人类iNOS基因启动子-1026C/A多态的功能研究
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摘要
人类iNOS基因启动子-1026C／A多态的功能研究
前言
一氧化氮合酶包括：神经型一氧化氮合酶(nNOS)、诱导型一氧化氮合酶(iNOS)和内皮型一氧化氮合酶(eNOS).其中,iNOS在正常生理状态下不表达或表达量极低,只有诱导后才大量表达,因此iNOS基因表达调控对NO的产生至关重要。iNOS基因在原发性高血压发生中发挥重要作用,一方面iNOS可通过产生NO引起血管平滑肌细胞舒张降低血压,另一方面还通过NO衍生物一过氧亚硝酸盐阴离子(ONOO-)发挥促高血压作用。
本课题组前期研究中,通过高血压高发区连锁分析发现17号染色体上的微卫星D17S1878与高血压存在连锁。进一步病例-对照人群和家系研究证实,iNOS基因启动子-1026C／A多态与高血压发生相关,其中-1026C等位基因及-1026CC基因型是高血压发生的独立危险因素。此外对iNOS启动子-1026C／A多态的初步功能研究发现,-1026位点存在转录因子YY1反应元件,-1026C／A多态影响了YY1-DNA结合模式以及iNOS启动子萤光素酶报告基因重组体p1173C/A-luc的转录活性,并推测可能继而通过影响NO的产生导致-1026C／C的高血压易感风险升高。然而,YY1是如何影响iNOS启动子,-1026C／A多态对iNOS基因转录的确切功能,以及多种高血压相关因子调控iNOS转录活性的效应和具体机制尚不明确。
材料与方法
一、实验材料
1、细胞系：人喉鳞癌细胞(Hep2),人胃癌细胞(BGC823),非洲绿猴肾(COS-7),小鼠巨噬细胞(RAW264.7)；
2、载体：萤火虫荧光素酶报告载体、海肾荧光素酶表达载体、YY1表达及RNA干扰载体、NFIC野生型及突变型表达载体、c-Jun表达载体、雌激素受体表达载体、糖皮质激素受体表达载体、盐皮质激素受体表达载体、p300野生型及突变型表达载体；
3、Western印迹杂交相关试剂及试剂盒；
4、基因克隆及萤光素酶报告基因检测相关试剂及试剂盒；
5、DNA-蛋白质结合实验、免疫共沉淀、电泳泳动迁移实验(EMSA)及染色质免疫沉淀(ChIP)相关试剂及试剂盒；
6、Real-time PCR相关试剂及试剂盒；
7、细胞刺激因子：细胞因子混合物(IFN-y、IL-1p和TNF-a)、丁酸钠、雌二醇、地塞米松、醛固酮、转化生长因子-β1、胰岛素样生长因子Ⅱ和胰岛素。
二、实验方法
1, iNOS启动子萤光素酶报告基因载体构建及检测：利用在线软件进行iNOS启动子转录因子预测分析,构建系列截短的萤光素酶报告基因重组体,应用双荧光素酶检测系统检测启动子的活性,鉴定iNOS基因关键转录调控区；
2、应用DNA-蛋白质结合实验、免疫共沉淀、EMSA和ChIP方法鉴定iNOS启动子-1026C／A多态位点DNA-蛋白质复合物组成,各转录因子相互作用,及DNA-结合亲和力；
3、共转染转录因子及激素受体表达载体,应用萤光素酶报告基因系统,检测YY1、NFI和AP-1对iNOS基础启动子活性的影响；以及雌二醇、地塞米松、醛固酮、转化生长因子-β1、胰岛素样生长因子Ⅱ和胰岛素在iNOS转录调控中的作用；
4、Real-time PCR方法检测YY1、NFI和AP-1过表达对细胞因子混合物诱导后iNOSmRNA表达的影响；
5、丁酸钠刺激,以及共转染野生型／突变型p300表达载体,检测乙酰化在iNOS表达调控中的作用。
结果
1、系列截短的萤光素酶报告基因活性检测发现iNOS启动子-1173bp～-1032bp的141-bp片段可能为负性转录调控区；含有-1026C／A多态位点的16-bp片段(-1032 bp～-1016 bp)为iNOS基因转录的关键正性调控区。
2、转录因子预测分析发现,除YY1外,iNOS启动子-1026C／A位点还存在另两个转录因子NFI和AP-1,DNA-蛋白质结合实验显示,-1026C／A位点存在由YY1,NFI和AP-1组成的蛋白质复合物,其中YY1与-1026C优势结合,而NFI与-1026A优势结合,免疫共沉淀结果提示AP-1和NFI之间存在相互作用,NFI和YY1之间也可能存在相互作用,而AP-1和YY1之间可能无直接的相互作用。
3、EMSA实验证实NFI能与-1026A特异性直接结合,而AP-1与-1026A之间的结合可能是间接的,ChIP实验显示细胞内NFI和YY1与含有-1026C／A位点iNOS启动子结合,且YY1与-1026C结合亲和力较强,NFI与-1026A结合亲和力较强。
4、通过YY1和NFI过表达及YY1的RNA干扰后检测p1173C/A-luc和p1032C/A-luc转录活性,发现YY1和NFI抑制iNOS基础启动子活性,该负性调控作用受正性转录调节因子AP-1的影响；其中,YY1的抑制作用明显强于NFI。
5、Real-time PCR结果显示,细胞因子混合物(IFN-γ> IL-1β和TNF-α)显著诱导BGC823细胞iNOS表达,YY1、NFI或AP-1单独过表达对iNOS的诱导表达影响不明显,而AP-1/NF1或AP-1/YY1联合过表达均抑制iNOS的诱导表达,且AP-1/YY1的抑制作用明显强于AP-1/NF1。
6、转录因子预测分析显示iNOS基因启动子1.2 kb序列中还存在一个TATA box、NF-κB/C/EBP、C/EBP、Spl以及多个糖皮质激素和雌激素反应元件；
7、体外培养BGC823、Hep2、COS-7和RAW264.7细胞发现,p1173C/A-luc转录活性在不同细胞系中差异明显,而-1026C／A在不同细胞系中均影响iNOS启动子活性。
8、类固醇激素(雌二醇、地塞米松、醛固酮)刺激及其受体过表达实验结果显示,雌激素下调p1173A-luc转录活性依赖于雌激素受体,醛固酮及盐皮质激素受体有上调p1173A-luc转录活性的趋势,而地塞米松及糖皮质激素受体对p1173A-luc转录活性无明显作用；此外,p1173C-luc转录活性不受这些激素的影响。
9、应用去乙酰化酶抑制剂丁酸钠刺激,以及乙酰转移酶辅助因子p300的过表达实验,发现丁酸钠处理可显著降低p1173C-luc和p1173A-luc的转录活性,且对p1173A-luc的抑制作用较强；而共转染野生型p300后p1173C-luc和p1173A-luc转录活性无显著变化；提示由丁酸钠介导的乙酰化修饰可能抑制iNOS基因的基础启动子活性。
10、应用血压调节因子(TGF-β1、IGFⅡ和胰岛素)处理Hep2细胞后p1173C／A-luc转录活性均无明显改变,-1026C／A多态的作用仍很显著,提示人iNOS基因1.2 kb启动子可能不是这些血压调节因子的直接作用靶点。
结论
1、iNOS启动子-1026C／A多态位点所在16-bp片段是基础转录活性的关键调控区,该位点DNA-蛋白质复合物包括YY1、NFI和AP-1,其中YY1和NFI直接结合DNA,而AP-1间接结合DNA；
2、YY1和NFI与-1026C／A位点的结合亲和力存在差异,YY1与-1026C优势结合,NFI与-1026A优势结合；
3、YY1和NFI均抑制iNOS基础启动子转录活性,且YY1的作用明显强于NFI,在细胞因子诱导后,AP-1/YY1对iNOS基因mRNA转录的抑制效应明显强于AP-1/NFI;
4、iNOS基因启动子可能存在多个转录因子反应元件,其中的雌激素反应元件(ERE)可能在雌激素下调iNOS启动子转录活性中起重要作用；
5、-1026C／A多态对iNOS启动子活性的影响在多种细胞系中趋势一致,但其作用效应存在一定的种属特异性；多种刺激因素也没有影响-1026C／A多态对转录调控作用的趋势；
6、乙酰化修饰对iNOS基因转录调控发挥重要作用,特别是丁酸钠对iNOS启动子转录活性的明显抑制作用值得进一步研究。
Functional identification of the-1026C/A polymorphism in the human iNOS promoter
Introduction
Nitric oxide synthases (NOS) include three isoforms, the neuronal type (nNOS), the inducible type (iNOS), and the endothelial type (eNOS). In the normal condition, iNOS does not express or expresses at a very low level, however, a large amount after induction, therefore, the regulation of iNOS expression have impact on the NO production. iNOS gene plays an important role in development of essential hypertension, which may exhibit an anti-hypertensive effect through relaxation of vascular muscle cells by NO, or a pro-hypertensive effect through oxidative stress by excess of the NO derivative peroxynitrite ONOO-.
In the previous study, we have linkage between chromosome 17 microsatellite D17S1878 and hypertension in a hypertension prevalence region. Further case-control population and family-based study demonstrated the association between the-1026C/A variant of the human iNOS promoter and susceptibility to hypertension, and found that the-1026C allele and-1026CC genotype were independent risk factors for hypertension. Moreover, functional investigation of the-1026C/A polymorphism in the human iNOS promoter revealed that-1026C/A altered the Yin Yang 1 (YY1)-binding pattern, and transcriptional activity of the iNOS promoter reporter constructs p1173C/A-luc, resulting in increased risk for hypertension through reduced NO production. However, how YY1 contributs to the iNOS promoter, the function of-1026C/A polymorphism on iNOS transcription, as well as the effect of various hypertension-related factors on iNOS transcriptional activity remained unclear.
Materials and Methods
Materials
1. Cell lines:Human epidermoid cancer cell (Hep2), human gastric carcinoma cell (BGC823), African Green Monkey kidney cell (COS-7), and mouse macrophage cell (RAW264.7);
2. Vector:pGL3-Basic, pRL-TK, pCMV-YY1, pBSU6-YY1, pcDNA3.1-NFIC, pcDNA3.1-NFICDBD, pcDNA3.1-Jun, expression vectors for estrogen, glucocorticoid, and mineralocorticoid receptor, p300w, and p300m;
3. Reagents and kits for Western blot;
4. Reagents and kits for gene cloning and luciferase reporter assay;
5. Reagents and kits for DNA-binding assay, Co-immunoprecipitation (Co-IP), electrophoresis mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP);
6. Reagents and kits for Real-time RT-PCR;
7. Stimuli in cell culture:cytomix (IFN-y, IL-1β, and TNF-a), sodium butyrate, estradiol, dexamethasone, aldosterone, transforming growth factor-β1, insulin-like growth factorⅡ, and insulin.
Methods
1. Construction iNOS promoter luciferase reporters and assay:transcription factors in the iNOS promoter were analyzed using online research program; a series of truncated luciferase reporter constructs were generated and assayed using Dual-Glo luciferase system to identify the key regulatory region of the iNOS gene.
2. DNA-binding assay, co-immunoprecipitaion, EMSA and ChIP were performed to identify the components of DNA-protein complex in the iNOS-1026C/A polymorphism, the interaction between these transcription factors, and their DNA-binding affinity.
3. Cotransfection of expression vectors for transcription factors and steroid hormone receptors, and luciferase reporter assay were performed to detect the effects of estradiol, dexamethasone, aldosterone, transforming growth factor-β1, insulin-like growth factor II, and insulin on regulation of the iNOS transcription.
4. Real-time PCR was used to evaluate the impact of overexpression of YY1, nuclear factor I (NFI), and active protein-1 (AP-1) on cytomix induced iNOS mRNA expression.
5. Stimulation using sodium butyrate, and cotransfection of p300w and p300m expression vectors were conducted to detect the effect of acetylation on iNOS expression.
Results
1. Truncated luciferase reporters assay demonstrated that a 141-bp segment from-1173 bp to-1032 bp in the iNOS promoter was a potential negative regulatory region, and a 16-bp segment from-1032 bp to-1016 bp was a key positive regulatory region for iNOS transcriptional regulation.
2. Transcription factors prediction revealed that besides YY1, two novel transcription factors NFI and AP1 were located in the iNOS promoter locus; DNA-binding assay showed that a protein complex formed by YY1, NFI, and AP-1 existed in-1026C/A, YY1 dominantly bound to-1026C, and NFI dominantly bound to-1026A; co-immunoprecipitation demonstrated an interaction between AP-1 and NFI, a possible interaction between NFI and YY1, but no direct interaction between AP-1 and YY1.
3. EMS A demonstrated a specific binding of NFI to-1026A, and suggested a indirect binding of AP-1 to-1026A; ChIP assay confirmed the binding of YY1 or NFI to iNOS promoter encompassing-1026C/Ain cell culture, wherein the binding affinity of YY1 to-1026C, as well as the binding affinity ofNFI to-1026A were dominant.
4. Transcriptional activity assay of pl173C/A-luc and p1032C/A-luc after overexpression of YY1 and NFI, or YY1 RNA interference showed that YY1 and NFI inhibited iNOS basal promoter activity, and the negative regulatory effects were influenced by the positive regulator AP-1, wherein the inhibitory effect of YY1 was more potent than NFI.
5. Real-time PCR results showed that the cytomix (IFN-y, IL-1(3 and TNF-a) significantly induced the iNOS expression in BGC823 cells, the independent effect of YY1, NFI, and AP-1 on the.iNOS induced-expression was not marked, however, overexpression of AP-1/NF1 or AP1/YY1 potently inhibited iNOS induced-expression, wherein the inhibitory effect of AP-1/YY1 was more dominant than AP-1/NF1.
6. Prediction of transcription factor demonstrated that a TATA box, NF-κB/CEBP、CEBP, Sp1, and several estrogen and glucocorticoid responsive elements existed in the 1.2 kb iNOS promoter.
7. The transcriptional activity of p1173C/A-luc significantly differed among BGC823, Hep2, COS-7, and RAW264.7 cells, however, the influence of-1026C/Aon the promoter activity was the same in different cell lines.
8. Steroid hormones (estradiol, dexamethasone, and aldosterone) treatment and overexpression of their receptors showed that estradiol downregulated p1173A-luc transcriptional activity in a receptor-dependent way, aldosterone and mineralocorticoid receptor had a tendency of p1173A-luc upregulation, whereas dexamethasone and glucocorticoid receptor did not affect the p1 173A-luc transcriptional activity; moreover, these hormones did not influence the transcriptional activity of p1173C-luc.
9. Cell stimulation using deacetylase inhibitor sodium butyrate and overexpression of p300 showed that sodium butyrate markedly reduced the transcriptional activities of p1173C-luc and p1173A-luc, and the inhibition was more significant for p1173A-luc than for p1173C-luc; whereas the transcription activities of p1173C/A-luc did not alter after cotransfection of expression vectors for p300, indicating the sodium butyrate-mediated acetylation may inhibit the iNOS basal promoter activity.
10. Stimulation of Hep2 cells using blood pressure regulators (TGF-β1, IGF II, and insulin) did not significantly alter thep1173C/A-luc transcriptional activity, while the effect of-1026C/A remained marked, suggesting the 1.2 kb human iNOS promoter may not direct target of these blood pressure regulators.
Conclusion
1. The iNOS promoter-1026C/A polymorphism was located in a 16-bp key regulatory region for basal transcriptional activity, wherein existed a protein complex formed by YY1, NFI and AP-1; the DNA-binding of YY1 and NFI was direct, whereas the DNA-binding of AP-1 was indirect.
2. YY1 and NFI bound to-1026C/A with different binding affinity, YY1 dominantly bound to-1026C, and NFI dominantly bound to-1026A.
3. Both YY1 and NFI inhibit iNOS basal promoter activity, and the inhibitory effect of YY1 was more potent than NFI; the AP-1/YY1 inhibited the cytokmix-induced iNOS mRNA expression more markedly than AP-1/NFI.
4. Several transcription factor responsive elements may exist in the promoter, in which the estrogen responsive element (ERE) play a vitol role in downregulation of iNOS transcriptional activity.
5. The regulation tendency of-1026C/Aon iNOS promoter activity was the same among different cell lines, while their impacts exhibited a species-specific maner; a number of stimuli did not influence the regulation tendency of-1026C/A on iNOS transcription.
6. Acetylation modification played an important role in the regulation of iNOS transcription, and the marked sodium butyrate-mediated inhibition of iNOS promoter activity needed further investigation.
前言
一氧化氮合酶包括：神经型一氧化氮合酶(nNOS)、诱导型一氧化氮合酶(iNOS)和内皮型一氧化氮合酶(eNOS).其中,iNOS在正常生理状态下不表达或表达量极低,只有诱导后才大量表达,因此iNOS基因表达调控对NO的产生至关重要。iNOS基因在原发性高血压发生中发挥重要作用,一方面iNOS可通过产生NO引起血管平滑肌细胞舒张降低血压,另一方面还通过NO衍生物一过氧亚硝酸盐阴离子(ONOO-)发挥促高血压作用。
本课题组前期研究中,通过高血压高发区连锁分析发现17号染色体上的微卫星D17S1878与高血压存在连锁。进一步病例-对照人群和家系研究证实,iNOS基因启动子-1026C／A多态与高血压发生相关,其中-1026C等位基因及-1026CC基因型是高血压发生的独立危险因素。此外对iNOS启动子-1026C／A多态的初步功能研究发现,-1026位点存在转录因子YY1反应元件,-1026C／A多态影响了YY1-DNA结合模式以及iNOS启动子萤光素酶报告基因重组体p1173C/A-luc的转录活性,并推测可能继而通过影响NO的产生导致-1026C／C的高血压易感风险升高。然而,YY1是如何影响iNOS启动子,-1026C／A多态对iNOS基因转录的确切功能,以及多种高血压相关因子调控iNOS转录活性的效应和具体机制尚不明确。
材料与方法
一、实验材料
1、细胞系：人喉鳞癌细胞(Hep2),人胃癌细胞(BGC823),非洲绿猴肾(COS-7),小鼠巨噬细胞(RAW264.7)；
2、载体：萤火虫荧光素酶报告载体、海肾荧光素酶表达载体、YY1表达及RNA干扰载体、NFIC野生型及突变型表达载体、c-Jun表达载体、雌激素受体表达载体、糖皮质激素受体表达载体、盐皮质激素受体表达载体、p300野生型及突变型表达载体；
3、Western印迹杂交相关试剂及试剂盒；
4、基因克隆及萤光素酶报告基因检测相关试剂及试剂盒；
5、DNA-蛋白质结合实验、免疫共沉淀、电泳泳动迁移实验(EMSA)及染色质免疫沉淀(ChIP)相关试剂及试剂盒；
6、Real-time PCR相关试剂及试剂盒；
7、细胞刺激因子：细胞因子混合物(IFN-y、IL-1p和TNF-a)、丁酸钠、雌二醇、地塞米松、醛固酮、转化生长因子-β1、胰岛素样生长因子Ⅱ和胰岛素。
二、实验方法
1, iNOS启动子萤光素酶报告基因载体构建及检测：利用在线软件进行iNOS启动子转录因子预测分析,构建系列截短的萤光素酶报告基因重组体,应用双荧光素酶检测系统检测启动子的活性,鉴定iNOS基因关键转录调控区；
2、应用DNA-蛋白质结合实验、免疫共沉淀、EMSA和ChIP方法鉴定iNOS启动子-1026C／A多态位点DNA-蛋白质复合物组成,各转录因子相互作用,及DNA-结合亲和力；
3、共转染转录因子及激素受体表达载体,应用萤光素酶报告基因系统,检测YY1、NFI和AP-1对iNOS基础启动子活性的影响；以及雌二醇、地塞米松、醛固酮、转化生长因子-β1、胰岛素样生长因子Ⅱ和胰岛素在iNOS转录调控中的作用；
4、Real-time PCR方法检测YY1、NFI和AP-1过表达对细胞因子混合物诱导后iNOSmRNA表达的影响；
5、丁酸钠刺激,以及共转染野生型／突变型p300表达载体,检测乙酰化在iNOS表达调控中的作用。
结果
1、系列截短的萤光素酶报告基因活性检测发现iNOS启动子-1173bp～-1032bp的141-bp片段可能为负性转录调控区；含有-1026C／A多态位点的16-bp片段(-1032 bp～-1016 bp)为iNOS基因转录的关键正性调控区。
2、转录因子预测分析发现,除YY1外,iNOS启动子-1026C／A位点还存在另两个转录因子NFI和AP-1,DNA-蛋白质结合实验显示,-1026C／A位点存在由YY1,NFI和AP-1组成的蛋白质复合物,其中YY1与-1026C优势结合,而NFI与-1026A优势结合,免疫共沉淀结果提示AP-1和NFI之间存在相互作用,NFI和YY1之间也可能存在相互作用,而AP-1和YY1之间可能无直接的相互作用。
3、EMSA实验证实NFI能与-1026A特异性直接结合,而AP-1与-1026A之间的结合可能是间接的,ChIP实验显示细胞内NFI和YY1与含有-1026C／A位点iNOS启动子结合,且YY1与-1026C结合亲和力较强,NFI与-1026A结合亲和力较强。
4、通过YY1和NFI过表达及YY1的RNA干扰后检测p1173C/A-luc和p1032C/A-luc转录活性,发现YY1和NFI抑制iNOS基础启动子活性,该负性调控作用受正性转录调节因子AP-1的影响；其中,YY1的抑制作用明显强于NFI。
5、Real-time PCR结果显示,细胞因子混合物(IFN-γ> IL-1β和TNF-α)显著诱导BGC823细胞iNOS表达,YY1、NFI或AP-1单独过表达对iNOS的诱导表达影响不明显,而AP-1/NF1或AP-1/YY1联合过表达均抑制iNOS的诱导表达,且AP-1/YY1的抑制作用明显强于AP-1/NF1。
6、转录因子预测分析显示iNOS基因启动子1.2 kb序列中还存在一个TATA box、NF-κB/C/EBP、C/EBP、Spl以及多个糖皮质激素和雌激素反应元件；
7、体外培养BGC823、Hep2、COS-7和RAW264.7细胞发现,p1173C/A-luc转录活性在不同细胞系中差异明显,而-1026C／A在不同细胞系中均影响iNOS启动子活性。
8、类固醇激素(雌二醇、地塞米松、醛固酮)刺激及其受体过表达实验结果显示,雌激素下调p1173A-luc转录活性依赖于雌激素受体,醛固酮及盐皮质激素受体有上调p1173A-luc转录活性的趋势,而地塞米松及糖皮质激素受体对p1173A-luc转录活性无明显作用；此外,p1173C-luc转录活性不受这些激素的影响。
9、应用去乙酰化酶抑制剂丁酸钠刺激,以及乙酰转移酶辅助因子p300的过表达实验,发现丁酸钠处理可显著降低p1173C-luc和p1173A-luc的转录活性,且对p1173A-luc的抑制作用较强；而共转染野生型p300后p1173C-luc和p1173A-luc转录活性无显著变化；提示由丁酸钠介导的乙酰化修饰可能抑制iNOS基因的基础启动子活性。
10、应用血压调节因子(TGF-β1、IGFⅡ和胰岛素)处理Hep2细胞后p1173C／A-luc转录活性均无明显改变,-1026C／A多态的作用仍很显著,提示人iNOS基因1.2 kb启动子可能不是这些血压调节因子的直接作用靶点。
结论
1、iNOS启动子-1026C／A多态位点所在16-bp片段是基础转录活性的关键调控区,该位点DNA-蛋白质复合物包括YY1、NFI和AP-1,其中YY1和NFI直接结合DNA,而AP-1间接结合DNA；
2、YY1和NFI与-1026C／A位点的结合亲和力存在差异,YY1与-1026C优势结合,NFI与-1026A优势结合；
3、YY1和NFI均抑制iNOS基础启动子转录活性,且YY1的作用明显强于NFI,在细胞因子诱导后,AP-1/YY1对iNOS基因mRNA转录的抑制效应明显强于AP-1/NFI;
4、iNOS基因启动子可能存在多个转录因子反应元件,其中的雌激素反应元件(ERE)可能在雌激素下调iNOS启动子转录活性中起重要作用；
5、-1026C／A多态对iNOS启动子活性的影响在多种细胞系中趋势一致,但其作用效应存在一定的种属特异性；多种刺激因素也没有影响-1026C／A多态对转录调控作用的趋势；
6、乙酰化修饰对iNOS基因转录调控发挥重要作用,特别是丁酸钠对iNOS启动子转录活性的明显抑制作用值得进一步研究。
Functional identification of the-1026C/A polymorphism in the human iNOS promoter
Introduction
Nitric oxide synthases (NOS) include three isoforms, the neuronal type (nNOS), the inducible type (iNOS), and the endothelial type (eNOS). In the normal condition, iNOS does not express or expresses at a very low level, however, a large amount after induction, therefore, the regulation of iNOS expression have impact on the NO production. iNOS gene plays an important role in development of essential hypertension, which may exhibit an anti-hypertensive effect through relaxation of vascular muscle cells by NO, or a pro-hypertensive effect through oxidative stress by excess of the NO derivative peroxynitrite ONOO-.
In the previous study, we have linkage between chromosome 17 microsatellite D17S1878 and hypertension in a hypertension prevalence region. Further case-control population and family-based study demonstrated the association between the-1026C/A variant of the human iNOS promoter and susceptibility to hypertension, and found that the-1026C allele and-1026CC genotype were independent risk factors for hypertension. Moreover, functional investigation of the-1026C/A polymorphism in the human iNOS promoter revealed that-1026C/A altered the Yin Yang 1 (YY1)-binding pattern, and transcriptional activity of the iNOS promoter reporter constructs p1173C/A-luc, resulting in increased risk for hypertension through reduced NO production. However, how YY1 contributs to the iNOS promoter, the function of-1026C/A polymorphism on iNOS transcription, as well as the effect of various hypertension-related factors on iNOS transcriptional activity remained unclear.
Materials and Methods
Materials
1. Cell lines:Human epidermoid cancer cell (Hep2), human gastric carcinoma cell (BGC823), African Green Monkey kidney cell (COS-7), and mouse macrophage cell (RAW264.7);
2. Vector:pGL3-Basic, pRL-TK, pCMV-YY1, pBSU6-YY1, pcDNA3.1-NFIC, pcDNA3.1-NFICDBD, pcDNA3.1-Jun, expression vectors for estrogen, glucocorticoid, and mineralocorticoid receptor, p300w, and p300m;
3. Reagents and kits for Western blot;
4. Reagents and kits for gene cloning and luciferase reporter assay;
5. Reagents and kits for DNA-binding assay, Co-immunoprecipitation (Co-IP), electrophoresis mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP);
6. Reagents and kits for Real-time RT-PCR;
7. Stimuli in cell culture:cytomix (IFN-y, IL-1β, and TNF-a), sodium butyrate, estradiol, dexamethasone, aldosterone, transforming growth factor-β1, insulin-like growth factorⅡ, and insulin.
Methods
1. Construction iNOS promoter luciferase reporters and assay:transcription factors in the iNOS promoter were analyzed using online research program; a series of truncated luciferase reporter constructs were generated and assayed using Dual-Glo luciferase system to identify the key regulatory region of the iNOS gene.
2. DNA-binding assay, co-immunoprecipitaion, EMSA and ChIP were performed to identify the components of DNA-protein complex in the iNOS-1026C/A polymorphism, the interaction between these transcription factors, and their DNA-binding affinity.
3. Cotransfection of expression vectors for transcription factors and steroid hormone receptors, and luciferase reporter assay were performed to detect the effects of estradiol, dexamethasone, aldosterone, transforming growth factor-β1, insulin-like growth factor II, and insulin on regulation of the iNOS transcription.
4. Real-time PCR was used to evaluate the impact of overexpression of YY1, nuclear factor I (NFI), and active protein-1 (AP-1) on cytomix induced iNOS mRNA expression.
5. Stimulation using sodium butyrate, and cotransfection of p300w and p300m expression vectors were conducted to detect the effect of acetylation on iNOS expression.
Results
1. Truncated luciferase reporters assay demonstrated that a 141-bp segment from-1173 bp to-1032 bp in the iNOS promoter was a potential negative regulatory region, and a 16-bp segment from-1032 bp to-1016 bp was a key positive regulatory region for iNOS transcriptional regulation.
2. Transcription factors prediction revealed that besides YY1, two novel transcription factors NFI and AP1 were located in the iNOS promoter locus; DNA-binding assay showed that a protein complex formed by YY1, NFI, and AP-1 existed in-1026C/A, YY1 dominantly bound to-1026C, and NFI dominantly bound to-1026A; co-immunoprecipitation demonstrated an interaction between AP-1 and NFI, a possible interaction between NFI and YY1, but no direct interaction between AP-1 and YY1.
3. EMS A demonstrated a specific binding of NFI to-1026A, and suggested a indirect binding of AP-1 to-1026A; ChIP assay confirmed the binding of YY1 or NFI to iNOS promoter encompassing-1026C/Ain cell culture, wherein the binding affinity of YY1 to-1026C, as well as the binding affinity ofNFI to-1026A were dominant.
4. Transcriptional activity assay of pl173C/A-luc and p1032C/A-luc after overexpression of YY1 and NFI, or YY1 RNA interference showed that YY1 and NFI inhibited iNOS basal promoter activity, and the negative regulatory effects were influenced by the positive regulator AP-1, wherein the inhibitory effect of YY1 was more potent than NFI.
5. Real-time PCR results showed that the cytomix (IFN-y, IL-1(3 and TNF-a) significantly induced the iNOS expression in BGC823 cells, the independent effect of YY1, NFI, and AP-1 on the.iNOS induced-expression was not marked, however, overexpression of AP-1/NF1 or AP1/YY1 potently inhibited iNOS induced-expression, wherein the inhibitory effect of AP-1/YY1 was more dominant than AP-1/NF1.
6. Prediction of transcription factor demonstrated that a TATA box, NF-κB/CEBP、CEBP, Sp1, and several estrogen and glucocorticoid responsive elements existed in the 1.2 kb iNOS promoter.
7. The transcriptional activity of p1173C/A-luc significantly differed among BGC823, Hep2, COS-7, and RAW264.7 cells, however, the influence of-1026C/Aon the promoter activity was the same in different cell lines.
8. Steroid hormones (estradiol, dexamethasone, and aldosterone) treatment and overexpression of their receptors showed that estradiol downregulated p1173A-luc transcriptional activity in a receptor-dependent way, aldosterone and mineralocorticoid receptor had a tendency of p1173A-luc upregulation, whereas dexamethasone and glucocorticoid receptor did not affect the p1 173A-luc transcriptional activity; moreover, these hormones did not influence the transcriptional activity of p1173C-luc.
9. Cell stimulation using deacetylase inhibitor sodium butyrate and overexpression of p300 showed that sodium butyrate markedly reduced the transcriptional activities of p1173C-luc and p1173A-luc, and the inhibition was more significant for p1173A-luc than for p1173C-luc; whereas the transcription activities of p1173C/A-luc did not alter after cotransfection of expression vectors for p300, indicating the sodium butyrate-mediated acetylation may inhibit the iNOS basal promoter activity.
10. Stimulation of Hep2 cells using blood pressure regulators (TGF-β1, IGF II, and insulin) did not significantly alter thep1173C/A-luc transcriptional activity, while the effect of-1026C/A remained marked, suggesting the 1.2 kb human iNOS promoter may not direct target of these blood pressure regulators.
Conclusion
1. The iNOS promoter-1026C/A polymorphism was located in a 16-bp key regulatory region for basal transcriptional activity, wherein existed a protein complex formed by YY1, NFI and AP-1; the DNA-binding of YY1 and NFI was direct, whereas the DNA-binding of AP-1 was indirect.
2. YY1 and NFI bound to-1026C/A with different binding affinity, YY1 dominantly bound to-1026C, and NFI dominantly bound to-1026A.
3. Both YY1 and NFI inhibit iNOS basal promoter activity, and the inhibitory effect of YY1 was more potent than NFI; the AP-1/YY1 inhibited the cytokmix-induced iNOS mRNA expression more markedly than AP-1/NFI.
4. Several transcription factor responsive elements may exist in the promoter, in which the estrogen responsive element (ERE) play a vitol role in downregulation of iNOS transcriptional activity.
5. The regulation tendency of-1026C/Aon iNOS promoter activity was the same among different cell lines, while their impacts exhibited a species-specific maner; a number of stimuli did not influence the regulation tendency of-1026C/A on iNOS transcription.
6. Acetylation modification played an important role in the regulation of iNOS transcription, and the marked sodium butyrate-mediated inhibition of iNOS promoter activity needed further investigation.
引文
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