Zuber Verena, Bettella Francesco, Witoelar Aree, Andreassen Ole A, Mills Ian G, Urbanucci Alfonso
Prostate Cancer Research Group, Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Faculty of Medicine, University of Oslo, Oslo, Norway.
NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
BMC Genomics. 2017 Mar 31;18(1):270. doi: 10.1186/s12864-017-3620-y.
Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs.
Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia.
This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
表观遗传信息可用于识别临床上相关的基因组变异，即癌症发展中具有功能重要性的单核苷酸多态性（SNP）。超级增强子是细胞特异性的DNA元件，作用是决定组织或细胞身份并驱动肿瘤进展。尽管之前已尝试多种方法来解释调控DNA元件中SNP相关的风险，但迄今为止，诸如含溴结构域蛋白4（BRD4）等表观遗传阅读器和超级增强子尚未用于注释SNP。在前列腺癌（PC）中，雄激素受体（AR）与染色质的结合位点已被用于对SNP进行功能注释。
在此，我们建立了适用于其他疾病和性状的增强子定位标准，以实现前列腺癌风险SNP的最佳组织特异性富集。我们使用分层Q-Q图和Fisher检验来评估映射到特定增强子类别的SNP的差异富集情况。我们发现BRD4是组织特异性增强子的关键判别因子，表明其在捕获前列腺癌特异性风险位点方面比AR结合信息更有效，并且在乳腺癌（BC）中具有类似效果，还可应用于精神分裂症等其他疾病。
这是第一项评估全基因组关联研究中增强子内SNP的表观遗传阅读器富集情况的研究，并为富集和优先排序前列腺癌和乳腺癌遗传风险位点提供了有力工具。我们的研究代表了一种适用于其他疾病和性状的原理证明，可用于重新定义人类表型变异的分子机制。
