CAJ | 학술논문

表观突变是指表观遗传调控出现错误,导致正常情况下表达的基因沉默或者正常情况下沉默的基因转录表达.表观突变通常被认为是局部体细胞事件,一般只存在于病变组织.但是,最近几年关于遗传性非息肉性结直肠癌的研究发现.在部分患者中,所有检测的正常组织均存在MLH1单等位基因启动子区域CpG岛甲基化,并证实这种异常甲基化是肿瘤形成的病因.随后,关于其他抑癌基因MSH2与BRCA1等的胚系异常甲基化也陆续有报道.这提示,表观突变也可以起源于胚系(生殖细胞形成期或胚胎发育早期),从而造成全身细胞广泛的基因转录沉默.这种胚系表观突变类似于经典的基因胚系序列突变,可能成为人类疾病发生的病因.本文着重对近年来抑癌基因胚系表观突变研究进展作一综述.探讨胚系表观突变可能的产生机制和代间遗传的可能性,并展望其给人类疾病病因研究所带来的深远影响.
표관돌변시지표관유전조공출현착오,도치정상정황하표체적기인침묵혹자정상정황하침묵적기인전록표체.표관돌변통상피인위시국부체세포사건,일반지존재우병변조직.단시,최근궤년관우유전성비식육성결직장암적연구발현.재부분환자중,소유검측적정상조직균존재MLH1단등위기인계동자구역CpG도갑기화,병증실저충이상갑기화시종류형성적병인.수후,관우기타억암기인MSH2여BRCA1등적배계이상갑기화야륙속유보도.저제시,표관돌변야가이기원우배계(생식세포형성기혹배태발육조기),종이조성전신세포엄범적기인전록침묵.저충배계표관돌변유사우경전적기인배계서렬돌변,가능성위인류질병발생적병인.본문착중대근년래억암기인배계표관돌변연구진전작일종술.탐토배계표관돌변가능적산생궤제화대간유전적가능성,병전망기급인류질병병인연구소대래적심원영향.
Epimutations are errors in the normal process of epigenetic regulation which can result in aberrant transcriptional silencing of a normally active gene or reactivation of a normally silent gene.Epimutations are generally considered to be somatic events and to be confined in affected tissues.However, recent studies of patients with hereditary nonpolyposis colorectal cancer(HNPCC) have showed that allele-specific hypermethylation of CpG islands in the promoter region of the MLH1 gene, one of the causes of the tumor,existed in all the tissues examined.In addition,germ-line epimutations of other tumor suppressor genes(TSGs),such as MSH2 and BRCA1,have also been reported,demonstrating that epimutations might arise in the germline(during gametogenesis or early embryonic development).The role of germ-line epimutations might be as important as germ-line mutations in human disease.We reviewed the update on germ-line epimutations of TSGs including the possible mechanisms underlying germ-line epimutations,the possibility of transgenerational inheritance.and their impact on our understanding of human disease.