Functional enhancers at the gene-poor 8q24 cancer-linked locus.
Functional enhancers at the gene-poor 8q24 cancer-linked locus.
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DOI：
10.1371/journal.pgen.1000597
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Coetzee GA
中科院分区：
文献类型：
--
作者：
Jia L;Landan G;Pomerantz M;Jaschek R;Herman P;Reich D;Yan C;Khalid O;Kantoff P;Oh W;Manak JR;Berman BP;Henderson BE;Frenkel B;Haiman CA;Freedman M;Tanay A;Coetzee GA
最近发现8q24的多个离散区域包含易患多种癌症的等位基因，包括前列腺癌、乳腺癌和结肠癌。这些区域远没有任何注释的基因，它们的生物学活性也是未知的。在这里，我们描述了一个5兆的染色质片段，它包含了RNA表达、组蛋白修饰的所有风险区域，以及RNA聚合酶II和雄激素受体(AR)所占据的位置。这导致了几个转录增强子的鉴定，并使用报告分析进行了验证。一个风险区域的两个增强子被AR占据，并对雄激素治疗有反应；一个包含单核苷酸多态(Rs11986220)，位于FoxA1结合位点，前列腺癌风险等位基因促进更强的FoxA1结合和更强的雄激素反应。这里报道的这项研究举例说明了一种方法，该方法可以应用于非蛋白质编码区的任何风险相关等位基因，因为它是从全基因组关联研究中出现的，以更好地了解复杂疾病的遗传易感性。对正常人群中遗传遗传变异的全基因组扫描最近发现了许多与癌症等复杂疾病的易感性相关的位置(位点)。然而，这些癌症相关基因中的一些是缺乏基因的(位于所谓的“基因沙漠”中)，而且这种关联的机制(S)并不是很明显。在这里报道的工作中，我们发现在染色体8q24区域发现的与基因沙漠中的几种癌症相关的基因位点作为增强子嵌入了影响基因表达的调控序列，在一个案例中，这种活性受到遗传变异的调节。这一结果为(S)控制遗传癌风险的机制提供了洞察力。
Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases. Genome-wide scans of inherited genetic variation in the normal population have recently identified many sites (loci) associated with the predisposition to complex diseases such as cancer. Some of these cancer-associated loci, however, are devoid of genes (situated in so-called “gene deserts”) and the mechanism(s) of the association are not readily apparent. In the work reported here, we show that loci associated with several cancers in a gene desert found at chromosomal area 8q24 have embedded regulatory sequences affecting gene expression as enhancers, and in one case this activity is modulated by genetic variation. The results provide insight into the mechanism(s) governing genetic cancer risk.
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影响因子：
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作者：
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通讯作者：
Coetzee, Gerhard A.