人IRF-3基因启动子的克隆与初步鉴定
摘要
目的:
克隆人干扰素调节因子3(Interferon regulatory factor 3,IRF-3)基因启动子并寻找其核心功能区域,鉴定与IRF-3基因启动子结合的转录因子,为阐明其表达调控机制奠定基础。
方法:
以HEK 293细胞基因组DNA为模板,采用PCR方法获取IRF-3基因5’侧翼序列,测序正确后插入pGL3-Basic载体。运用双荧光素酶报告基因检测系统鉴定其启动子活性。采用缺失分析法分别从IRF-3基因5’侧翼的5’端逐段缺失,克隆得到不同长度的截短片段,插入pGL3-Basic载体,使用双荧光素酶检测系统定位IRF-3基因启动子核心功能区域,鉴定其启动子活性。利用点突变技术、凝胶迁移实验(EMSA)、染色质免疫沉淀(ChIP)、RNA干扰和基因过表达等实验,分析IRF-3启动子区的转录因子结合位点。
结果:
克隆到的IRF-3基因5’侧翼序列与Genbank中记录完全一致,荧光素酶活性分析结果显示其在HEK 293细胞中具有明显的启动子活性。自5’端缺失的截短片段其活性表现为先升高后降低,-149～+18 bp截短片段表现出接近最高的启动子活性,而-93～+18 bp截短片段的活性基本消失,提示IRF-3的核心启动子区域位于-149～-93 bp之间。生物信息学预测该区域包含了Sp1/3、E2F、CEBP-α和GATA-1等结合位点,点突变结果表明Sp1/3和E2F位点维持了IRF-3的基本转录活性。EMSA和ChIP实验结果表明Sp1、Sp3和E2F1转录因子与IRF-3的启动子区有结合。RNA干扰和基因过表达实验表明Sp1和Sp3增强了IRF-3的启动子活性,E2F1抑制了IRF-3的启动子活性。
结论:
人IRF-3基因的核心启动子区域位于转录起始位点上游-149至-93 bp处,在核心启动子调控方面,Sp1、Sp3和E2F1起关键调控作用,Sp1和Sp3正调控,E2F1负调控。
Objective To clone IRF-3 gene promoter and identify its core promoter region.
Methods Approximately 1 kb of the 5' flanking sequence of IRF-3 was cloned from the genomic DNA of HEK 293 cells.After sequencing, the 5'flanking sequence was directly subcloned into pGL3-Basic vector and then the dual-luciferase reporter assay system was employed to identify its transcriptional activity in HEK 293 cells.In the deletion analysis of IRF-3 promoter, we prepared 5' truncations of 1 kb fragments and identified the core promoter essential for transcriptional activation.With point mutations, electrophoresis mobility shift assay (EMSA), chromatin immune precipitation (ChIP), small RNA interference and overexpression, we identified the location and features of the core promoter and its upstream regulatory region of IRF-3.
Results In this study, the 5'flanking sequence of IRF-3 is consistent with the record in Genbank.In HEK 293 cells,the IRF-3 promoter exhibited high transcriptional activities.The transcriptional activity increased first and then decreased with 5' truncations.In HEK 293,-149 to -93 bp truncated fragment exhibited the maximal transcriptional activity.Sp1/3 and E2F sites were essential for maintaining the basal transcriptional activity of the human IRF-3 promoter. EMSA and ChIP assays demonstrate the occupancy of the IRF-3 promoter by Sp1、Sp3 and E2F1 in vitro or in vivo. Overexpression of Sp1 or Sp3 transactivated the human IRF-3 promoter, whereas small interfering RNA-mediated blockage of Sp1 or Sp3 gene expression inhibited markedly its activity. Overexpression of E2F1 protein reduced the transcription activity, while small interfering RNA-mediated blockage of E2F1 gene expression upregulated markedly its activity.
Conclusion The -149 to -93 bp region in IRF-3 promoter was the core promoter region.Sp1、Sp3 and E2F1 played a critical role in regulating basal IRF-3 promoter activity in HEK 293 cells.
克隆人干扰素调节因子3(Interferon regulatory factor 3,IRF-3)基因启动子并寻找其核心功能区域,鉴定与IRF-3基因启动子结合的转录因子,为阐明其表达调控机制奠定基础。
方法:
以HEK 293细胞基因组DNA为模板,采用PCR方法获取IRF-3基因5’侧翼序列,测序正确后插入pGL3-Basic载体。运用双荧光素酶报告基因检测系统鉴定其启动子活性。采用缺失分析法分别从IRF-3基因5’侧翼的5’端逐段缺失,克隆得到不同长度的截短片段,插入pGL3-Basic载体,使用双荧光素酶检测系统定位IRF-3基因启动子核心功能区域,鉴定其启动子活性。利用点突变技术、凝胶迁移实验(EMSA)、染色质免疫沉淀(ChIP)、RNA干扰和基因过表达等实验,分析IRF-3启动子区的转录因子结合位点。
结果:
克隆到的IRF-3基因5’侧翼序列与Genbank中记录完全一致,荧光素酶活性分析结果显示其在HEK 293细胞中具有明显的启动子活性。自5’端缺失的截短片段其活性表现为先升高后降低,-149～+18 bp截短片段表现出接近最高的启动子活性,而-93～+18 bp截短片段的活性基本消失,提示IRF-3的核心启动子区域位于-149～-93 bp之间。生物信息学预测该区域包含了Sp1/3、E2F、CEBP-α和GATA-1等结合位点,点突变结果表明Sp1/3和E2F位点维持了IRF-3的基本转录活性。EMSA和ChIP实验结果表明Sp1、Sp3和E2F1转录因子与IRF-3的启动子区有结合。RNA干扰和基因过表达实验表明Sp1和Sp3增强了IRF-3的启动子活性,E2F1抑制了IRF-3的启动子活性。
结论:
人IRF-3基因的核心启动子区域位于转录起始位点上游-149至-93 bp处,在核心启动子调控方面,Sp1、Sp3和E2F1起关键调控作用,Sp1和Sp3正调控,E2F1负调控。
Objective To clone IRF-3 gene promoter and identify its core promoter region.
Methods Approximately 1 kb of the 5' flanking sequence of IRF-3 was cloned from the genomic DNA of HEK 293 cells.After sequencing, the 5'flanking sequence was directly subcloned into pGL3-Basic vector and then the dual-luciferase reporter assay system was employed to identify its transcriptional activity in HEK 293 cells.In the deletion analysis of IRF-3 promoter, we prepared 5' truncations of 1 kb fragments and identified the core promoter essential for transcriptional activation.With point mutations, electrophoresis mobility shift assay (EMSA), chromatin immune precipitation (ChIP), small RNA interference and overexpression, we identified the location and features of the core promoter and its upstream regulatory region of IRF-3.
Results In this study, the 5'flanking sequence of IRF-3 is consistent with the record in Genbank.In HEK 293 cells,the IRF-3 promoter exhibited high transcriptional activities.The transcriptional activity increased first and then decreased with 5' truncations.In HEK 293,-149 to -93 bp truncated fragment exhibited the maximal transcriptional activity.Sp1/3 and E2F sites were essential for maintaining the basal transcriptional activity of the human IRF-3 promoter. EMSA and ChIP assays demonstrate the occupancy of the IRF-3 promoter by Sp1、Sp3 and E2F1 in vitro or in vivo. Overexpression of Sp1 or Sp3 transactivated the human IRF-3 promoter, whereas small interfering RNA-mediated blockage of Sp1 or Sp3 gene expression inhibited markedly its activity. Overexpression of E2F1 protein reduced the transcription activity, while small interfering RNA-mediated blockage of E2F1 gene expression upregulated markedly its activity.
Conclusion The -149 to -93 bp region in IRF-3 promoter was the core promoter region.Sp1、Sp3 and E2F1 played a critical role in regulating basal IRF-3 promoter activity in HEK 293 cells.
引文
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