5-hydroxymethylcytosine in human cancer

5-羟甲基胞嘧啶在人类癌症中的作用

• 批准号: 8990561
• 负责人: Gerd P Pfeifer
• 金额: $ 33.81万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990561
• 关键词: hydroxymethylcytosine; human; cancer

DESCRIPTION (provided by applicant): Cell differentiation, reprogramming and malignant transformation are major events characterized by remarkable changes in the epigenome and involve remodeling of DNA methylation patterns. In cancer tissues, DNA methylation patterns are drastically different from those in normal tissues. Two major events are observed, (i) global DNA hypomethylation in cancer affecting predominantly repetitive DNA sequences, and (ii) gene-specific hypermethylation of CpG islands affecting hundreds of genes. The mechanisms how these cancer-associated DNA methylation patterns arise are largely unknown. In 2009, it was reported that a sixth DNA base, 5-hydroxymethylcytosine, is present in substantial amounts in certain mammalian cell types. 5-hydroxymethylcytosine (5hmC) is created from 5-methylcytosine (5mC) by enzymatic oxidation carried out by the TET family of proteins. One model proposes that 5hmC is an intermediate in DNA demethylation. Our hypothesis is that defects in the 5mC oxidation pathway are responsible for altered DNA methylation patterns in human tumors. We have established methodology for precise quantification and genome-wide mapping of 5mC and 5hmC. Our goal is to determine the level and the genomic distribution of 5hmC in normal human tissues and in malignant tumors. These data will be compared directly with the distribution of 5mC in the same tissues. We will focus primarily on two tumor types: (1) human grade II/III astrocytomas, because these tumors frequently contain mutations in isocitrate dehydrogenases (IDH1 or IDH2), an enzymatic activity potentially impacting on the 5mC oxidation pathway; and (2) myelodysplastic syndrome (MDS), because this malignancy often is characterized by mutations in one of the TET genes, TET2. The third Aim will focus on functional studies of TET and TET-associated proteins and their aberrations in cancer.

描述（由申请人提供）：细胞分化、重编程和恶性转化是主要事件，其特征在于表观基因组的显著变化，并涉及DNA甲基化模式的重塑。在癌症组织中，DNA甲基化模式与正常组织中的DNA甲基化模式截然不同。观察到两个主要事件，（i）癌症中的总体DNA低甲基化，主要影响重复DNA序列，以及（ii）影响数百个基因的CpG岛的基因特异性高甲基化。这些癌症相关的DNA甲基化模式如何出现的机制在很大程度上是未知的。2009年，有报道称，第六种DNA碱基5-羟甲基胞嘧啶在某些哺乳动物细胞类型中大量存在。5-羟甲基胞嘧啶（5 hmC）是通过蛋白质的泰特家族进行的酶促氧化由5-甲基胞嘧啶（5 mC）产生的。一种模型认为5 hmC是DNA去甲基化的中间体。我们的假设是，在5 mC氧化途径的缺陷是负责改变人类肿瘤中的DNA甲基化模式。我们已经建立了5 mC和5 hmC的精确定量和全基因组定位的方法。我们的目标是确定5 hmC在正常人体组织和恶性肿瘤中的水平和基因组分布。这些数据将直接与相同组织中的5 mC分布进行比较。我们将主要关注两种肿瘤类型：（1）人类II/III级星形细胞瘤，因为这些肿瘤经常包含异柠檬酸脱氢酶（IDH 1或IDH 2）突变，这是一种可能影响5 mC氧化途径的酶活性;（2）骨髓增生异常综合征（MDS），因为这种恶性肿瘤的特征通常是泰特基因之一TET 2突变。第三个目标将集中在泰特和TET相关蛋白及其在癌症中的畸变的功能研究。