人类锌指蛋白家族新基因ZNF552的克隆与功能研究
摘要
锌指蛋白家族是最大的转录因子家族之一，它们在细胞增殖、细胞分化、细胞凋亡过程中发挥着重要的作用。研究表明，许多锌指基因的突变或表达异常会导致人类疾病的发生。克隆新的锌指基因及阐明其生物学功能，对于理解人类疾病的发生机理和利用基因治疗技术根治人类遗传疾病具有十分重要的理论和实践意义。
ZNF552是本文作者在利用生物信息学方法筛选人类心脏发育候选基因的过程中发现的一个人类新基因。ZNF552具有三个外显子和两个内含子，并且定位于19号染色体上；其cDNA全长2352个碱基，包括一个长为1224个碱基的开放阅读框(ORF)，编码一个长407个氨基酸残基的蛋白质；该蛋白包含一个KRAB框和七个C2H2型锌指结构域。组织表达分析表明该基因只有一个大约2.4 kb的转录本，在成体中的肝脏、肺、肾、脾以及睾丸组织中表达，其中肺和睾丸组织中表达水平较高。亚细胞定位分析表明ZNF552蛋白主要在细胞核和细胞质中表达；报告基因信号途径分析表明，该蛋白作为一个转录抑制子对AP-1和SRE信号途径起着极强的抑制作用，基因分段研究揭示了该抑制作用通过KRAB框表现出来。RNA干扰实验能够解除ZNF552对AP-1和SRE信号途径的抑制作用。这些结果证明ZNF552是一个锌指蛋白抑制因子。
另外，本人还做了其它两方面的工作。首先是利用酵母双杂交系统筛选基因TRIM45的相互作用蛋白，得到两个候选相互作用蛋白SLC25A3(登录号为NM-005888)和DnaJB6(登录号为NM-005494)，但还需进一步证实其相互作用的真实性。其次，成功克隆了一个人类心脏发育候选基因POPDC2，相关工作正在开展之中。
The zinc finger protein family is one of the largest transcription factor families in the human genome and play important roles in various cellular functions, including cell proliferation, differentiation, and apoptosis. It is demonstrated that, mutations and mal-function of zinc finger genes are frequently targeted for disruption in many human diseases and cancers. The cloning of novel zinc finger genes and the illustration of their biological function is very important for us to understand the mechanism of the human disease and to explore new strategy for genetic disease by applying the gene therapy treatment.
In this study, we report the identification and characterization of a novel C2H2 zinc finger protein, ZNF552, from a human embryonic heart cDNA library. A search of the human genome sequence (NCBI) indicates ZNF552 is composed of three exons and two introns and maps to chromosome 19q13.43. The complete sequence of the ZNF552 cDNA is 2352-bp in length and contains a putative open reading frame(ORF) of 1224 nucleotides, which encodes a putative protein of 407 amino acid protein with an amino-terminal KRAB domain and seven carboxyl-terminal C2H2 zinc finger motifs. Northern blotting analysis indicated that a 2.4-kb transcript specific for ZNF552 was expressed in liver, lung, spleen, testis, kidney, and especially at a higher level in the lung and testis in human adult tissues. ZNF552 protein was located both in the nucleus and cytoplasm when it was overexpressed in cultured cells. Reporter gene assays showed that ZNF552 was a transcriptional repressor, and overexpression of ZNF552 in the HEK 293T cells inhibited the transcriptional activities of AP-1 and SRE. Deletion studies showed that the KRAB domain of ZNF552 may be involved in this inhibition. However, the inhibition of which ZNF552 acted on AP-1 and SRE can be relieved through RNAi analysis. These results clearly indicate that ZNF552 is a member of the zinc finger transcription factor family.
In addition, another two researches have been performed. Firstly, screening for TRIM45 interacting proteins was carried out by using the Matchmaker SystemⅡand two interacting protein candidates, SLC25A3 (NM-005888), and DnaJB6 (NM-005494) were obtained. Further research confirming the reality of interaction between them needs to be done in future. Secondly, POPDC2, a human heart development-related candidate gene was cloned and further studies are in process.
ZNF552是本文作者在利用生物信息学方法筛选人类心脏发育候选基因的过程中发现的一个人类新基因。ZNF552具有三个外显子和两个内含子，并且定位于19号染色体上；其cDNA全长2352个碱基，包括一个长为1224个碱基的开放阅读框(ORF)，编码一个长407个氨基酸残基的蛋白质；该蛋白包含一个KRAB框和七个C2H2型锌指结构域。组织表达分析表明该基因只有一个大约2.4 kb的转录本，在成体中的肝脏、肺、肾、脾以及睾丸组织中表达，其中肺和睾丸组织中表达水平较高。亚细胞定位分析表明ZNF552蛋白主要在细胞核和细胞质中表达；报告基因信号途径分析表明，该蛋白作为一个转录抑制子对AP-1和SRE信号途径起着极强的抑制作用，基因分段研究揭示了该抑制作用通过KRAB框表现出来。RNA干扰实验能够解除ZNF552对AP-1和SRE信号途径的抑制作用。这些结果证明ZNF552是一个锌指蛋白抑制因子。
另外，本人还做了其它两方面的工作。首先是利用酵母双杂交系统筛选基因TRIM45的相互作用蛋白，得到两个候选相互作用蛋白SLC25A3(登录号为NM-005888)和DnaJB6(登录号为NM-005494)，但还需进一步证实其相互作用的真实性。其次，成功克隆了一个人类心脏发育候选基因POPDC2，相关工作正在开展之中。
The zinc finger protein family is one of the largest transcription factor families in the human genome and play important roles in various cellular functions, including cell proliferation, differentiation, and apoptosis. It is demonstrated that, mutations and mal-function of zinc finger genes are frequently targeted for disruption in many human diseases and cancers. The cloning of novel zinc finger genes and the illustration of their biological function is very important for us to understand the mechanism of the human disease and to explore new strategy for genetic disease by applying the gene therapy treatment.
In this study, we report the identification and characterization of a novel C2H2 zinc finger protein, ZNF552, from a human embryonic heart cDNA library. A search of the human genome sequence (NCBI) indicates ZNF552 is composed of three exons and two introns and maps to chromosome 19q13.43. The complete sequence of the ZNF552 cDNA is 2352-bp in length and contains a putative open reading frame(ORF) of 1224 nucleotides, which encodes a putative protein of 407 amino acid protein with an amino-terminal KRAB domain and seven carboxyl-terminal C2H2 zinc finger motifs. Northern blotting analysis indicated that a 2.4-kb transcript specific for ZNF552 was expressed in liver, lung, spleen, testis, kidney, and especially at a higher level in the lung and testis in human adult tissues. ZNF552 protein was located both in the nucleus and cytoplasm when it was overexpressed in cultured cells. Reporter gene assays showed that ZNF552 was a transcriptional repressor, and overexpression of ZNF552 in the HEK 293T cells inhibited the transcriptional activities of AP-1 and SRE. Deletion studies showed that the KRAB domain of ZNF552 may be involved in this inhibition. However, the inhibition of which ZNF552 acted on AP-1 and SRE can be relieved through RNAi analysis. These results clearly indicate that ZNF552 is a member of the zinc finger transcription factor family.
In addition, another two researches have been performed. Firstly, screening for TRIM45 interacting proteins was carried out by using the Matchmaker SystemⅡand two interacting protein candidates, SLC25A3 (NM-005888), and DnaJB6 (NM-005494) were obtained. Further research confirming the reality of interaction between them needs to be done in future. Secondly, POPDC2, a human heart development-related candidate gene was cloned and further studies are in process.
引文
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