Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders
Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders
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DOI：
10.4161/cc.8.23.10113
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发表时间：
2009-12-01
期刊：
影响因子：
4.3
通讯作者：
Glinsky, Gennadi V.
中科院分区：
文献类型：
--
作者：
Glinskii, Anna B.;Ma, Jun;Glinsky, Gennadi V.
在多达712，253个样本的全基因组关联研究（GWAS）（包括221，158个疾病病例、322，862个对照和168，233个肥胖GWAS病例/对照受试者）中鉴定的SNP变异的基因组坐标的荟萃分析揭示，与22种常见人类疾病相关的39%的SNP位于基因间区域内。基于H3 K4 me 3-H3 K36 me 3标签的染色质状态图显示，许多基因间疾病相关的SNP位于K4-K36结构域的边界内，表明携带SNP的基因组区域被转录。在这里，我们报告鉴定了13种长度为100至200个核苷酸的反式调节RNA（transRNA），它们含有与克罗恩病、类风湿性关节炎、1型糖尿病、白癜风、高血压和多种类型的上皮恶性肿瘤（前列腺癌、乳腺癌、卵巢癌和结直肠癌）相关的基因间SNP序列。我们证明NALP 1基因座基因间SNP序列rs 2670660在人类细胞中表达，并可能通过产生transRNA的不同等位基因变体而导致自身免疫和自身炎性表型的临床表现。transRNA的等位基因特异性正义和反义变体的稳定表达显著改变细胞行为，影响细胞周期进程，并干扰单核细胞/巨噬细胞转分化。在分子水平上，transRNA的等位基因特异性正义和反义变体的强制表达对数百种microRNA和mRNA的丰度产生了等位基因特异性的全基因组效应。使用慢病毒基因转移、微阵列和Q-RT-PCR技术，我们鉴定了rs 2670660等位基因特异性基因表达特征（GES），这些特征似乎可用于检测来自185名对照受试者和350名诊断为9种常见人类疾病（包括克罗恩病、溃疡性结肠炎、类风湿性关节炎、亨廷顿病、孤独症、阿尔茨海默病、肥胖症、前列腺癌和乳腺癌。临床样品的微阵列分析表明，rs 2670660等位基因特异性GES参与患者的外周血单核细胞（PBMC），其在免疫监视和稳态监测期间在人体的连贯组织中遇到病理状况。这些数据表明，由特定基因间序列编码的transRNA的表达可以触发先天免疫/炎性体途径的激活，并有助于自身炎症和自身免疫综合征的临床发展。在这项工作中记录的单碱基取代驱动的分子和生物学拮抗作用的基因间SNP的transRNAs建议的选择和保留的表型兼容的基因间变异在进化过程中的指导机制。根据该模型，将选择产生与祖先等位基因相比具有拮抗性表型改变效应的transRNA的随机遗传变异并将其保留为SNP变体。
Meta-analysis of genomic coordinates of SNP variations identified in genome-wide association studies (GWAS) of up to 712,253 samples (comprising 221,158 disease cases, 322,862 controls, and 168,233 case/control subjects of obesity GWAS) reveals that 39% of SNPs associated with 22 common human disorders are located within intergenic regions. Chromatin-state maps based on H3K4me3-H3K36me3 signatures show that many intergenic disease-linked SNPs are located within the boundaries of the K4-K36 domains, suggesting that SNP-harboring genomic regions are transcribed. Here we report identification of 13 trans-regulatory RNAs (transRNAs) 100 to 200 nucleotides in length containing intergenic SNP sequences associated with Crohn's disease, rheumatoid arthritis, type 1 diabetes, vitiligo, hypertension and multiple types of epithelial malignancies (prostate, breast, ovarian and colorectal cancers). We demonstrate that NALP1 loci intergenic SNP sequence, rs2670660, is expressed in human cells and may contribute to clinical manifestations of autoimmune and auto-imflammatory phenotypes by generating distinct allelic variants of transRNAs. Stable expression of allele-specific sense and anti-sense variants of transRNAs markedly alters cellular behavior, affect cell cycle progression, and interfere with monocyte/macrophage transdifferentiation. On a molecular level, forced expression of allele-specific sense and anti-sense variants of transRNAs asserts allele-specific genome-wide effects on abundance of hundreds microRNAs and mRNAs. Using lentiviral gene transfer, microarray and Q-RT-PCR technologies, we identify rs2670660 allele-specific gene expression signatures (GES) which appear useful for detecting the activated states of innate immunity/inflammasome pathways in similar to 700 clinical samples from 185 control subjects and 350 patients diagnosed with nine common human disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, Huntington disease, autism, Alzheimer disease, obesity, prostate and breast cancers. Microarray analysis of clinical samples demonstrates that rs2670660 allele-specific GES are engaged in patients' peripheral blood mononuclear cells (PBMC) which encounter pathological conditions in coherent tissues of a human body during immune surveillance and homeostasis monitoring. These data indicate that expression of transRNAs encoded by specific intergenic sequences can trigger activation of innate immunity/inflammasome pathways and contribute to clinical development of autoinflammatory and autoimmune syndromes. Documented in this work single-base substitution-driven molecular and biological antagonisms of intergenic SNP-containing transRNAs suggest a guiding mechanism of selection and retention of phenotype-compatible intergenic variations during evolution. According to this model, random genetic variations which generate transRNAs asserting antagonistic phenotype-altering effects compared to ancestral alleles will be selected and retained as SNP variants.