Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, 46202, USA.
Horm Cancer. 2012 Apr;3(1-2):37-43. doi: 10.1007/s12672-011-0086-2.
The ESR2 gene encodes the estrogen receptor beta protein. Several studies have shown that genetic variants in the ESR2 gene are associated with a variety of clinical phenotypes. However, very little is known about the functional significance of ESR2 genetic variants. We used a bioinformatics approach to identify regions of the ESR2 promoter that is evolutionarily conserved across the genomes of several species. We resequenced 1.6 kb of the ESR2 gene which included 0.8 kb of the promoter, 0.3 kb of exon ON, and 0.5 kb of the following intron. We identified five single-nucleotide polymorphisms (SNPs) in the ESR2 promoter and one SNP in the intron. Phase analysis indicated that the SNPs likely exist in 11 different haplotypes. Three of the SNPs (rs8008187, rs3829768, rs35036378) were predicted to alter transcription factor binding sites in the ESR2 promoter. All three were detected only in African American subjects. The rs35036378 SNP was in the TATA box and was highly conserved across species. ESR2 promoter reporter assays in LNCaP and SKBR3 cell lines showed that the variant construct containing the rs35036378 SNP allele had approximately 50% less activity relative to the wild-type construct. We conclude that the rs35036378 SNP appears to cause a reduced promoter activity of the ESR2 gene.
ESR2 基因编码雌激素受体β蛋白。有几项研究表明，ESR2 基因中的遗传变异与多种临床表型有关。然而，关于 ESR2 遗传变异的功能意义知之甚少。我们使用生物信息学方法来确定 ESR2 启动子中在多个物种的基因组中进化保守的区域。我们对 ESR2 基因的 1.6kb 区域进行了重测序，其中包括 0.8kb 的启动子、0.3kb 的外显子 ON 和 0.5kb 的后续内含子。我们在 ESR2 启动子中发现了五个单核苷酸多态性（SNP）和一个内含子中的 SNP。相位分析表明，这些 SNP 可能存在于 11 种不同的单倍型中。三个 SNP（rs8008187、rs3829768、rs35036378）被预测会改变 ESR2 启动子中的转录因子结合位点。所有这三个 SNP 都只在非裔美国人中检测到。rs35036378SNP 位于 TATA 盒中，在物种间高度保守。在 LNCaP 和 SKBR3 细胞系中的 ESR2 启动子报告基因实验表明，含有 rs35036378SNP 等位基因的变体构建体的活性比野生型构建体低约 50%。我们得出结论，rs35036378SNP 似乎导致 ESR2 基因的启动子活性降低。
