環境壓力造成真菌細胞的黏附性、細胞生理、或是細胞形態﹙二形性，dimorphism﹚改變。二形性是指真菌細胞可以酵母菌/菌絲兩種形態方式行營養生長。前人研究中，外界氮源缺乏會刺激Saccharomyces cerevisiae的兩條訊息傳遞路徑﹙cAMP-dependent PKA pathway和MAPK pathway﹚的活化，促使路徑下游的FLO11基因轉錄，造成S. cerevisiae細胞產生偽菌絲。從實驗室所保存由環境分離的酵母菌，篩得一株具二形性的酵母菌株，SE4-R，培養在YM培養基上時，該菌細胞形態為卵形、圓形、檸檬形或紡綞形的酵母細胞，以極性或雙極性﹙bipolar﹚方式出芽生殖，依形態、生理、生化與LSU 26S rDNA和ITS 的DNA序列分析，鑑定為Pseudozyma sp.。將SE4-R培養在碳氮源缺乏的MBS培養基時，會自酵母形轉成真菌絲形態﹙R1﹚穩定生長。當培養在十倍鈣離子濃度﹙6.8mM﹚的TMBS培養基時，酵母細胞菌落周圍出現真/偽菌絲（R2）。形態混雜的菌絲細胞，菌落中央保持出芽生殖的酵母形﹙YF﹚細胞。依據S. cerevisiae的FLO11基因中保守的S1區域核酸序列設計引子，STA1/STA1引子對可由S. cerevisiae全量核酸，增幅出一段476 bp的片段﹙C1-5﹚，解序後確認為S1蛋白基因序列，以DIG標定此片段製成探針，可偵測到SE4-R的基因體內有微量的雜合訊號，顯示SE4-R具類似片段但基因重複數低。再以STA1/STA2引子對經booster PCR增幅SE4-R的全量核酸，獲得549 bp的產物﹙SEpp﹚，其序列與S. cerevisiae的該片段C1-5有94%的序列相似度。但是將SEpp片段製作成探針，試圖了解SE4-R不同形態細胞﹙真菌絲/真偽菌絲﹚間，FLO11基因表現量是否不同，但以SEpp未能偵測到任何一形態細胞內FLO11基因的表現。此外，以Affymetrix Yeast S98 microarray微陣列分析法分析三形態細胞﹙R1、R2、YF﹚的基因表現。該晶片上點陣的探針是依據S. cerevisiae基因體內6,400個ORF的序列所設計，用三形態細胞的RNA與晶片雜合後，經晶片讀值分析，唯一找到比YF細胞RNA表現量高兩倍的基因是PHD1，出現在R1細胞的RNA中，Phd1是一個轉錄活化因子，其主要功能是調控FLO11基因的轉錄，促進偽菌絲生長，PHD1與Aspergillus nidulans的STUA基因和C. albicans的EFG1具同源性。但在R2細胞中則沒有找到表現量比YF高兩倍的基因，結果未找到與FLO11基因相同或是同屬FLO基因家族的基因﹙FLO gene family﹚，與實驗前一部分的雜合結果相符。在R1、R2的RNA內還找到一些被促進且與菌絲生長相關的基因，顯示用不同物種的核酸與S. cerevisiae的晶片雜合，雖然可能由於序列相差過大使得能辨識出有兩倍表現量差異的基因很少，但依然可以從中獲得一些相關的資訊。

The environmental stress causes some changes of cell adhesion or cell physiology and even cell morphology﹙such as dimorphism﹚of fungal cells. Nitrogen depletion activates two signalling transduction pathway, cAMP-dependent PKA pathway and MAPK pathway in S. cerevisiae, positively regulating the transcription of downstream target gene FLO11 result in filamentous growth of yeast cell. A dimorphic yeast strain, SE4-R was obtained from screening laboratory-stored yeast strains collected from the environment. Growing on rich YM medium, SE4-R has ovoid, round, lemon-shaped or spindle-shape yeast form cells, they are polar or bipolar budding. SE4-R was identified as Pseudozyma sp. based on cell morphology, physiological and biochemical characteristics, also on LSU 26S rDNA and ITS sequence information. Growing on poor medium MBS, SE4-R changes it’s morphology from yeast form to hypha cell (R1) and hyphae morphology remain stable; when growing on TMBS medium, a MBS medium with ten fold calcium concentration (6.8mM), appeared pseudo-/hyphae filament (R2) in the edge of cell colony and yeast form cells remain as budding cell in the middle of the R2 colony. Designing STA1/STA2 primer pair according to the sequence of conserved S1 region in FLO11 gene in S. cerevisiae, STA1/STA2 primers can amplify a 476 bp fragment (C1-5) from S. cerevisiae genomic DNA. After sequencing, fragment C1-5 is surely part of the S1 region sequence. Using DIG-labeled C1-5 fragment doing dot-blot hybridization to SE4-R genomic DNA, a slight hybridization signal can be detected which indicate that the homology sequence may exist in SE4-R genome but in quite small amount. Indeed, STA1/STA2 primer can amplify a 549 bp fragment (SEpp) from SE4-R genomic DNA by booster PCR.The sequence of SEpp has 94% similarity to the one of C1-5. In order to verify if FLO11 gene expressed differently in yeast form cell and filament cell, SEpp fragment was DIG-labeled and hybridized to the RNA of YF, R1, R2 cells. But FLO11 gene expression can’t be detected in any one of three morphology type cell. In addition, Affymetrix Yeast S98 microarray is used to analyze filamentation associated genes in wider aspect. It has high dendity probes arrayed on the Affymetrix chip. After analysis of the microarray, there is only one gene in R1 with 2-fold chang higher than YF cells. PHD1 is a transcription activator with main function in regulating the expression of FLO11 gene and enhancing pseudohyphae growth in S. cerevisiae. It is homologous to STUA gene of Aspergillus nidulans and EFG1 gene lf Candida albicans. There is no any result in microarray analysis shows any gene similar to FLO11 which can correspond to the result in the previous study. There’re still some genes found related to filamentous growth induced in R1 and R2 cells, indicated that although there may be some difficulties to identify more genes with 2-fold change expression, some useful information still can be obtained.

目錄 Ⅰ
表目錄 Ⅵ
圖目錄 Ⅶ
中文摘要
英文摘要
第一章、SE4-R菌株的二形性與FLO11基因的研究 1
前言 1
研究目的 20
材料方法 20
一、篩選具二形性的酵母菌株 20
菌株來源 20
菌株的保存與活化 21
以貧養高鈣的MBS培養基促進酵母菌產生二形性 21
測試菌絲細胞與酵母形細胞形態轉換率 22
二、鑑定未知酵母菌株 23
﹙一﹚傳統鑑定方法鑑定酵母菌 23
菌落外觀觀察 23
細胞形態觀察 23
投擲孢子觀察 25
生理生化特性 25
1.Biolog MicrologTM system鑑定系統 25
2.碳源同化測試 27
3.生長溫度之測試 28
4.Diazonium Blue B呈色反應 28
5胞外類澱粉形成測試 28
﹙二﹚分子生物學方法鑑定酵母菌 29
核酸分析 29
1.酵母菌DNA的萃取 29
2.核酸的定量與純度比較 30
3.聚合酶連鎖反應﹙Polymerase Chain Reaction，PCR﹚ 30
4.瓊脂膠體電泳分析PCR產物 31
5.序列分析 31

菌落外觀觀察 23
細胞形態觀察 23
投擲孢子觀察 25
生理生化特性 25
1.Biolog MicrologTM system鑑定系統 25
2.碳源同化測試 27
3.生長溫度之測試 28
4.Diazonium Blue B呈色反應 28
5胞外類澱粉形成測試 28
﹙二﹚分子生物學方法鑑定酵母菌 29
核酸分析 29
1.酵母菌DNA的萃取 29
2.核酸的定量與純度比較 30
3.聚合酶連鎖反應﹙Polymerase Chain Reaction，PCR﹚ 30
4.瓊脂膠體電泳分析PCR產物 31
5.序列分析 31

二、鑑定SE4-R菌株 42
﹙一﹚傳統鑑定方法鑑定酵母菌 42
﹙二﹚分子生物學方法鑑定酵母菌 44
三、尋找SE4-R基因體中與FLO11基因序列具同源性的核酸片段 47
﹙一﹚PCR相關實驗 47
﹙二﹚核酸雜合試驗 51
討論 52
第二章、以寡核苷酸微陣列分析與菌絲生長相關的基因 60
前言 60
材料方法 64
取得品質良好的RNA樣本 64
晶片雜合試驗 64
晶片讀值分析 65
結果 66
RNA 品質 66
晶片讀值分析 67

相關基因功能分析 68
討論 71
參考文獻 75
附錄一 本研究所用之培養基及緩衝液 132
附錄圖一 136
附錄圖二 137
附錄圖三 138





表目錄
表一、 SE4-R三種形態細胞（R1、R2、YF）在不同形態間的轉換率 87
表二、 以Biolog快速鑑定系統(version 3.0 database)鑑定SE4-R菌株 88
表三、 SE4-R菌株於Biolog YT MicroPlateTM上的94個生理生化反應結果 89

表四、 比較SE4-R以Biolog測試的26項生理生化結果與The Yeast書中其他菌株的結果 91
表五、 SE4-R LSU rDNA D1/D2與rDNA ITS區域序列 93
表六、 SE4-R菌株rDNA D1/D2區域(641bp)與ITS區域(736bp)之序列與基因庫中相近菌種比對的相似度 94
表七、 R1細胞中表現量高兩倍的八個開放讀架 95
表八、 三十二個在R1細胞中被促進的基因 96
表九、 五十六個在R1細胞中被抑制的基因 98
表十、 三十三個與鈣離子相關的基因 102
表十一、 五十個在R2細胞中被促進的基因 105
表十二、 十一個在R2細胞中被抑制的基因 110
圖目錄
圖ㄧ、 12株供試酵母菌在YM 培養基與貧養的MBS培養基上的菌落形態 111
圖二、 SE4-R的酵母形 (YF)、真菌絲形 (R1)與真/偽菌絲形 (R2)細胞的菌落形態 113

圖三、 SE4-R的酵母形 (YF)、真菌絲形 (R1)與真/偽菌絲形 (R2)細胞的細胞形態 114
圖四、 SE4-R三種形態細胞（R1、R2、YF）在不同形態間的轉換率 116
圖五、 SE4-R菌株的菌落及細胞圖 117
圖六、 以SE4-R與Ustilaginaceae其他屬菌種的LSU D1/D2區域序列建構類源關係樹 118
圖七、 比對與FLO11基因序列相似的核酸序列 119
圖八、 PCR反應條件最佳化 123
圖九、 以STA1/STA2引子對，增幅YM培養基上的SE4-R全量核酸(1)並且再以booster PCR增幅一次(2) 124
圖十、 以STA1/STA2引子對增幅插入pGEMT-easy vector 的核酸片段 125
圖十一、 比對以STA1/STA2增幅的S. cerevisiae PCR產物(C1-5) 與SE4-R PCR產物序列(SEPP)以及FLO11部分序列 (STA1-2476) 126
圖十二、 檢查探針標記的效率與探針的適用性 129
圖十三、 RNA電泳圖 130
圖十四、 RNA樣本的品質確認 131

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