylated CpG island sequences become methylated de novo in adult somatic cells and whether this event plays a direct role in gene silencing. We have recently demonstrated that cells engineered to overexpress DNA MTase can be used to model the progression of CpG island methylation as it might occur during the early stages of tumorigenesis. To address the molecular mechanisms underlying aberrant promoter region methylation and the role of this event in human breast carcinogenesis, we propose to develop an in vitro model of de nov methylation in human breast epithelial cells. Specifically, we will determine whether increased expression of DNA MTase can drive the methylation of genes known to be silenced in association with CpG island methylation in human breas tumors. Secondly, we will determine whether locus-specific signals serve to direct the de novo methylation of CpG island promoters in breast epithelial cells. Lastly, we will determine whether de novo methylation of CpG island sequences is sufficient to initiate the gene silencing process by determining the downstream effects of DNA MTase-driven CpG island methylation on gene expression. A further understanding of the genesis and consequences of aberran de novo methylation during carcinogenesis will provide the basis for the futur development of novel demethylation strategies in the treatment of human breast cancer and other neoplastic diseases.