The Bellvitge Institute forBiomedical Research , L'Hospitalet de Llobregat, Barcelona,Catalonia, Spain.
Adv Genet. 2010;70:27-56. doi: 10.1016/B978-0-12-380866-0.60002-2.
DNA methylation is one of the most intensely studied epigenetic modifications in mammals. In normal cells, it assures the proper regulation of gene expression and stable gene silencing. DNA methylation is associated with histone modifications and the interplay of these epigenetic modifications is crucial to regulate the functioning of the genome by changing chromatin architecture. The covalent addition of a methyl group occurs generally in cytosine within CpG dinucleotides which are concentrated in large clusters called CpG islands. DNA methyltransferases are responsible for establishing and maintenance of methylation pattern. It is commonly known that inactivation of certain tumor-suppressor genes occurs as a consequence of hypermethylation within the promoter regions and a numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types. On the other hand, global hypomethylation, inducing genomic instability, also contributes to cell transformation. Apart from DNA methylation alterations in promoter regions and repetitive DNA sequences, this phenomenon is associated also with regulation of expression of noncoding RNAs such as microRNAs that may play role in tumor suppression. DNA methylation seems to be promising in putative translational use in patients and hypermethylated promoters may serve as biomarkers. Moreover, unlike genetic alterations, DNA methylation is reversible what makes it extremely interesting for therapy approaches. The importance of DNA methylation alterations in tumorigenesis encourages us to decode the human epigenome. Different DNA methylome mapping techniques are indispensable to realize this project in the future.
DNA 甲基化是哺乳动物中研究最多的表观遗传修饰之一。在正常细胞中,它确保了基因表达的适当调节和基因的稳定沉默。DNA 甲基化与组蛋白修饰有关,这些表观遗传修饰的相互作用对于通过改变染色质结构来调节基因组的功能至关重要。甲基通常在富含 CpG 二核苷酸的胞嘧啶中发生共价添加,这些 CpG 二核苷酸集中在称为 CpG 岛的大簇中。DNA 甲基转移酶负责建立和维持甲基化模式。众所周知,某些肿瘤抑制基因的失活是由于启动子区域的过度甲基化引起的,大量研究表明,在不同的癌症类型中,DNA 甲基化沉默了广泛的基因。另一方面,全局低甲基化诱导基因组不稳定性,也有助于细胞转化。除了启动子区域和重复 DNA 序列中的 DNA 甲基化改变外,这种现象还与非编码 RNA(如 microRNA)表达的调节有关,microRNA 可能在肿瘤抑制中发挥作用。DNA 甲基化在患者中的潜在翻译应用似乎很有前景,高甲基化的启动子可能作为生物标志物。此外,与遗传改变不同,DNA 甲基化是可逆的,这使其成为治疗方法的极具吸引力。DNA 甲基化改变在肿瘤发生中的重要性促使我们对人类表观基因组进行解码。不同的 DNA 甲基组图谱技术对于未来实现这一项目是不可或缺的。