可逆性组蛋白乙酰化修饰在人WT1基因转录调控中的作用及其分子机制研究
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摘要
组蛋白的翻译后修饰所引起的染色质结构的重塑在真核生物基因表达调控中发挥着重要的作用。其中研究得最深入的是由组蛋白乙酰转移酶(HATs)和组蛋白去乙酰化酶(HDACs)催化的乙酰化反应。这两种酶通过对核心组蛋白尾部赖氨酸残基进行可逆的乙酰化修饰来调控转录的起始,并由此介导基因的激活或抑制。转录辅激活子p300/CBP 和 P/CAF 是具有组蛋白乙酰转移酶活性的蛋白,能通过多种机制参与许多基因的转录调控过程。
WT1 基因编码一种锌指结构的蛋白 WT1。WT1 蛋白在调控生长和分化方面起重要作用,主要参与肾和生殖腺的发育过程,另外在造血系统的早期发育过程中也起作用。WT1基因的改变除了能引起维耳姆斯氏瘤(Wilms’tumor)之外,还与几种发育异常综合征和白血病、间皮瘤、生殖腺肿瘤等其它肿瘤有关。因此,阐明 WT1 基因的转录调控机制不仅对胚胎发育的研究有意义,而且将为治疗 WT1 相关疾病奠定理论基础。
本论文旨在确定可逆的组蛋白乙酰化修饰是否参与WT1基因的转录调控,并试图探讨其分子机制。通过一系列瞬时转染和相对荧光素酶活性分析以及RT-PCR实验,我们发现组蛋白乙酰转移酶p300/CBP不仅能促进WT1启动子和内部增强子的活性,而且能提高内源WT1 mRNA的表达水平。E1A蛋白能抑制p300对WT1报告基因转录激活的促进作用,而其突变体E1A delta 2-36因不能与p300/CBP结合而没有这种作用,这也间接地证明了p300/CBP能促进WT1基因的表达。我们的结果还表明p300/CBP可分别与转录因子Sp1、c-Myb和Ets-1协同地促进WT1报告基因的转录活性。通过WT1内部增强子克隆方向不同的质粒,我们证明p300/CBP促进WT1报告基因的转录激活不受内部增强子方向的影响。此外,通过采用HAT区缺失突变的p300表达质粒的转染实验,我们证明了p300/CBP的组蛋白乙酰转移酶活性在WT1基因转录调控过程中发挥重要作用。通过染色质免疫沉淀实验(ChIP),我们发现p300/CBP能够提高WT1内部增强子处组蛋白H3的乙酰化水平。另外,我们的结果表明另一种组蛋白乙酰转移酶P/CAF不仅能促进WT1报告基因的表达,而且在此过程中与p300/CBP具有协同作用。在它们协同地促进WT1报告基因表达的过程中,p300/CBP和P/CAF的HAT活性都非常重要。另一方面,我们验证了六种人组蛋白去乙酰化酶(HDAC1-6)对WT1报告基因表达水平的影响。结果表明,HDAC4和HDAC5不仅能抑制WT1报告基因的活性,而且能下调内源WT1 mRNA的表达水平。在瞬时转染和报告基因活性分析中,HDAC4和HDAC5能抑制p300对WT1报告基因转录激活的促进作用。
本论文的结果首次揭示了组蛋白可逆的乙酰化修饰参与WT1基因的转录调控,并对其分子机制进行了初步的探讨,为深入研究WT1基因转录调控机制和WT1相关疾病的研究奠定了基础。
The remodeling of the chromatin structure mediated by histone posttranslationalmodifications plays a crucial role in the expression regulation of eukaryotic genes. Among thehistone posttranslational modifications, the histone acetylation catalyzed by histoneacetyltransferases (HATs) and histone deacetylases (HDACs) plays a critical role in generegulation and hence has been intensively studied. The reversible acetylation/deacetylationmodification of lysine residues in core histone tails mediated by these two enzymes modulatesthe initiation of transcription, thus leads to the activation/suppression of gene expression.Transcriptional coactivators p300/CBP and P/CAF, which possess histone acetyltransferaseactivities, are involved in transcriptional regulation of many genes by distinct mechanisms.
WT1 gene encodes a zinc finger protein, which plays an important role in the regulationof growth and differentiation. WT1 proteins are mainly involved in the development ofkidney and gonad. Moreover, WT1 proteins are associated with the early development ofhematopoietic system. Apart from Wilms’ tumor, alterations of WT1 gene have been shown tobe associated with several developmental abnormality syndromes and other tumors such asleukemias, mesotheliomas, gonadoblastoma, etc. Therefore, the elucidation of themechanisms of WT1 transcriptional regulation will be helpful not only in studies ofembryonic development, but also in the establishing theoretical bases for the cure of WT1-associated diseases.
The aim of this study was to clarify whether the reversible histoneacetylation/deacetylation modification participates in the regulation of WT1 gene transcriptionand to explore its molecular mechanisms. By applying a series of transient transfection andrelative luciferase activity assays, as well as semiquantitative RT-PCR, we found that histoneacetyltransferases p300/CBP not only promoted the activities of the WT1 promoter andintronic enhancer, but also increased the expression of endogenous WT1 mRNA. E1A proteinrepressed the promotion of WT1 transcription by p300, while the p300/CBP-binding defectiveE1A delta 2-36 did not. This result further confirmed the effects of p300/CBP in promotingthe WT1 gene expression. Our results also indicated that p300/CBP and transcription factorsSp1, c-Myb, and Ets-1 synergistically activated WT1 reporter gene transcription. By using theplasmids with opposite orientations of insertion of the WT1 intronic enhancer, p300/CBP wasshown to be able to activate WT1 reporter gene transcription independent the orientation ofWT1 intronic enhancer. In addition, by using the HAT domain-deleted p300 mutant, weshowed that the histone acetyltransferase activity of p300/CBP was important in regulation ofWT1 gene expression. With the chromatin immunoprecipitation assay (ChIP), we found thatp300/CBP enhanced the acetylation of the histone H3 at the WT1 intronic enhancer.
Furthermore, our results showed that another histone acetyltransferase P/CAF could alsoactivate WT1 reporter gene expression and this process required the synergism betweenP/CAF and p300/CBP. The histone acetyltransferase activities of P/CAF and p300/CBP wereboth important in the activation of WT1 reporter gene expression. With regard to histonedeacetylases, we tested the influences of six human histone deacetylases (HDAC1-6) on WT1gene expression. The results showed that HDAC4 and HDAC5 were able to not only repressthe activity of the WT1 promoter/intronic enhancer/luciferase reporter gene, but alsodecreased the expression of endogenous WT1 mRNA. By transient transfection and reportergene assay, we demonstrated that HDAC4 and HDAC5 repressed the promotion of WT1reporter gene transcription by p300. Data presented in this thesis demonstrated, for the first time, that the reversible histoneacetylation/deacetylation modification was involved in the transcriptional regulation of WT1gene. The molecular mechanisms of histone acetylation in WT1 gene regulation were brieflyexploited. This study provides further insight into the mechanisms of transcriptional
WT1 基因编码一种锌指结构的蛋白 WT1。WT1 蛋白在调控生长和分化方面起重要作用,主要参与肾和生殖腺的发育过程,另外在造血系统的早期发育过程中也起作用。WT1基因的改变除了能引起维耳姆斯氏瘤(Wilms’tumor)之外,还与几种发育异常综合征和白血病、间皮瘤、生殖腺肿瘤等其它肿瘤有关。因此,阐明 WT1 基因的转录调控机制不仅对胚胎发育的研究有意义,而且将为治疗 WT1 相关疾病奠定理论基础。
本论文旨在确定可逆的组蛋白乙酰化修饰是否参与WT1基因的转录调控,并试图探讨其分子机制。通过一系列瞬时转染和相对荧光素酶活性分析以及RT-PCR实验,我们发现组蛋白乙酰转移酶p300/CBP不仅能促进WT1启动子和内部增强子的活性,而且能提高内源WT1 mRNA的表达水平。E1A蛋白能抑制p300对WT1报告基因转录激活的促进作用,而其突变体E1A delta 2-36因不能与p300/CBP结合而没有这种作用,这也间接地证明了p300/CBP能促进WT1基因的表达。我们的结果还表明p300/CBP可分别与转录因子Sp1、c-Myb和Ets-1协同地促进WT1报告基因的转录活性。通过WT1内部增强子克隆方向不同的质粒,我们证明p300/CBP促进WT1报告基因的转录激活不受内部增强子方向的影响。此外,通过采用HAT区缺失突变的p300表达质粒的转染实验,我们证明了p300/CBP的组蛋白乙酰转移酶活性在WT1基因转录调控过程中发挥重要作用。通过染色质免疫沉淀实验(ChIP),我们发现p300/CBP能够提高WT1内部增强子处组蛋白H3的乙酰化水平。另外,我们的结果表明另一种组蛋白乙酰转移酶P/CAF不仅能促进WT1报告基因的表达,而且在此过程中与p300/CBP具有协同作用。在它们协同地促进WT1报告基因表达的过程中,p300/CBP和P/CAF的HAT活性都非常重要。另一方面,我们验证了六种人组蛋白去乙酰化酶(HDAC1-6)对WT1报告基因表达水平的影响。结果表明,HDAC4和HDAC5不仅能抑制WT1报告基因的活性,而且能下调内源WT1 mRNA的表达水平。在瞬时转染和报告基因活性分析中,HDAC4和HDAC5能抑制p300对WT1报告基因转录激活的促进作用。
本论文的结果首次揭示了组蛋白可逆的乙酰化修饰参与WT1基因的转录调控,并对其分子机制进行了初步的探讨,为深入研究WT1基因转录调控机制和WT1相关疾病的研究奠定了基础。
The remodeling of the chromatin structure mediated by histone posttranslationalmodifications plays a crucial role in the expression regulation of eukaryotic genes. Among thehistone posttranslational modifications, the histone acetylation catalyzed by histoneacetyltransferases (HATs) and histone deacetylases (HDACs) plays a critical role in generegulation and hence has been intensively studied. The reversible acetylation/deacetylationmodification of lysine residues in core histone tails mediated by these two enzymes modulatesthe initiation of transcription, thus leads to the activation/suppression of gene expression.Transcriptional coactivators p300/CBP and P/CAF, which possess histone acetyltransferaseactivities, are involved in transcriptional regulation of many genes by distinct mechanisms.
WT1 gene encodes a zinc finger protein, which plays an important role in the regulationof growth and differentiation. WT1 proteins are mainly involved in the development ofkidney and gonad. Moreover, WT1 proteins are associated with the early development ofhematopoietic system. Apart from Wilms’ tumor, alterations of WT1 gene have been shown tobe associated with several developmental abnormality syndromes and other tumors such asleukemias, mesotheliomas, gonadoblastoma, etc. Therefore, the elucidation of themechanisms of WT1 transcriptional regulation will be helpful not only in studies ofembryonic development, but also in the establishing theoretical bases for the cure of WT1-associated diseases.
The aim of this study was to clarify whether the reversible histoneacetylation/deacetylation modification participates in the regulation of WT1 gene transcriptionand to explore its molecular mechanisms. By applying a series of transient transfection andrelative luciferase activity assays, as well as semiquantitative RT-PCR, we found that histoneacetyltransferases p300/CBP not only promoted the activities of the WT1 promoter andintronic enhancer, but also increased the expression of endogenous WT1 mRNA. E1A proteinrepressed the promotion of WT1 transcription by p300, while the p300/CBP-binding defectiveE1A delta 2-36 did not. This result further confirmed the effects of p300/CBP in promotingthe WT1 gene expression. Our results also indicated that p300/CBP and transcription factorsSp1, c-Myb, and Ets-1 synergistically activated WT1 reporter gene transcription. By using theplasmids with opposite orientations of insertion of the WT1 intronic enhancer, p300/CBP wasshown to be able to activate WT1 reporter gene transcription independent the orientation ofWT1 intronic enhancer. In addition, by using the HAT domain-deleted p300 mutant, weshowed that the histone acetyltransferase activity of p300/CBP was important in regulation ofWT1 gene expression. With the chromatin immunoprecipitation assay (ChIP), we found thatp300/CBP enhanced the acetylation of the histone H3 at the WT1 intronic enhancer.
Furthermore, our results showed that another histone acetyltransferase P/CAF could alsoactivate WT1 reporter gene expression and this process required the synergism betweenP/CAF and p300/CBP. The histone acetyltransferase activities of P/CAF and p300/CBP wereboth important in the activation of WT1 reporter gene expression. With regard to histonedeacetylases, we tested the influences of six human histone deacetylases (HDAC1-6) on WT1gene expression. The results showed that HDAC4 and HDAC5 were able to not only repressthe activity of the WT1 promoter/intronic enhancer/luciferase reporter gene, but alsodecreased the expression of endogenous WT1 mRNA. By transient transfection and reportergene assay, we demonstrated that HDAC4 and HDAC5 repressed the promotion of WT1reporter gene transcription by p300. Data presented in this thesis demonstrated, for the first time, that the reversible histoneacetylation/deacetylation modification was involved in the transcriptional regulation of WT1gene. The molecular mechanisms of histone acetylation in WT1 gene regulation were brieflyexploited. This study provides further insight into the mechanisms of transcriptional
引文
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