人Elongator复合物及其组蛋白乙酰转移酶活性在基因表达调控中的功能研究
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摘要
真核生物DNA紧密包装成染色质结构，影响了包括转录、复制和修复等在内的以DNA为模板的每一个生物过程。其mRNA的合成是个多步骤的复杂过程，由控制该过程的多个辅因子协助RNAPⅡ完成。一个完整的转录循环包括RANPⅡ和通用转录因子被招募至启动子、RAN链合成的起始和RANPⅡ从启动子的脱逸、RNA链的延伸以及伴随RANPⅡ和新生RNA链从DNA模板释放的转录终止等过程。当RNAPⅡ离开基因的启动子转录编码区时，遇到包括核小体在内的多种障碍。近来研究表明组蛋白尾部尤其是H3、H4四聚体的尾部强烈影响通过核小体的转录延伸速率，而尾部的乙酰化修饰可抑制这种影响。延伸中的RNAPⅡ的辅因子可能具有这种作用。与磷酸化的RNAPⅡ结合的Elongator复合物具有组蛋白乙酰转移酶(HAT)活性，它可能执行这一功能。
酵母Elongator是与染色质组分结合，并与延伸中的磷酸化形式的RNAPⅡ相互作用的复合物，是个六亚基的功能整体，在高盐处理或MonoQ层析时易于分解为两个三亚基亚复合物，其中一个是含Elp3的核心复合物，另一个含Elp4／5／6亚基。缺失yELP3(或其它yELP)可导致一系列表型，有的与转录延伸缺陷有关。Elp3具有HAT活性，该活性为复合物行使功能所必需。使Elp3的HAT活性严重丧失的点突变可引起所有elp表型。完整的复合物可直接修饰组蛋白H3和H4尾部，其优先乙酰化位点是H3 K14和H4 K8。复合物的HAT活性需要Elp4／5／6的存在，它们只与核心复合物相互作用(不与RNAPⅡ作用)，可能对核心复合物的HAT活性具调控作用。
近来人Elongator也被分离，它也是个不稳定的六亚基复合物，可与RNAPⅡ相互作用，具有HAT活性，能乙酰化H3和H4，在HeLa细胞核抽提物中去除Elongator可降低抽提物对染色质模板的转录延伸速率，提供了该复合物在染色质为模板的转录延伸中有功能的生化证据，但是上面的信息都来自体外研究。尚未见对人Elongator复合物及其亚基功能的体内研究的报道。
本文以酿酒酵母为实验材料，利用其易于进行遗传操作的优点，
对人Elongator的功能特点进行体内研究。证明了人与酵母的Elp3在
功能上是保守的，初步确定了hElp3及其拥有的HAT活性在复合物中
的功能地位，了解了复合物HAT活性在基因表达调控中的作用方式。
得到的主要结果和结论如下:
1、建立了以酵母为材料对人Elongator复合物作用特点进行分析的功
能互补和基因表达分析的实验体系
2、利用上述体系证实J送洗P3、.叻凡P3和力凡P3分别可以完全、显著、
部分补偿妊弘P3缺失引起的生长缺陷，并分别能够在诱导条件下完
全、显著、部分恢复.此艺P3缺失引起的月敬万和汉5刀3基因表达延迟
的缺陷。HAT区催化结构域缺失的动凡尸夯别拜口力云艺尸狱刹厂没有上
述功能。表明人与酵母的凡P3在功能上是保守的，力凡P3的HAT区
可以替代夕凡P3的HAT区，hEIP3的HAT活性为其行使功能所必需。
3、利用功能互补和RT一PCR证明力几P4可部分补偿不必艺用缺失引起的生
长缺陷，并能在一定程度上恢复其产y左又夕掀.55刀3表达延迟的缺陷，
表明与yElp4相似，hElp4所在的较小亚复合物可能对核心复合物
的HAT活性行使调控功能。
4、利用点突变和Plasmid Shuffle等技术构建了含H3 K14一R、H4 KS
~R单突变和H3 K14一侧H4 KS一R双突变的e1P3乙菌株，通过功
能互补实验分析少凡P3对突变株的补偿功能，证实酵母Elongator
可对H3 14K/H4 SK进行乙酞化修饰。同时以转入_汪艺P3为参照确
立了研究hElp3的HAT活性作用方式的体内检测体系。
5、通过对力几P3相关质粒转入含H3/H4K一R突变的e幼3乙菌株的功
能互补实验，发现在供试条件下组蛋白突变均使少艺艺P3、，动乙艺P3和
力凡P3补偿能力下降。在H3 K14一侧H4 KS~R双突变的e助3』菌
株中，三个基因的补偿功能都近乎丧失，表明在体内组蛋白(H3 K14、
H4KS)是hElp3及其所在的Elongator复合物的重要靶位点，同时
表明人Elongat叮复合物与转录相关的染色质的修饰和改构
(remondeling)有关。
6、在对H3/H4K~R突变株的功能互补实验中，我们发现H3 K14一R
舰4 KS一R双突变使e助了乙菌株产生更为严重的缺陷表型，表明细
胞内其它乙酞转移酶与EIP3在功能上有重叠，同时也表明体内维持
一定的乙酞化水平对细胞正常生长或迅速适应条件变化非常重要。
7、H4 KS一R对I功五艺P3、力几P3与少凡P3功能的影响大于H3 K14一R，
表明体内组蛋白不同位点的乙酞化修饰对基因表达有不同的影响。
人与酵母的Elp3对组蛋白H4 KS的乙酞化修饰可能有比H3 K14更
重要的作用。
The packaging of eukaryotic DNA into chromatin influences various processes that utilize DNA as a template, including transcription, replication and repair. Eukaryotic messenger RNAs are synthesized by the multisubunit enzyme RNA polymerase II, aided by myriad cofactors that control different events in this multistep process. A complete round of transcription involves the recruitment of polymerase and general transcription factors to the promoter, RNA chain synthesis initiation and polymerase escape form the promoter, RNA chain elongation, and finally termination with relaease of polymerase and nascent transcript from the DNA template. As RNA polymerase II leaves a gene promotor to transcribe the coding region, it faces many obstacles, including nucleosomes. Recent data have demonstrated that the tails of histones H3 and H4 greatly reduce the speed of transcript elongation through a nucelosome, and tail acetylation suppresses this effect. Accessory factors for elongating polymerase would be expected to carry out these modifications. The RNAPII -associated complex Elongator has histone acetyltransferase (HAT) activity and thus might fulfil such a role.
Yeast Elongator was isolated as a complex that associates with the chromatin fraction and interacts with the elongating phosphorylated form of RNAP II. The functional entity of Elongator complex has recently been shown to be an unstable six-subunit complex, termed holo-Elongator, which can dissociate into two discrete three-subunit subcomplexes upon treatment with high salt and /or MonoQ chromatography. One of these subcompexes is the Elp3-containing core complex, and the other is a complex of the Elp4, Elp5 and Elp6 proteins. Deletion of ELP3 (or other ELP genes) confers a set of phenotypes, some of which are associated with elongation defects. Significantly, the Elp3 subunit is a highly conserved histone acetyltransferase (HAT). Mutations that debilitate the HAT activity of EIp3 in vitro also confer elp phenotypes in vivo, indicating that the HAT activity of Elongator is required for its function. The activity of intact Elongator complex is directed specifically toward the amino-terminal tails of histone H3 and H4, the predominant acetylation sites are lysine-14 of
histone H3 and lysine-8 of histone H4. The small subcomlexes composed of Elp4/5/6 is required for the HAT activity, it interacts preferentially with the core complex(rather than in complex with RNAPII) and was therefore proposed to have a regulatory function.
Recently, human Elongator complexes have been isolated. The human complex is a fragile six-subunit complex that interacts with RNAP II and has HAT activity directed against histone H3 and H4. Depletion of Elongator from HeLa nuclear extracts reduces the ability of these extracts to transcribe chromatin templates, providing biochemical support for the proposed role of Elongator during transcript elongation in chromatin. However all of these data come from in vitro studies. There have been no reports so far on the characterization of human Elongator complex in vivo.
In this thesis, we studied the function of HAT activity of human Elongator complex in gene expression and regulation in Saccharomyces cerevisiae. The results have shown that the HAT activity ofELP3, which is essential for its function in vivo, is evolutionarily conserved between human and yeast. Human Elongator complex serves a role in chromatin remodeling through modifying the lysine residues of histone H3 and H4 during transcription elongation in higher cells. The main results and conclusions are as followings.
1 Using depletion strain of yeast as material, we have established a system for complementation test and gene expression analysis of human Elongator complex.
2, By using the above system, we demonstrated that yELP3, yhELP3 and hELP3 were able to completely, dramatically and partially complement the growth defects and the slow activation of PHO5 and SSA3 gene caused by the depletion of yELP3, respectively, while yhELPBHAT' whose catalytic domain was partially de
酵母Elongator是与染色质组分结合，并与延伸中的磷酸化形式的RNAPⅡ相互作用的复合物，是个六亚基的功能整体，在高盐处理或MonoQ层析时易于分解为两个三亚基亚复合物，其中一个是含Elp3的核心复合物，另一个含Elp4／5／6亚基。缺失yELP3(或其它yELP)可导致一系列表型，有的与转录延伸缺陷有关。Elp3具有HAT活性，该活性为复合物行使功能所必需。使Elp3的HAT活性严重丧失的点突变可引起所有elp表型。完整的复合物可直接修饰组蛋白H3和H4尾部，其优先乙酰化位点是H3 K14和H4 K8。复合物的HAT活性需要Elp4／5／6的存在，它们只与核心复合物相互作用(不与RNAPⅡ作用)，可能对核心复合物的HAT活性具调控作用。
近来人Elongator也被分离，它也是个不稳定的六亚基复合物，可与RNAPⅡ相互作用，具有HAT活性，能乙酰化H3和H4，在HeLa细胞核抽提物中去除Elongator可降低抽提物对染色质模板的转录延伸速率，提供了该复合物在染色质为模板的转录延伸中有功能的生化证据，但是上面的信息都来自体外研究。尚未见对人Elongator复合物及其亚基功能的体内研究的报道。
本文以酿酒酵母为实验材料，利用其易于进行遗传操作的优点，
对人Elongator的功能特点进行体内研究。证明了人与酵母的Elp3在
功能上是保守的，初步确定了hElp3及其拥有的HAT活性在复合物中
的功能地位，了解了复合物HAT活性在基因表达调控中的作用方式。
得到的主要结果和结论如下:
1、建立了以酵母为材料对人Elongator复合物作用特点进行分析的功
能互补和基因表达分析的实验体系
2、利用上述体系证实J送洗P3、.叻凡P3和力凡P3分别可以完全、显著、
部分补偿妊弘P3缺失引起的生长缺陷，并分别能够在诱导条件下完
全、显著、部分恢复.此艺P3缺失引起的月敬万和汉5刀3基因表达延迟
的缺陷。HAT区催化结构域缺失的动凡尸夯别拜口力云艺尸狱刹厂没有上
述功能。表明人与酵母的凡P3在功能上是保守的，力凡P3的HAT区
可以替代夕凡P3的HAT区，hEIP3的HAT活性为其行使功能所必需。
3、利用功能互补和RT一PCR证明力几P4可部分补偿不必艺用缺失引起的生
长缺陷，并能在一定程度上恢复其产y左又夕掀.55刀3表达延迟的缺陷，
表明与yElp4相似，hElp4所在的较小亚复合物可能对核心复合物
的HAT活性行使调控功能。
4、利用点突变和Plasmid Shuffle等技术构建了含H3 K14一R、H4 KS
~R单突变和H3 K14一侧H4 KS一R双突变的e1P3乙菌株，通过功
能互补实验分析少凡P3对突变株的补偿功能，证实酵母Elongator
可对H3 14K/H4 SK进行乙酞化修饰。同时以转入_汪艺P3为参照确
立了研究hElp3的HAT活性作用方式的体内检测体系。
5、通过对力几P3相关质粒转入含H3/H4K一R突变的e幼3乙菌株的功
能互补实验，发现在供试条件下组蛋白突变均使少艺艺P3、，动乙艺P3和
力凡P3补偿能力下降。在H3 K14一侧H4 KS~R双突变的e助3』菌
株中，三个基因的补偿功能都近乎丧失，表明在体内组蛋白(H3 K14、
H4KS)是hElp3及其所在的Elongator复合物的重要靶位点，同时
表明人Elongat叮复合物与转录相关的染色质的修饰和改构
(remondeling)有关。
6、在对H3/H4K~R突变株的功能互补实验中，我们发现H3 K14一R
舰4 KS一R双突变使e助了乙菌株产生更为严重的缺陷表型，表明细
胞内其它乙酞转移酶与EIP3在功能上有重叠，同时也表明体内维持
一定的乙酞化水平对细胞正常生长或迅速适应条件变化非常重要。
7、H4 KS一R对I功五艺P3、力几P3与少凡P3功能的影响大于H3 K14一R，
表明体内组蛋白不同位点的乙酞化修饰对基因表达有不同的影响。
人与酵母的Elp3对组蛋白H4 KS的乙酞化修饰可能有比H3 K14更
重要的作用。
The packaging of eukaryotic DNA into chromatin influences various processes that utilize DNA as a template, including transcription, replication and repair. Eukaryotic messenger RNAs are synthesized by the multisubunit enzyme RNA polymerase II, aided by myriad cofactors that control different events in this multistep process. A complete round of transcription involves the recruitment of polymerase and general transcription factors to the promoter, RNA chain synthesis initiation and polymerase escape form the promoter, RNA chain elongation, and finally termination with relaease of polymerase and nascent transcript from the DNA template. As RNA polymerase II leaves a gene promotor to transcribe the coding region, it faces many obstacles, including nucleosomes. Recent data have demonstrated that the tails of histones H3 and H4 greatly reduce the speed of transcript elongation through a nucelosome, and tail acetylation suppresses this effect. Accessory factors for elongating polymerase would be expected to carry out these modifications. The RNAPII -associated complex Elongator has histone acetyltransferase (HAT) activity and thus might fulfil such a role.
Yeast Elongator was isolated as a complex that associates with the chromatin fraction and interacts with the elongating phosphorylated form of RNAP II. The functional entity of Elongator complex has recently been shown to be an unstable six-subunit complex, termed holo-Elongator, which can dissociate into two discrete three-subunit subcomplexes upon treatment with high salt and /or MonoQ chromatography. One of these subcompexes is the Elp3-containing core complex, and the other is a complex of the Elp4, Elp5 and Elp6 proteins. Deletion of ELP3 (or other ELP genes) confers a set of phenotypes, some of which are associated with elongation defects. Significantly, the Elp3 subunit is a highly conserved histone acetyltransferase (HAT). Mutations that debilitate the HAT activity of EIp3 in vitro also confer elp phenotypes in vivo, indicating that the HAT activity of Elongator is required for its function. The activity of intact Elongator complex is directed specifically toward the amino-terminal tails of histone H3 and H4, the predominant acetylation sites are lysine-14 of
histone H3 and lysine-8 of histone H4. The small subcomlexes composed of Elp4/5/6 is required for the HAT activity, it interacts preferentially with the core complex(rather than in complex with RNAPII) and was therefore proposed to have a regulatory function.
Recently, human Elongator complexes have been isolated. The human complex is a fragile six-subunit complex that interacts with RNAP II and has HAT activity directed against histone H3 and H4. Depletion of Elongator from HeLa nuclear extracts reduces the ability of these extracts to transcribe chromatin templates, providing biochemical support for the proposed role of Elongator during transcript elongation in chromatin. However all of these data come from in vitro studies. There have been no reports so far on the characterization of human Elongator complex in vivo.
In this thesis, we studied the function of HAT activity of human Elongator complex in gene expression and regulation in Saccharomyces cerevisiae. The results have shown that the HAT activity ofELP3, which is essential for its function in vivo, is evolutionarily conserved between human and yeast. Human Elongator complex serves a role in chromatin remodeling through modifying the lysine residues of histone H3 and H4 during transcription elongation in higher cells. The main results and conclusions are as followings.
1 Using depletion strain of yeast as material, we have established a system for complementation test and gene expression analysis of human Elongator complex.
2, By using the above system, we demonstrated that yELP3, yhELP3 and hELP3 were able to completely, dramatically and partially complement the growth defects and the slow activation of PHO5 and SSA3 gene caused by the depletion of yELP3, respectively, while yhELPBHAT' whose catalytic domain was partially de
引文
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