Ushijima Toshikazu
Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Gan To Kagaku Ryoho. 2010 Sep;37(9):1645-9.
Epigenetic modifications, involving DNA methylation and histone modifications, are maintained upon somatic cell replication, and are fundamental mechanisms for cellular memory. DNA methylation of promoter CpG islands of tumor-suppressor genes can silence their downstream genes, and can be causally involved in cancer development and progression. Since this effect is the same with that of inactivating mutations, the natures of DNA methylation were once considered to be similar to mutations. However, recently, it was revealed that a large number of epigenetic alterations are present in a single cancer cell, that a large number of cells have an epigenetic alteration of a specific gene in non-cancerous, thus polyclonal, tissues, that gene specificity in methylation induction is present according to tissue types and inducers, and that chronic inflammation is deeply involved in methylation induction. These facts suggest that epigenetic alterations of key genes involved in acquired chronic disorders can be present in a significant fraction of cells in a tissue, and thus can impair the function of the tissue. Associations between epigenetic alterations and behavior, memory, mental disorders, neurological disorders, metabolic disorders, allergy, autoimmune disorders, and other disorders have been reported. Further research in the field is necessary to clarify the causal roles of these epigenetic alterations in disease development, and to apply the findings to new strategies of disease prevention, diagnosis, and treatment.
表观遗传修饰,包括DNA甲基化和组蛋白修饰,在体细胞复制时得以维持,是细胞记忆的基本机制。肿瘤抑制基因启动子CpG岛的DNA甲基化可使其下游基因沉默,并可能在癌症发生和发展中起因果作用。由于这种效应与失活突变相同,DNA甲基化的本质曾一度被认为与突变相似。然而,最近有研究表明,单个癌细胞中存在大量表观遗传改变,大量细胞在非癌性(即多克隆)组织中存在特定基因的表观遗传改变,根据组织类型和诱导剂的不同,甲基化诱导存在基因特异性,并且慢性炎症与甲基化诱导密切相关。这些事实表明,与获得性慢性疾病相关的关键基因的表观遗传改变可能在组织中的相当一部分细胞中存在,从而损害组织功能。已有报道表明表观遗传改变与行为、记忆、精神障碍、神经障碍、代谢障碍、过敏、自身免疫性疾病及其他疾病之间存在关联。该领域需要进一步研究,以阐明这些表观遗传改变在疾病发展中的因果作用,并将研究结果应用于疾病预防、诊断和治疗的新策略中。