摘要
丝状真菌是自然界中降解木质纤维素的主要微生物类别,其中瑞氏木霉(Trichoderma reesei,红褐肉座菌Hypocrea jecorina的无性型)是最重要的代表菌株,其可以产生内切葡聚糖酶、外切葡聚糖酶和β-葡萄糖苷酶三类不同的纤维素降解酶,其中外切纤维素酶CBH I占瑞氏木霉分泌纤维素酶系的60%。研究表明,CBH I基因的表达受到碳源的严格调控,在纤维素存在条件下,其表达量可提高1000倍以上,而在葡萄糖条件下,其表达被完全抑制。目前,纤维素酶的高效诱导表达机制的研究尚处于探索阶段。
近几年的研究工作主要集中于对主要纤维素酶基因的启动子活性进行分析,分离鉴定了几个与启动子相互作用的转录因子,它们通过正调控与负调控的双重控制机制调控纤维素酶基因的转录表达。其中,Cre1是最早鉴定的与启动子相互作用的碳代谢抑制因子,可以结合在cbhl基因转录起始位点上游700bp的5'-SYGGRG-3'反向重复序列上,Cre1的缺失导致在葡萄糖培养条件中发生去阻遏。然而,Cre1并不参与所有纤维素酶基因的转录调控,比如cbh2, xyn2及bgl1.随后通过酵母单杂交体系获得了转录因子Ace1和Ace2,体外结合实验表明二者识别的共有序列分别为AGGCA和GGSTAATA,最初这两个蛋白都被认为具有转录激活活性,但后续试验表明,ace1缺失后xyn1及一些纤维素酶基因转录水平提高,而ace2缺失后导致cbhl,cbh2,egll及egl2转录mRNAs的诱导动力学降低,且诱导后期相关纤维素酶及Xyn2酶活降低30-70%；木聚糖酶调控因子Xyr1是作为黑曲霉中转录因子XlnR的同源蛋白被得以鉴定识别,该基因的缺失造成包括cbhl, cbh2, egll, xynl与xyn2在内的主要纤维素酶和半纤维素酶基因的不转录,是纤维素酶基因诱导转录过程中的关键转录激活因子。此外,体外实验表明Xyr1可结合到单独或反向重复的GGC(A/T)3序列上。上述转录因子的鉴定以及对它们不同结合位点的识别,意味着纤维素酶基因的诱导转录是一个多转录因子参与、与顺式调控元件相互作用的复杂过程。
真核生物的染色体是由核小体组成的,核小体结构过于紧密通常会阻碍RNA polⅡ的结合而抑制转录,因此基因转录的激活除了需要转录激活因子与靶DNA序列的结合外,启动子区域的局部染色质结构变化、重构和修饰也是必需的。这种染色质结构变化主要包括组蛋白的翻译后修饰以及ATP-依赖的重构复合物的形成。T. reesei是一种丝状真菌,因此纤维素酶基因的转录也应该存在这种控制机制。目前,已经证实纤维素酶基因cbh2的转录与核心启动子区的核小体定位和移除有关,但这种染色质发生变化的机制目前未见报道。因此,本论文针对纤维素酶基因的高效表达机制进行了系统研究,包括组蛋白的乙酰化修饰和染色体重构在纤维素酶基因诱导转录中的作用和机制,主要结果如下：
一、分离鉴定了T. reesei中的一个乙酰化转移酶基因Tr_gcn5,证明了该基因在碳源代谢、菌丝生长、孢子形成及纤维素酶基因转录中发挥重要功能
Gcn5是在酵母中发现的一种组蛋白乙酰化酶,参与基因的转录激活过程。本研究通过氨基酸序列比对和系统进化树分析首次在T. reesei中分离鉴定了酵母Gcn5的同源蛋白TrGcn5,并在酵母中通过功能回补实验证明了该蛋白具有乙酰基转移酶活性。进一步发现该基因在T. reesei中缺失后,菌株在不同碳源的培养基上的生长能力下降,菌丝体的形态也发生了实质性变化,最显著的是缺失菌株基本丧失了孢子形成能力。除此以外,gcn5敲除菌株中主要的纤维素酶基因cbh1在诱导过程中的转录一直维持在很低的水平,发酵液中也检测不到相应的纤维素酶活性。我们的结果显示在T. reesei中,gcn5对基因组水平上的基因表达有广泛的影响,参与了碳源代谢、菌丝生长、无性生殖以及包括纤维素酶诱导在内的压力响应过程。
二、通过高通量转录组测序,从全基因水平上考察了野生菌株和△gcn5菌株在纤维素酶诱导过程中的基因转录差异,从而系统深入的分析了gcn5基因缺失对细胞的诱导响应、信号传递、能量合成、基础代谢等途径的影响和可能的机制,为揭示纤维素酶基因转录调控网络提供了更详尽的数据和较清晰的脉络。
分别提取同样诱导条件下的野生菌株和△gcn5菌株的RNA,分离：nRNA后进行全序列测定,对测序得到的数据进行分析归类后,得到了以下结果：(1)两株菌响应纤维素诱导条件的基因不同。野生菌株有703个基因转录上调,而Agcn5菌株有804个基因转录上调；有422个转录上调的基因重叠；分别占差异表达基因总数的31.5%和33.4%；说明△gcn5菌株在诱导条件下有更多的基因表现为上调来回补gcn5缺失造成的影响；(2)表达差异的基因主要集中在碳水化合物的合成和分解代谢过程中。通过GO (Gene Ontology)显著性富集分析发现,碳水化合物降解和代谢途径差异较大,推测在该途径中的影响是特异的。同时,由于gcn5的缺失对葡聚糖代谢的影响,造成了细胞壁合成的障碍,也妨碍了孢子的形成；(3)△gcn5菌株中细胞骨架调控途径中只有两个基因上调,一个基因下调,但这种变化抑制了肌动蛋白的合成,这可以解释菌丝的生长和扩散变弱,可能也是孢子不能形成的原因；(4)两株菌的差异表达基因在氧化磷酸化,TCA循环和糖酵解途径中都没有表现出显著富集,说明gcn5的缺失并没有影响胞内的能量水平；(5)主要的纤维素酶基因以及转录激活因子Xyr1在gcn5的缺失的情况下都不能转录,这种影响途径是特异的；(6)在△gcn5菌株中一共发现了三个具有乙酰化酶活性的未知蛋白出现转录上调,部分回补了由于gcn5缺失造成的影响。
三、通过优化条件,改进了T. reesei的染色质免疫共沉淀技术；进一步分析了诱导过程中主要纤维素酶基因启动子上的组蛋白乙酰化变化
经典的染色质免疫共沉淀技术(ChIP)多以哺乳动物细胞或酵母菌为基础建立,T. reesei为丝状真菌,对ChIP结果准确性的可能造成影响的因素不明确,因此我们对通过逐一考察ChIP实验中的每个环节,对经典的染色体免疫共沉淀的技术进行了优化。优化结果为：甲醛交联的时间确定为10min,菌体震荡破碎的最佳条件为200μl菌体+200μl破碎珠+500μl裂解液,5000rpm20s运行3次,全细胞破碎液离心之后用35%的超声破碎功率进行破碎,同时确定了细胞裂解液中去污剂的成分及浓度。通过优化条件,发现T. reesei中ChIP关键的控制点为甲醛交联时间和染色体的破碎程度,对结果的稳定性和可重复性最重要。
为了验证优化和改进的ChIP方法的可行性,我们选取了可以有效识别T.reesei组蛋白H4和H3乙酰化的抗体,研究了T. reesei纤维素酶基因cbhl的转录曲线,对cbhl和cbh2基因在诱导转录时启动子上组蛋白的乙酰化水平进行了检测,证实了该技术方案可在T. reesei中应用。为深入研究纤维素酶基因诱导转录时启动子上组蛋白的乙酰化的变化和染色质的重构,以及这些变化与纤维素酶基因高效转录之间的关系奠定了坚实的基础。
四、阐明了启动子区核小体组蛋白的乙酰化水平是影响纤维素酶基因转录的重要因素,而乙酰化酶Gcn5通过影响转录因子xyrl基因启动子上组蛋白的乙酰化水平以及核小体的丢失来影响xyr1基因的转录,从而进一步调控纤维素酶基因的转录
首先分析了不同的诱导碳源的培养条件下,野生型和Agcn5菌株中cbhl基因启动子的乙酰化水平,发现前者诱导条件下cbhl基因启动子区乙酰化水平不同程度提高,而后者始终维持在非诱导水平；推测乙酰化的水平决定着纤维素酶基因的转录水平,因此又构建了组蛋白持续乙酰化(Q)和非乙酰化(R)的突变体,进一步证实了组蛋白乙酰化水平变化能够影响纤维素酶基因的转录。当检测纤维素酶基因通用的转录激活因子xyrl基因的转录水平时发现其在Agcn5菌株中丧失转录。在其他组蛋白突变体中,其转录水平都受到不同程度的影响,同时发现,xyrl转录水平的高低对应着cbhl基因转录水平的高低,因此,我们又研究了△xyr1菌株中cbhl基因启动子的乙酰化水平,发现xyrl的缺失也影响了乙酰化水平。因此我们推测xyrl的转录受到其自身启动子的乙酰化水平的影响,一旦Xyr1结合到纤维素酶基因启动子,又会征募组蛋白乙酰化酶复合物,引起纤维素酶基因启动子上的乙酰化水平的变化,从而调控转录。
综合以上结果我们可以推测Gcn5参与的组蛋白乙酰化与纤维素酶基因诱导转录之间之间的关系模式图：在纤维素酶诱导过程中,首先乙酰化酶Gcn5通过改变xyrl基因启动子上组蛋白的乙酰化水平,参与了xyrl基因的转录过程；当xyrl转录翻译后便结合到cbhl基因启动子上,开始征募Gcn5乙酰化酶复合物,进而又使cbhl启动子上组蛋白的乙酰化水平提高,从而引起转录起始位点的暴露,有利于RNA聚合酶的结合而起始转录。
五、通过酵母单杂交实验对转录因子Xyr1与纤维素酶基因启动子的相互作用以及转录激活性质进行了分析
自纤维素酶基因的转录因子Acel, Ace2和Xyr1被相继鉴定后,已报道的结果主要集中于通过遗传学手段研究这些基因缺失后对纤维素酶基因表达的影响,以及通过体外凝胶迁移实验(EMSA)在体外证明了这三个转录因子可明显结合特定的DNA序列。但是关于这些蛋白在体内与纤维素酶基因启动子相互作用的实验证据,目前尚未见报道。因此,我们分别选取包含Xyr1的DNA结合结构域(DBD)和激活结构域(AD)的不同长度的DNA序列,导入含有不同启动子控制的报告基因的酿酒酵母中,通过酵母单杂交体系来研究Xyr1与DNA的相互作用,并试图对其AD结构域定位。结果表明,在酿酒酵母中Xyr1的DBD区不能有效的结合cbhl启动子,同时其AD区也没有表现出转录激活活性,可能有以下原因：1) Xyrl DBD与Gal4AD的杂合蛋白在酿酒酵母中折叠错误或其它原因导致蛋白不稳定,进而影响了其功能；2)杂合蛋白封闭了Xyrl与DNA相互作用的位点；3)杂合蛋白在酿酒酵母中不能准确地定位到细胞核内,导致无法与靶DNA结合。此外,研究还发现米曲霉中的转录因子XlnR(Xyr1的同源蛋白)与靶DNA结合和转录激活能力有效发挥的前提是该蛋白发生磷酸化修饰,而构巢曲霉中参与氨代谢的转录因子NirA(锌核双簇蛋白)的定位和与DNA的结合需要GATA因子AreA的协助。这些研究结果都暗示了Xyr1很可能需要发生转录后修饰或与其它因子共同作用才能实现纤维素酶基因的激活转录,而酿酒酵母中可能并不存在这些因子。而大肠杆菌中异源表达的Xyr1的DBD区易于形成二聚体,这也暗示了转录因子在体内可能以二聚体的形式发挥作用。这些都可能是在酿酒酵母中未检测到Xyrl DBD和Ga14AD的杂合蛋白转录激活活性的原因。体内实验检测转录因子与启动子的结合及其作用机制仍有待于研究。
Filamentous fungi are the dominant microorganisms in nature that exert the ability of degrading cellulose. Trichoderma reesei (teleomorph Hypocrea jecorina) is one of the most prolific cellulase producers in industry and an organism to look into the transcriptional regulation of cellulase genes, partly due to the fact that this strain can produce three kinds of cellulase including endoglucanase, exoglucanase and β-glucosidase, among which the CBH1account for approximately60%. Research results indicated that cbhl gene was strictly regulated by carbon source. The expression level of CBH1was1000-fold higher in the presence of cellulose than that from glycerol. Moreover, the cbhl gene was completely inhibited when glucose was used as sole carbon source. However, the little was known about the detailed mechanism of transcriptional regulation of these genes.
The binding between RNApol Ⅱ and target site within promoter, which effectively initiated the gene transcription, was usually influenced by the compactness of the nucleosomes, which consisted of the chromosome in eukaryotic cells. As a result, gene transcription in eukaryotic cells required not only the interaction between transcriptional factors and their corresponding target nucleotide sequences but also the reconstitution, alteration and modification of chromatin, which generally comprised the histone acetylation as well as the formation of ATP-dependent reconstitution complex. As a filamentous fungus, the transcriptional regulation of cellulase genes in T. reesei should also follow this manner. Although it is reported that histone location and removal was involved in the transcription of cbh2, the detailed mechanism of the chromatin modification was largely unknown. To this point, this thesis focused on the function and mechanism of histone acetylation as well chromatin reconstitution in the transcription of cellulase genes.
1. T. reesei homologue of S. cerevisiae histone acetyltransferase protein Gcn5was identified by using biochemical and genetic method. The results proved that TrGcn5 played a critical role in filamentous growth, morphogenesis and transcriptional activation of specific genes including cellulase encoding genes.
2. The gene expression differentiation was evaluated by transcriptome analysis between wild-type and△gcn5strains. Several genes including those respond to cellulase inducing signals, those involved in metabolic pathway and signal transduction were identified. These results supplied us with more details about the transcriptional regulation of cellulase in T. reesei.
3. Chromatin immunoprecipitation was optimized in T. reesei by investigating the factors and procedure that may affect the validated results. Histone acetylation of the cellulase gene promoters were studied with the improved protocol.
4. It is proved that the level of histone acetylation is the key factor facilitating cellulase genes transcription. The level of histone acetylation on xyrl promoter was affected by histone acetyltransferase protein Gcn5, and then affected the transcription of xyrl gene, which further regulated the cellulase gene transcription.
5. The interaction between transcriptional regulator Xyrl and promoter of cellulase genes were studied by yeast-one-hybridization.
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