B细胞淋巴瘤内miR-17-92基因转录调控机制研究
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摘要
MicroRNA (miRNAs)是一类由内源基因编码的长度约为22个核苷酸的非编码单链RNA分子,其在动植物体内对调控某些基因的表达具有重要作用。近期,miRNAs被发现存在于细菌,绿藻类,病毒及广泛的动物体中。其通过对信使RNA的调控使其降解或者抑制其转录使得miRNAs在真核生物基因转录调节中具有重要作用。miRNAs的重要功能还包括调控细胞增值,细胞凋亡,调控发育时间,分化及胚胎发生。
越来越多证据表明,miRNAs与癌症中有着重要的关系,它既可以是癌基因又可以是抑癌基因,并且在特定的情况下具有双重的角色。目前,在HomoSapiens中已有677个miRNAs被发现,并且越来越多的科学研究关注于miRNAs的基因调控功能。
miR—17-92基因簇位于C13orf25基因的第一个内含子中,因含此基因的染色体在恶性淋巴瘤中扩增而被首次描述。miR—17-92基因簇可产生有六个不同的成熟miRNA:miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a。miR—17～92基因簇具有癌基因的功能。具体表现在,抑制癌细胞的细胞凋亡,促进细胞增殖,促使肿瘤血管生成。人类miR—17-92基因簇位于C13orf25基因的第三个内含子的中,它通常过表达于不同类型的B细胞淋巴瘤中,包括Burkitt淋巴瘤,弥漫性大壁淋巴瘤,滤泡性淋巴瘤,套细胞淋巴瘤,也过表达于其它实体肿瘤中,例如肺癌,胰腺癌,前列腺癌,乳房癌,胃癌,结肠癌。
虽然对miR—17Y92基因簇的基因调控功能了解到越来越多,但是对于miR-17～92簇基因本身的转录调控机制知之甚少。近期研究仅仅发现其可被转录因子c-Myc和E2F激活。因此,本论文对miR—17～92基因簇的转录调控机制进行了研究。
通过荧光素酶检测试验,本研究鉴定了此基因的核心启动子区域。通过对基因启动子的删除和突变研究发现,此启动子被多个转录因子所共同调控,每个单独的转录因子对启动子有适度的调控作用。本研究发现,对转录因子SP1的假定结合点进行突变后,减少了70%的启动子活性。已知c-Myc可以诱导此基因的的转录,我们发现在启动子区将c-Myc的结合位点突变后,启动子的活性非但没有减弱,反而被增强。通过进一步研究证实发现,具有转录抑制活性的MYC家族转录因子Mxi1直接结合在启动子区域。为了进一步了解启动子附近区域对基因转录调节的影响,本文对包含此基因22.5kb的区域进行了研究。试验证明,此基因具有DNaseⅠ超敏感区域和组蛋白修饰活跃区,预示了其具有增强子元件。通过研究,本文证实了在启动子附近至少两个区域具有增强子活性。
在一些肿瘤中C13orf25基因是一个重要的癌基因,其转录产物microRNA所调控的基因对细胞增殖以及存活有重要的调控作用,因此,需要对miR-17Y92的转录水平调控进行进一步的研究。
MicroRNAs (miRNAs) are endogenous-22 nucleotide (nt) non-conding RNAs that regulate gene expression in plants and animals. Rencently, miRNAs have been found in bacteria, green algae, viruses and more deep branching animals. They play an important gene-regulatory roles in eukaryotic organisms by pairing to the mRNAs of protein-coding genes inducing mRNA degradation or translational inhibition. The important functions of miRNAs include regulation of cell proliferation, apoptosis, control of developmental timing, organogensis and differentiation, embryogenesis. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. Recent studies show that some miRNAs play a role in cancer.
More and more evidence indicates that miRNAs plays an important role in cancer and they can either act as oncogenes or tumor suppressors but also can act both depending on certain situation. Now more and more studies are focus on the importance of regulation by miRNAs and 677 miRNAs are found in Homo Sapiens by now.
The miR-17～92 cluster locate in the first intron of the gene C13orf25 which was first described as target for chromosomal amplification in malignant lymphoma. The miR-17～92 cluster produces a single polycistronic primary transcript that yields six miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) locating within the third intron of the open reading frame 13 over 800 nt on 13q31.3The miR-17～92 cluster and its paralogs are known to act as oncogenes. The oncogenic role of these miRNAs includes suppressing apoptosis of cancer cells, promoting cell proliferation and inducing tumor angiogenesis. The human miR-17～92 cluster is located in the third intron of the primary transcript C13orf25. It is amplified and overexpressed in different types of B-cell lymphoma, including Burkitt lyphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and other solid tumors such as those derived from lung, pancreas, prostate, breast, stomach, and colon.
The transcriptional regulation of the miR-17～92 cluster is poorly understood. Recent studies only have shown that C13orf25 is activated by c-Myc and E2F transcription factors. Thus, the thesis is focous on the transcriptional regulation of the miR-17-92 cluster.
Using luciferase reporter assays, we identified the region required for full promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually has only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. c-Myc is known to regulate the gene; surprisingly, mutation of a putative promoter Myc binding site enhanced promoter activity. We found that the inhibitory MYC family member Mxi1 bound to this region. To determine whether more distal regions also contribute to transcriptional regulation, we mapped the chromatin structure of a>22.5 kb region encompassing the gene. We found DNase hypersensivity and peaks of activating histone marks within the gene, suggesting the presence of enhancers, and confirmed that at least two regions have enhancer activity. Because C13orf25 acts as an important oncogene in several cancers and its product microRNAs target genes important in regulating cell proliferation and survival, further studies of its transcriptional control are warranted.
越来越多证据表明,miRNAs与癌症中有着重要的关系,它既可以是癌基因又可以是抑癌基因,并且在特定的情况下具有双重的角色。目前,在HomoSapiens中已有677个miRNAs被发现,并且越来越多的科学研究关注于miRNAs的基因调控功能。
miR—17-92基因簇位于C13orf25基因的第一个内含子中,因含此基因的染色体在恶性淋巴瘤中扩增而被首次描述。miR—17-92基因簇可产生有六个不同的成熟miRNA:miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a。miR—17～92基因簇具有癌基因的功能。具体表现在,抑制癌细胞的细胞凋亡,促进细胞增殖,促使肿瘤血管生成。人类miR—17-92基因簇位于C13orf25基因的第三个内含子的中,它通常过表达于不同类型的B细胞淋巴瘤中,包括Burkitt淋巴瘤,弥漫性大壁淋巴瘤,滤泡性淋巴瘤,套细胞淋巴瘤,也过表达于其它实体肿瘤中,例如肺癌,胰腺癌,前列腺癌,乳房癌,胃癌,结肠癌。
虽然对miR—17Y92基因簇的基因调控功能了解到越来越多,但是对于miR-17～92簇基因本身的转录调控机制知之甚少。近期研究仅仅发现其可被转录因子c-Myc和E2F激活。因此,本论文对miR—17～92基因簇的转录调控机制进行了研究。
通过荧光素酶检测试验,本研究鉴定了此基因的核心启动子区域。通过对基因启动子的删除和突变研究发现,此启动子被多个转录因子所共同调控,每个单独的转录因子对启动子有适度的调控作用。本研究发现,对转录因子SP1的假定结合点进行突变后,减少了70%的启动子活性。已知c-Myc可以诱导此基因的的转录,我们发现在启动子区将c-Myc的结合位点突变后,启动子的活性非但没有减弱,反而被增强。通过进一步研究证实发现,具有转录抑制活性的MYC家族转录因子Mxi1直接结合在启动子区域。为了进一步了解启动子附近区域对基因转录调节的影响,本文对包含此基因22.5kb的区域进行了研究。试验证明,此基因具有DNaseⅠ超敏感区域和组蛋白修饰活跃区,预示了其具有增强子元件。通过研究,本文证实了在启动子附近至少两个区域具有增强子活性。
在一些肿瘤中C13orf25基因是一个重要的癌基因,其转录产物microRNA所调控的基因对细胞增殖以及存活有重要的调控作用,因此,需要对miR-17Y92的转录水平调控进行进一步的研究。
MicroRNAs (miRNAs) are endogenous-22 nucleotide (nt) non-conding RNAs that regulate gene expression in plants and animals. Rencently, miRNAs have been found in bacteria, green algae, viruses and more deep branching animals. They play an important gene-regulatory roles in eukaryotic organisms by pairing to the mRNAs of protein-coding genes inducing mRNA degradation or translational inhibition. The important functions of miRNAs include regulation of cell proliferation, apoptosis, control of developmental timing, organogensis and differentiation, embryogenesis. miRNAs have diverse functions, including the regulation of cellular differentiation, proliferation and apoptosis. Recent studies show that some miRNAs play a role in cancer.
More and more evidence indicates that miRNAs plays an important role in cancer and they can either act as oncogenes or tumor suppressors but also can act both depending on certain situation. Now more and more studies are focus on the importance of regulation by miRNAs and 677 miRNAs are found in Homo Sapiens by now.
The miR-17～92 cluster locate in the first intron of the gene C13orf25 which was first described as target for chromosomal amplification in malignant lymphoma. The miR-17～92 cluster produces a single polycistronic primary transcript that yields six miRNAs (miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a) locating within the third intron of the open reading frame 13 over 800 nt on 13q31.3The miR-17～92 cluster and its paralogs are known to act as oncogenes. The oncogenic role of these miRNAs includes suppressing apoptosis of cancer cells, promoting cell proliferation and inducing tumor angiogenesis. The human miR-17～92 cluster is located in the third intron of the primary transcript C13orf25. It is amplified and overexpressed in different types of B-cell lymphoma, including Burkitt lyphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and other solid tumors such as those derived from lung, pancreas, prostate, breast, stomach, and colon.
The transcriptional regulation of the miR-17～92 cluster is poorly understood. Recent studies only have shown that C13orf25 is activated by c-Myc and E2F transcription factors. Thus, the thesis is focous on the transcriptional regulation of the miR-17-92 cluster.
Using luciferase reporter assays, we identified the region required for full promoter activity. Additional deletions and mutations indicated that the promoter is regulated by the collaborative activity of several transcription factors, most of which individually has only a moderate effect; mutation of a cluster of putative SP1-binding sites, however, reduces promoter activity by 70%. c-Myc is known to regulate the gene; surprisingly, mutation of a putative promoter Myc binding site enhanced promoter activity. We found that the inhibitory MYC family member Mxi1 bound to this region. To determine whether more distal regions also contribute to transcriptional regulation, we mapped the chromatin structure of a>22.5 kb region encompassing the gene. We found DNase hypersensivity and peaks of activating histone marks within the gene, suggesting the presence of enhancers, and confirmed that at least two regions have enhancer activity. Because C13orf25 acts as an important oncogene in several cancers and its product microRNAs target genes important in regulating cell proliferation and survival, further studies of its transcriptional control are warranted.
引文
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