Expression of the CTCF-paralogous cancer-testis gene, brother of the regulator of imprinted sites (BORIS), is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors.
Expression of the CTCF-paralogous cancer-testis gene, brother of the regulator of imprinted sites (BORIS), is regulated by three alternative promoters modulated by CpG methylation and by CTCF and p53 transcription factors.
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CTCF - 多个癌症测试基因的表达是印迹位点调节剂（Boris）的兄弟，受到CPG甲基化调节的三个替代启动子的调节，由CPG甲基化和CTCF和p53转录因子调节。
DOI：
10.1093/nar/gkm896
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发表时间：
2007
影响因子：
14.9
通讯作者：
Lobanenkov, Victor
中科院分区：
文献类型：
--
作者：
Renaud, Stephanie;Pugacheva, Elena M;Delgado, M Dolores;Braunschweig, Richard;Abdullaev, Ziedulla;Loukinov, Dmitri;Benhattar, Jean;Lobanenkov, Victor
与“癌症/睾丸抗原”家族的其他成员一样，BORIS通常在睾丸生殖细胞中表达，在体细胞中受到抑制，但在癌症中异常激活。为了了解人类BORIS表达的调控机制，我们对其5 '侧区进行了表征。使用5 ' RACE，我们确定了三个启动子，分别命名为A， B和C，分别对应于第一个ATG上游- 1447，- 899和- 658 bp的转录起始位点。不同启动子的使用产生了至少五个不同剪接的BORIS mrna，其半衰期由不同的5 ' - utr决定。在正常睾丸中，BORIS是由所有三个启动子转录而来，但在30个被测试的癌细胞系中，84%只使用启动子A和/或C，而其他细胞系主要使用启动子B和C。正常细胞和癌细胞之间启动子使用的差异表明它们受到不同的调控。我们发现DNA甲基化和功能性p53有助于每个启动子的负调控。此外，在正常BORIS阴性的人成纤维细胞中，CTCF的减少导致BORIS启动子的抑制。这些结果为理解CTCF单倍体不足与BORIS抑制之间的癌症相关关系，以及缺乏功能性p53与BORIS异常激活之间的关系提供了机制基础。
BORIS, like other members of the ‘cancer/testis antigen’ family, is normally expressed in testicular germ cells and repressed in somatic cells, but is aberrantly activated in cancers. To understand regulatory mechanisms governing human BORIS expression, we characterized its 5′-flanking region. Using 5′ RACE, we identified three promoters, designated A, B and C, corresponding to transcription start sites at −1447, −899 and −658 bp upstream of the first ATG. Alternative promoter usage generated at least five alternatively spliced BORIS mRNAs with different half-lives determined by varying 5′-UTRs. In normal testis, BORIS is transcribed from all three promoters, but 84% of the 30 cancer cell lines tested used only promoter(s) A and/or C while the others utilized primarily promoters B and C. The differences in promoter usage between normal and cancer cells suggested that they were subject to differential regulation. We found that DNA methylation and functional p53 contributes to the negative regulation of each promoter. Moreover, reduction of CTCF in normally BORIS-negative human fibroblasts resulted in derepression of BORIS promoters. These results provide a mechanistic basis for understanding cancer-related associations between haploinsufficiency of CTCF and BORIS derepression, and between the lack of functional p53 and aberrant activation of BORIS.