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

Regulation of BRCA1 transcription in ovarian cancer: A crosstalk between sites 1 and 2 hypermethylation and loss of H3K9 ac enrichment

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。

Objective：To investigate the expression of BRCA1 in ovarian cancer specimens,and provide novel insight 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 pyrosequencing.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 methylation-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 transcription in ovarian cancer.