基因序列多态性对易感基因的功能作用及其对病毒抵抗RNAi的影响
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摘要
随着人类基因组计划的进展,基因序列多态性在复杂性状疾病的发病机制、药物敏感性的个体差异、病毒的生存与耐受等方面具有广阔前景。本课题通过研究人基因5'UTR启动子区SNP多态性位点对基因转录影响、3'UTR区插入/缺失多态性位点对基因表达的影响以及RNA病毒基因组序列的变异对RNAi抑制转录作用的影响这三个角度,验证了基因序列多态性对不同层面基因表达调控的功能作用,从而为复杂性状疾病的发病机制以及病毒对基因治疗产生耐受机制做出有益的探索。
第一部分:位于人基因5'UTR区SNP对TNF-α基因表达的影响
研究目的:肿瘤坏死因子-alpha(TNF-α)作为促炎细胞因子参与自身免疫性疾病和感染性疾病的致病过程,最近的研究发现TNF-α基因上游启动子区-857T等位基因与自发性急性前葡萄膜炎、成人重症腹膜炎、子宫内膜异位症、类风湿性关节炎等多种疾病相关。而且,本教研室前期对汉族人群强直性脊柱炎与TNF-α单核苷酸多态性及单倍型的关联分析表明,在TNF-α启动子区-857C→T是TNF-α独立于HLA-B27而与强直性脊柱炎相关的最有可能的SNP位点。以上的多种报道,很可能是由于TNF-α的-857SNP参与了TNF-α的表达过程,从而使其与多种疾病相关。本课题旨在检测次等位基因-857T,与主等位基因-857C相比,是否对人TNF-α表达产生影响。研究方法:在RAW264.7与HeLa细胞中,运用报告基因方法检测其对转录的影响;运用实时定量反转录聚合酶链法和酶联免疫吸附法,分别从mRNA和蛋白水平,对健康对照个体(基因型为-857C/C)与强直性脊柱炎病人(基因型为-857C/T)外周血单个核细胞中TNF-α表达水平进行了比较。结果:报告基因检测结果表明,与主等位基因-857C比较,次等位基因-857T对TNF-α启动子具有更强的转录激活作用;在基因型为-857C/C的健康人以及-857C/T的强直性脊柱炎病人PBMCs之间,TNF-α在mRNA和蛋白水平未发现明显差异。结论:我们的研究表明TNF-α启动子-857T次等位基因可能直接对TNF-α具有调控作用,且可能以组织特异性方式进行;在解释TNF-α与AS相关时,除TNF-α启动子-857SNP之外,也可能存在其它确切影响TNF-α表达的因素。
第二部分:位于人基因3'UTR区ins/del插入缺失多态性对IGF-2R基因表达的影响
研究目的:microRNAs(miRNAs)主要通过转录后翻译水平的抑制作用调控人内源性基因的表达并参与重要的生理、病理过程,最新研究表明位于靶基因3'非翻译区(3'UTR)的DNA序列多态性(DSPs)可能参与这些过程。Villuendas et al.等研究发现2型糖尿病与胰岛素样生长因子2受体(IGF2R)基因3'UTR的ACAA-插入/缺失多态性有关,但机制未明。本课题旨在检测ACAA-插入/缺失多态性是否存在miRNA介导的多态性调控模式。研究方法:本研究中,使用网络预测工具microInspector和miRanda预测能与IGF2R基因的DNA序列多态性ACAA-插入/缺失位点结合的miRNAs分子;荧光素酶报告基因实验检测候选miRNAs对IGF2R的3'UTR作用以及ACAA-插入/缺失变异对此作用的影响;用RT-qPCR及ELISA方法分别检测HepG2细胞中转染候选miRNAs后IGF2R的mRNA与蛋白质水平变化。结果:生物信息学预测表明IGF2R基因的ACAA-插入/缺失位点位于hsa-miR-657和hsa-miR-453的结合位点内;报告基因实验表明,hsa-miR-657通过多态性模式调控IGF2R基因的表达,即与ACAA插入相比,ACAA缺失对转录活性产生了更高的抑制作用;mRNA与蛋白质水平定量分析表明,hsa-miR-657对IGF2R的mRNA水平无影响,而减少可溶性IGF2R水平。结论:本实验证实,ACAA-插入/缺失多态性,至少可能通过hsa-miR-657介导调控方式,引起IGF2R表达水平的变化。这可能在机制上部分的解释了2型糖尿病的发病,并提示miRNAs或与功能性DNA序列多态性协同,在2型糖尿病的防治中具有一定的应用价值。
第三部分:位于FMDV的VP1基因区的序列变异位点对siRNAs抑制病毒复制作用的影响
研究目的:自从在植物与脉孢菌中发现了双链RNA诱导的基因沉默,以及在蠕虫秀丽隐杆线虫中对RNA干扰现象的机制做出决定性的阐释以来,RNA干扰不仅是研究内源性基因功能的重要工具,而且已被作为实验室强大的抗病毒工具,并对病毒感染提供了一种新的治疗手段。本课题旨在筛选能有效抑制口蹄疫病毒的siRNAs分子并检测FMDV病毒基因组序列的变异对RNAi效果的影响。研究方法:本课题运用体外重组报告基因实验和流式细胞术,以及对攻毒BHK-21细胞进行FMDV含量、上清病毒滴度、细胞病理效应等检测手段,筛选对FMDV的VP1基因起明显抑制作用的siRNAs分子;同时,用定点突变重组报告基因方法检测FMDV基因序列变异对siRNAs抑制作用的影响。结果:筛选到3个能短暂抑制FMDV的有效siRNAs分子;对FMDV基因组序列分析发现口蹄疫病毒的VP1基因序列中第410位点变异,且经报告基因实验证实其可减弱siRNA对VP1基因的抑制作用。结论:FMDV基因组内siRNA结合区的变异可导致siRNA抑制效果的减弱;提示对抗病毒的复制应使用新一代识别突变位点的siRNAs分子。
总之,通过本课题的研究,分别验证了三种不同形式的基因序列多态性对基因表达的功能影响,并揭示出其在致病过程及病毒耐受中的机制模型;TNF-α基因启动子区顺式作用元件内的-857的单核苷酸多态性改变了基因启动子的转录活性而可能参与易感基因TNF-α对强直性脊柱炎的致病作用;IGF2R的3'UTR的插入/缺失多态性改变了miRNA对IGF2R基因翻译水平的抑制作用机制而可能参与2型糖尿病的发病;口蹄疫病毒的VP1基因序列中第410位点变异可能减弱siRNA抑制病毒复制的效力,提示新一代识别突变位点的siRNAs应用于对抗病毒的复制。
With the development of human genome project, gene sequence polymorphism increasingly shows comprehensive promise in pathogenesis of complex disease, individual difference in drug susceptibility, existence and resistance of virus, and other aspects in biomedicine. In this study, the effect of a single nucleotide polymorphism within 5'UTR of TNF-αgene on the expression of AS susceptible gene TNF-α, the effect of an insertion/deletion polymorphism site within 3'UTR of IGF2R gene on the expression of type 2 diabetes susceptible gene IGF2R and the effect of a variation site within FMDV RNA genome on the resistance of FMDV for siRNA targeting were explored, separately. The verification of functional effects of gene sequence polymorphism/variation from different control layer will contribute to the elucidation for those issues, such as the mechanism underlying the susceptibility to specific complex disease, resistance of virus for antiviral gene therapeutics, and so on.
PartⅠ: Effects of a single nucleotide polymorphism within gene 5'UTR region on the expression of human TNF-α
Tumor necrosis factorα(TNFα) plays a prominent role in inflammation and is a proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious disease. Recent association studies have found that the TNFα-857T allele was associated with several disorders. Here we demonstrate, with reporter genes under the control of the two allelic TNFαpromoters, that the minor allele -857T is a much stronger transcriptional activator than the major allele -857C in RAW264.7 cell line in response to lipopolysaccharide (LPS) stimulation. However, the result was not consistent in HeLa cell line. Furthermore, for the quantitative analysis of TNFαsynthesis between the -857C/C genotype from healthy subjects and the -857C/T genotype from AS patients, the quantitative reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed, separately. There was no significant difference between the two groups at the level of mRNA and protein. These results show that this polymorphism may have a direct effect on TNFαregulation in a tissue-specific manner, and aside from the polymorphism at -857 in the TNFαpromoter, there may be other factors affecting the expression of TNFα.
PartⅡ: Effects of an insertion/deletion polymorphism within gene 3'UTR region on the expression of human insulin-like growth factor 2 receptor
The biological mechanism of a recent discovered association of type 2 diabetes with the ACAA-insertion/deletion polymorphism at the 3'UTR of the IGF2R gene has remained unclear. A very recently emerging novel polymorphic control layer by microRNAs (miRNAs) makes it possible to elucidate this issue. In this study, a prediction from web tools microInspector and miRanda demonstrated that DNA sequence polymorphism (DSPs) ACAA-insertion/deletion in IGF2R 3'UTR is located within hsa-miR-657 and hsa-miR-453 binding sites. And luciferase reporter assay revealed that hsa-miR-657 acts directly at the 3'-UTR of the IGF2R. Furthermore, ACAA-deletion exerted a further repression compared with ACAA-insertion, indicating that hsa-miR-657 regulates IGF2R gene expression in a polymorphic control manner. Importantly, we also demonstrated that hsa-miR-657 can translationally regulate the IGF2R expression levels in HepG2 cells. Thus, our findings testify the possibility that the ACAA-insertion/deletion polymorphism may result in the change of IGF2R expression levels at least in part by hsa-miR-657-mediated regulation, contributing to the elucidation for the pathogenesis of type 2 diabetes and raise the possibility that miRNAs or in combination with functional DNA sequence polymorphism may be valuable in the treatment of human type 2 diabetes.
PartⅢ: Effects of a variation within VP1 gene on the resistance of FMDV to RNAi
Foot-and-mouth disease virus (FMDV) is the causative agent of foot-and-mouth disease, a severe, clinically acute, vesicular disease of cloven-hoofed animals. RNA interference (RNAi) is a mechanism for silencing gene expression posttranscriptionally that is being exploited as a rapid antiviral strategy. To identify efficacious small interfering RNAs (siRNAs) to inhibit the replication of FMDV, candidate siRNAs corresponding to FMDV VP1 gene were designed and synthesized in vitro using T7 RNA polymerase. In reporter assays, five siRNAs showed significant sequence-specific silencing effects on the expression of VP1-EGFP fusion protein from plasmid pVP1-EGFP-N1, which was cotransfected with siRNA into 293T cells. Furthermore, using RT-qPCR, viral titration and viability assay, we identified VP1-siRNA517, VP1-siRNA113 and VP1-siRNA519 that transiently acted as potent inhibitors of FMDV replication when BHK-21 cells were infected with FMDV. In addition, variations within multiple regions of the quasispecies of FMDV were retrospectively revealed by sequencing of FMDV genes, and a single nucleotide substitution was identified as the main factor in resistance to RNAi. Our data demonstrated that the three siRNA molecules synthesized with T7 RNA polymerase could have transient inhibitory effects on the replication of FMDV, and that FMDV may escape the antiviral activity of siRNA by a specific single nucleotide variation in targeted sequence. Second generation siRNAs that recognize the variatioin may be recommended to prevent the emergence of resistant FMDV.
In conclusion, our results demonstrate that -857SNP within TNF-α5'UTR promoter region could change the promoter transcription activity, contributing to the susceptibility to AS, that ACAA-insertion/deletion polymorphism could stabilize the interaction between hsa-miR-657 and IGF2R, contributing to the susceptibility to type 2 diabetes, and that the 410nt variation within VP1 gene region could decrease the inhibition of a specific siRNA targeting FMDV, indicating the need for a new generation of siRNAs corresponding to virus genome variation. Therefore, the verified effects of three different type of gene sequence polymorphism/variation on related gene expression show novel molecular models for pathogenesis of complex disease and virus escape from antiviral therapeutics.
第一部分:位于人基因5'UTR区SNP对TNF-α基因表达的影响
研究目的:肿瘤坏死因子-alpha(TNF-α)作为促炎细胞因子参与自身免疫性疾病和感染性疾病的致病过程,最近的研究发现TNF-α基因上游启动子区-857T等位基因与自发性急性前葡萄膜炎、成人重症腹膜炎、子宫内膜异位症、类风湿性关节炎等多种疾病相关。而且,本教研室前期对汉族人群强直性脊柱炎与TNF-α单核苷酸多态性及单倍型的关联分析表明,在TNF-α启动子区-857C→T是TNF-α独立于HLA-B27而与强直性脊柱炎相关的最有可能的SNP位点。以上的多种报道,很可能是由于TNF-α的-857SNP参与了TNF-α的表达过程,从而使其与多种疾病相关。本课题旨在检测次等位基因-857T,与主等位基因-857C相比,是否对人TNF-α表达产生影响。研究方法:在RAW264.7与HeLa细胞中,运用报告基因方法检测其对转录的影响;运用实时定量反转录聚合酶链法和酶联免疫吸附法,分别从mRNA和蛋白水平,对健康对照个体(基因型为-857C/C)与强直性脊柱炎病人(基因型为-857C/T)外周血单个核细胞中TNF-α表达水平进行了比较。结果:报告基因检测结果表明,与主等位基因-857C比较,次等位基因-857T对TNF-α启动子具有更强的转录激活作用;在基因型为-857C/C的健康人以及-857C/T的强直性脊柱炎病人PBMCs之间,TNF-α在mRNA和蛋白水平未发现明显差异。结论:我们的研究表明TNF-α启动子-857T次等位基因可能直接对TNF-α具有调控作用,且可能以组织特异性方式进行;在解释TNF-α与AS相关时,除TNF-α启动子-857SNP之外,也可能存在其它确切影响TNF-α表达的因素。
第二部分:位于人基因3'UTR区ins/del插入缺失多态性对IGF-2R基因表达的影响
研究目的:microRNAs(miRNAs)主要通过转录后翻译水平的抑制作用调控人内源性基因的表达并参与重要的生理、病理过程,最新研究表明位于靶基因3'非翻译区(3'UTR)的DNA序列多态性(DSPs)可能参与这些过程。Villuendas et al.等研究发现2型糖尿病与胰岛素样生长因子2受体(IGF2R)基因3'UTR的ACAA-插入/缺失多态性有关,但机制未明。本课题旨在检测ACAA-插入/缺失多态性是否存在miRNA介导的多态性调控模式。研究方法:本研究中,使用网络预测工具microInspector和miRanda预测能与IGF2R基因的DNA序列多态性ACAA-插入/缺失位点结合的miRNAs分子;荧光素酶报告基因实验检测候选miRNAs对IGF2R的3'UTR作用以及ACAA-插入/缺失变异对此作用的影响;用RT-qPCR及ELISA方法分别检测HepG2细胞中转染候选miRNAs后IGF2R的mRNA与蛋白质水平变化。结果:生物信息学预测表明IGF2R基因的ACAA-插入/缺失位点位于hsa-miR-657和hsa-miR-453的结合位点内;报告基因实验表明,hsa-miR-657通过多态性模式调控IGF2R基因的表达,即与ACAA插入相比,ACAA缺失对转录活性产生了更高的抑制作用;mRNA与蛋白质水平定量分析表明,hsa-miR-657对IGF2R的mRNA水平无影响,而减少可溶性IGF2R水平。结论:本实验证实,ACAA-插入/缺失多态性,至少可能通过hsa-miR-657介导调控方式,引起IGF2R表达水平的变化。这可能在机制上部分的解释了2型糖尿病的发病,并提示miRNAs或与功能性DNA序列多态性协同,在2型糖尿病的防治中具有一定的应用价值。
第三部分:位于FMDV的VP1基因区的序列变异位点对siRNAs抑制病毒复制作用的影响
研究目的:自从在植物与脉孢菌中发现了双链RNA诱导的基因沉默,以及在蠕虫秀丽隐杆线虫中对RNA干扰现象的机制做出决定性的阐释以来,RNA干扰不仅是研究内源性基因功能的重要工具,而且已被作为实验室强大的抗病毒工具,并对病毒感染提供了一种新的治疗手段。本课题旨在筛选能有效抑制口蹄疫病毒的siRNAs分子并检测FMDV病毒基因组序列的变异对RNAi效果的影响。研究方法:本课题运用体外重组报告基因实验和流式细胞术,以及对攻毒BHK-21细胞进行FMDV含量、上清病毒滴度、细胞病理效应等检测手段,筛选对FMDV的VP1基因起明显抑制作用的siRNAs分子;同时,用定点突变重组报告基因方法检测FMDV基因序列变异对siRNAs抑制作用的影响。结果:筛选到3个能短暂抑制FMDV的有效siRNAs分子;对FMDV基因组序列分析发现口蹄疫病毒的VP1基因序列中第410位点变异,且经报告基因实验证实其可减弱siRNA对VP1基因的抑制作用。结论:FMDV基因组内siRNA结合区的变异可导致siRNA抑制效果的减弱;提示对抗病毒的复制应使用新一代识别突变位点的siRNAs分子。
总之,通过本课题的研究,分别验证了三种不同形式的基因序列多态性对基因表达的功能影响,并揭示出其在致病过程及病毒耐受中的机制模型;TNF-α基因启动子区顺式作用元件内的-857的单核苷酸多态性改变了基因启动子的转录活性而可能参与易感基因TNF-α对强直性脊柱炎的致病作用;IGF2R的3'UTR的插入/缺失多态性改变了miRNA对IGF2R基因翻译水平的抑制作用机制而可能参与2型糖尿病的发病;口蹄疫病毒的VP1基因序列中第410位点变异可能减弱siRNA抑制病毒复制的效力,提示新一代识别突变位点的siRNAs应用于对抗病毒的复制。
With the development of human genome project, gene sequence polymorphism increasingly shows comprehensive promise in pathogenesis of complex disease, individual difference in drug susceptibility, existence and resistance of virus, and other aspects in biomedicine. In this study, the effect of a single nucleotide polymorphism within 5'UTR of TNF-αgene on the expression of AS susceptible gene TNF-α, the effect of an insertion/deletion polymorphism site within 3'UTR of IGF2R gene on the expression of type 2 diabetes susceptible gene IGF2R and the effect of a variation site within FMDV RNA genome on the resistance of FMDV for siRNA targeting were explored, separately. The verification of functional effects of gene sequence polymorphism/variation from different control layer will contribute to the elucidation for those issues, such as the mechanism underlying the susceptibility to specific complex disease, resistance of virus for antiviral gene therapeutics, and so on.
PartⅠ: Effects of a single nucleotide polymorphism within gene 5'UTR region on the expression of human TNF-α
Tumor necrosis factorα(TNFα) plays a prominent role in inflammation and is a proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious disease. Recent association studies have found that the TNFα-857T allele was associated with several disorders. Here we demonstrate, with reporter genes under the control of the two allelic TNFαpromoters, that the minor allele -857T is a much stronger transcriptional activator than the major allele -857C in RAW264.7 cell line in response to lipopolysaccharide (LPS) stimulation. However, the result was not consistent in HeLa cell line. Furthermore, for the quantitative analysis of TNFαsynthesis between the -857C/C genotype from healthy subjects and the -857C/T genotype from AS patients, the quantitative reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed, separately. There was no significant difference between the two groups at the level of mRNA and protein. These results show that this polymorphism may have a direct effect on TNFαregulation in a tissue-specific manner, and aside from the polymorphism at -857 in the TNFαpromoter, there may be other factors affecting the expression of TNFα.
PartⅡ: Effects of an insertion/deletion polymorphism within gene 3'UTR region on the expression of human insulin-like growth factor 2 receptor
The biological mechanism of a recent discovered association of type 2 diabetes with the ACAA-insertion/deletion polymorphism at the 3'UTR of the IGF2R gene has remained unclear. A very recently emerging novel polymorphic control layer by microRNAs (miRNAs) makes it possible to elucidate this issue. In this study, a prediction from web tools microInspector and miRanda demonstrated that DNA sequence polymorphism (DSPs) ACAA-insertion/deletion in IGF2R 3'UTR is located within hsa-miR-657 and hsa-miR-453 binding sites. And luciferase reporter assay revealed that hsa-miR-657 acts directly at the 3'-UTR of the IGF2R. Furthermore, ACAA-deletion exerted a further repression compared with ACAA-insertion, indicating that hsa-miR-657 regulates IGF2R gene expression in a polymorphic control manner. Importantly, we also demonstrated that hsa-miR-657 can translationally regulate the IGF2R expression levels in HepG2 cells. Thus, our findings testify the possibility that the ACAA-insertion/deletion polymorphism may result in the change of IGF2R expression levels at least in part by hsa-miR-657-mediated regulation, contributing to the elucidation for the pathogenesis of type 2 diabetes and raise the possibility that miRNAs or in combination with functional DNA sequence polymorphism may be valuable in the treatment of human type 2 diabetes.
PartⅢ: Effects of a variation within VP1 gene on the resistance of FMDV to RNAi
Foot-and-mouth disease virus (FMDV) is the causative agent of foot-and-mouth disease, a severe, clinically acute, vesicular disease of cloven-hoofed animals. RNA interference (RNAi) is a mechanism for silencing gene expression posttranscriptionally that is being exploited as a rapid antiviral strategy. To identify efficacious small interfering RNAs (siRNAs) to inhibit the replication of FMDV, candidate siRNAs corresponding to FMDV VP1 gene were designed and synthesized in vitro using T7 RNA polymerase. In reporter assays, five siRNAs showed significant sequence-specific silencing effects on the expression of VP1-EGFP fusion protein from plasmid pVP1-EGFP-N1, which was cotransfected with siRNA into 293T cells. Furthermore, using RT-qPCR, viral titration and viability assay, we identified VP1-siRNA517, VP1-siRNA113 and VP1-siRNA519 that transiently acted as potent inhibitors of FMDV replication when BHK-21 cells were infected with FMDV. In addition, variations within multiple regions of the quasispecies of FMDV were retrospectively revealed by sequencing of FMDV genes, and a single nucleotide substitution was identified as the main factor in resistance to RNAi. Our data demonstrated that the three siRNA molecules synthesized with T7 RNA polymerase could have transient inhibitory effects on the replication of FMDV, and that FMDV may escape the antiviral activity of siRNA by a specific single nucleotide variation in targeted sequence. Second generation siRNAs that recognize the variatioin may be recommended to prevent the emergence of resistant FMDV.
In conclusion, our results demonstrate that -857SNP within TNF-α5'UTR promoter region could change the promoter transcription activity, contributing to the susceptibility to AS, that ACAA-insertion/deletion polymorphism could stabilize the interaction between hsa-miR-657 and IGF2R, contributing to the susceptibility to type 2 diabetes, and that the 410nt variation within VP1 gene region could decrease the inhibition of a specific siRNA targeting FMDV, indicating the need for a new generation of siRNAs corresponding to virus genome variation. Therefore, the verified effects of three different type of gene sequence polymorphism/variation on related gene expression show novel molecular models for pathogenesis of complex disease and virus escape from antiviral therapeutics.
引文
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