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首页> 外文期刊>Cell cycle >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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Identification of intergenic trans-regulatory RNAs containing a disease-linked SNP sequence and targeting cell cycle progression/differentiation pathways in multiple common human disorders.

机译：鉴定与多种疾病相关的SNP序列并靶向多种人类常见疾病的细胞周期进展/分化途径的基因间反式调节RNA。

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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 autoimflammatory 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 approximately 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.
机译：在全基因组关联研究（GWAS）中鉴定的SNP变异的基因组座标的荟萃分析，涉及多达712,253个样本（包括221,158个疾病病例，322,862个对照和168,233个肥胖症GWAS病例/对照受试者），发现39％的SNP相关有22种常见人类疾病的病原体位于基因间区域内。基于H3K4me3-H3K36me3签名的染色质状态图显示，许多与基因相关的与疾病相关的SNP位于K4-K36域的边界内，表明转录了SNP携带基因组区域。在这里，我们报告鉴定了13个反式调节RNA（transRNA），其长度为100至200个核苷酸，其中包含与克罗恩病，类风湿性关节炎，1型糖尿病，白癜风，高血压和多种上皮恶性肿瘤（前列腺，乳腺，卵巢）相关的基因间SNP序列和大肠癌）。我们证明了NALP1基因座基因间SNP序列，rs2670660，在人类细胞中表达，并可能通过产生不同的等位基因transRNA来促进自身免疫和自发炎表型的临床表现。 transRNA的等位基因特异性有义和反义变体的稳定表达显着改变细胞行为，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的等位基因特异性有义和反义变体的强制表达对数百种microRNA和mRNA的丰度提出了等位基因特异性全基因组效应。使用慢病毒基因转移，微阵列和Q-RT-PCR技术，我们鉴定了rs2670660等位基因特异性基因表达特征（GES），这些特征对于检测来自185个对照受试者的大约700个临床样品中的先天免疫/炎性体途径的激活状态似乎很有用。 350名被诊断患有9种常见人类疾病的患者，包括克罗恩病，溃疡性结肠炎，类风湿性关节炎，亨廷顿病，自闭症，阿尔茨海默氏病，肥胖症，前列腺癌和乳腺癌。临床样品的微阵列分析表明，rs2670660等位基因特异的GES参与了患者外周血单核细胞（PBMC），这些细胞在免疫监测和体内稳态监测过程中会在人体相干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。这项工作中记录的基因间含SNP的transRNA的单碱基取代驱动分子和生物拮抗作用提示了在进化过程中选择和保留表型兼容基因间变异的指导机制。根据该模型，将选择与祖先等位基因相比产生断言具有拮抗表型改变作用的transRNA的随机遗传变异并将其保留为SNP变异。

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