卵巢癌组织BRCA1转录调节:启动子位点1-2高甲基化介导的组蛋白修饰H3K9ac富集丢失

摘要

Objective:To investigate the expression of BRCA1 in ovarian cancer specimens,and provide novel in-sight into the DNA methtlation involved in BRCA1 transcription. Methods:BRCA1 level was analysed by real-time quantitative PCR. The methylation level of BRCA1 core promoter (sites 1 and 2)was determined using pyrosequenc-ing. Chromatin immunoprecipitation was used for detecting the H3K9ac pattern. Results:High methylation levels of sites 1 and 2 in the BRCA1 core promoter were accompanied by decreasing BRCA1 expression. Hypermethylated sites 1 and 2 were a key regulatory element for the BRCA1 transcription. Mechanistically,the abnormal sites 1 and 2 methy-lation-mediated loss of H3K9ac enrichment inhibited the transcription of BRCA1. Conclusion:Our findings imply that epigenetic mechanisms (such as DNA methylation and histone modification)are jointly involved in BRCA1 tran-scription in ovarian cancer.%目的:探讨卵巢癌组织介导BRCA1转录调节的甲基化机制.方法:利用实时荧光定量PCR方法检测卵巢癌组织中BRCA1的表达样式;采用焦磷酸测序技术分析卵巢癌标本BRCA1基因启动子区域位点1和2的甲基化水平;采用染色质免疫共沉淀研究BRCA1启动子区域差异甲基化位点周边组蛋白H3K9ac富集情况.结果:卵巢癌组织BRCA1启动子高甲基化常常伴随BRCA1表达水平降低;BRCA1启动子区域位点1和2的异常甲基化是其转录调节的重要机制;位点1和2异常高甲基化介导的H3K9ac富集水平降低显著抑制BRCA1转录.结论:在卵巢癌组织中,BRCA1基因启动子的异常甲基化及其介导的差异组蛋白修饰H3K9ac富集协同参与BRCA1的转录调控.