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首页> 外文期刊>Cell cycle >Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders.
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Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders.

机译：基因间远程增强子和snpRNA的网络驱动前列腺癌去势抵抗性表型，并导致多种常见人类疾病的发病机理。

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The mechanistic relevance of intergenic disease-associated genetic loci (IDAGL) containing highly statistically significant disease-linked SNPs remains unknown. Here, we present experimental and clinical evidence supporting the importantance of the role of IDAGL in human diseases. A targeted RT-PCR screen coupled with sequencing of purified PCR products detects widespread transcription at multiple IDAGL and identifies 96 small noncoding trans-regulatory RNAs of ~100-300 nt in length containing SNPs (snpRNAs) associated with 21 common disorders. Multiple independent lines of experimental evidence support functionality of snpRNAs by documenting their cell type-specific expression and evolutionary conservation of sequences, genomic coordinates and biological effects. Chromatin state signatures, expression profiling experiments and luciferase reporter assays demonstrate that many IDAGL are Polycomb-regulated long-range enhancers. Expression of snpRNAs in human and mouse cells markedly affects cellular behavior and induces allele-specific clinically relevant phenotypic changes: NLRP1-locus snpRNAs rs2670660 exert regulatory effects on monocyte/macrophage transdifferentiation, induce prostate cancer (PC) susceptibility snpRNAs and transform low-malignancy hormone-dependent human PC cells into highly malignant androgen-independent PC. Q-PCR analysis and luciferase reporter assays demonstrate that snpRNA sequences represent allele-specific "decoy" targets of microRNAs that function as SNP allele-specific modifiers of microRNA expression and activity. We demonstrate that trans-acting RNA molecules facilitating resistance to androgen depletion (RAD) in vitro and castration-resistant phenotype (CRP) in vivo of PC contain intergenic 8q24-locus SNP variants (rs1447295; rs16901979; rs6983267) that were recently linked with increased risk of PC. Q-PCR analysis of clinical samples reveals markedly increased and highly concordant (r = 0.896; p < 0.0001) snpRNA expression levels in tumor tissues compared with the adjacent normal prostate [122-fold and 45-fold in Gleason 7 tumors (p = 0.03); 370-fold and 127-fold in Gleason 8 tumors (p = 0.0001) for NLRP1-locus and 8q24-locus snpRNAs, respectively]. Our experiments indicate that RAD and CR phenotype of human PC cells can be triggered by ncRNA molecules transcribed from the NLRP1-locus intergenic enhancer at 17p13 and by downstream activation of the 8q24-locus snpRNAs. Our results define the IDAGL at 17p13 and 8q24 as candidate regulatory loci of RAD and CR phenotypes of PC, reveal previously unknown molecular links between the innate immunity/inflammasome system and development of hormone-independent PC and identify novel molecular and genetic targets with diagnostic and therapeutic potentials, exploration of which should be highly beneficial for personalized clinical management of PC.
机译：尚不存在具有高度统计意义的与疾病相关的SNP的基因间疾病相关遗传基因座（IDAGL）的机制相关性。在这里，我们提供了支持IDAGL在人类疾病中的重要性的实验和临床证据。靶向的RT-PCR筛选与纯化的PCR产物的测序相结合，可检测多个IDAGL处的广泛转录，并鉴定96个小的非编码反调节RNA，其长度约为100-300 nt，其中包含与21种常见疾病相关的SNP（snpRNA）。多个独立的实验证据系列通过记录snpRNA的细胞类型特异性表达和序列的进化保守性，基因组坐标和生物学效应来支持snpRNA的功能。染色质状态签名，表达谱实验和萤光素酶报告基因检测表明，许多IDAGL是Polycomb调节的远程增强子。 snpRNA在人和小鼠细胞中的表达显着影响细胞行为并诱导等位基因特异性临床相关表型变化：NLRP1-基因座snpRNA rs2670660对单核细胞/巨噬细胞转分化起调节作用，诱导前列腺癌（PC）易感性snpRNA并转化低恶性激素依赖性人类PC细胞转变为高度恶性的雄激素非依赖性PC。 Q-PCR分析和荧光素酶报告基因分析表明，snpRNA序列代表了microRNA的等位基因特异性“诱饵”靶标，这些靶点充当microRNA表达和活性的SNP等位基因特异性修饰剂。我们证明了促进PC体外抗雄激素耗竭（RAD）和体内去势抵抗表型（CRP）的反式作用RNA分子包含基因间8q24位点SNP变体（rs1447295; rs16901979; rs6983267），最近与增加有PC危险。临床样品的Q-PCR分析显示，与相邻的正常前列腺相比，肿瘤组织中的snpRNA表达水平显着提高且高度一致（r = 0.896; p <0.0001）[在Gleason 7肿瘤中为122倍和45倍（p = 0.03） ）;对于NLRP1基因座和8q24基因座snpRNA，在Gleason 8肿瘤中（p = 0.0001）分别是370倍和127倍]。我们的实验表明，人PC细胞的RAD和CR表型可以由NLRP1-基因座基因间增强子在17p13转录的ncRNA分子和8q24基因座snpRNA的下游激活来触发。我们的研究结果将IDAGL在17p13和8q24定义为RAD和PC CR表型的候选调控位点，揭示了先天免疫/炎性体系统与激素非依赖性PC发育之间未知的分子联系，并鉴定了具有诊断和诊断意义的新型分子和遗传靶标治疗潜力，其探索应对PC的个性化临床管理高度有益。

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