臺灣博碩士論文加值系統

中文摘要
CSB (Conserved Sequence Block) 為座落於 T 細胞接受器 α/δ 基因座內 Jα 基因片段 Jα3 和 Jα4 之間的一段包含 125 個核■酸的 DNA 片段。 其序列在人和老鼠之間呈現高度保留的特性 (95% similarity)﹐此保留的程度遠比T細胞接受器 α/δ 基因座內其他已知的調節元素在人和老鼠間之相似性來的高。 早期研究發現﹐當以 CSB 作為探針和老鼠不同組織的訊息RNA (mRNA) 進行雜合反應 (hybridization) 時﹐ 並無法偵測到雜合訊號﹐此一結果顯示 CSB 並不會被轉錄為RNA。此外﹐以 CSB 為探針進行 genomic zoo blot 分析時發現﹐很多脊椎動物的基因體 DNA (genomic DNA) 都出現雜合訊號﹐此結果意味著 CSB 序列在其他脊椎動物似乎亦是被保留的。 從上述 CSB 的特色可以推論﹐CSB 很可能具有調控 T 細胞接受器 α/δ 基因座內基因的重組或表現之功能。
在本論文的研究中﹐即以各種生化及分子生物學的方法來探究 CSB 可能的功能。 由 transient transfection 的結果顯示﹐當 CSB 和 T細胞接受器 α 加強子共同接於 CAT 基因的表現載體時﹐可使 T 細胞接受器 α 加強子的活性增加兩倍﹐而 CSB 本身則不具有促進基因表現的活性。 EMSA (Electrophoretic Mobility Shift Assay) 的結果顯示淋巴特異性及 T 細胞特異性的細胞核因子﹐均參與 CSB 結合複合體的生成﹐且 CSB-蛋白質複合體的生成隱含了極為錯綜複雜的 "CSB 與蛋白質之間" 及 "蛋白質與蛋白質之間" 的交互作用。這些結果顯示 CSB 是一個可和多個組織特異性的細胞核因子結合﹐且能促使 T 細胞接受器 α 加強子活性增強的調節性元素。
T 細胞接受器基因的重組及表現是具發育時期特異性的 (developmental stage specific)。在本論文的第二部份即研究 CSB 結合因子於 T 細胞的不同發育時期及老鼠各種不同發育時期的器官之表現情形﹐以進一步瞭解 CSB 的功能。實驗結果顯示﹐某些參與 CSB 結合複合體生成的細胞核因子之表現是具發育時期特異性的。 同時﹐本部份的實驗結果亦證明 Oct-1 及具淋巴特異性的 GATA-3﹑Oct-2 等 DNA 結合蛋白﹐在老鼠胸腺細胞中均參與 in vitro 及 in vivo CSB 結合複合體的生成。 另外﹐本論文的研究結果亦發現﹐小雞器官的細胞核萃取液和老鼠相似﹐都具有形成組織特異性 CSB 結合複合體的能力﹐且 GATA-3 及 Oct-2 等在演化過程中被保留的 DNA 結合蛋白﹐亦參與小雞 in vitro CSB 結合複合體的生成。
綜合本論文所得的結果可以推論﹐CSB 的功能很可能是藉由調控 T 細胞接受器 α/δ 基因座中與 CSB 相鄰的 Jα 區域之染色質結構﹐使得該區域中 V到 Jα 的重組在 T細胞發育過程中得以在適當的空間及時間下進行。進一步鑑定與 CSB 交互作用的蛋白質因子﹐將有助於瞭解調控 T 細胞接受器 α/δ 基因座在 T 細胞發育過程中﹐基因重組和表現的分子機制。

Abstract
CSB (Conserved Sequence Block), a block of 125 nucleotide in length, is located between Jα3 and Jα4, approximately 5 kb to the 5'' end of Cα exon l, and its sequence is highly conserved between human and mouse. There are only six differences over 125 nucleotide positions (95% similar). This degree of conservation is much higher than the ~71% overall sequence similarity found between human and mouse in the non-coding region of the TCR Cα/Cδ loci, and is also higher than that obtained when TCR α enhancer region sequences are compared. In addition, no transcript was shown to hybridize to the CSB region in different mouse tissues and zoo blot analysis using the CSB as a probe suggests that this sequence may be conserved in other vertebrates. Given these observations, it seems plausible that this conserved sequence may play a role relevant to the evolutionarily conserved coordinate regulation of TCR gene expression/rearrangement.
In this study, a series of detailed analyses were performed to explore the function of CSB. Transient transfection results showed that the CSB-containing element in conjunction with the TCR α enhancer up-regulated the α enhancer activity, whereas no enhancer activity was detected when CSB alone was assayed. In vitro occupancy analyses of CSB by nuclear factors revealed the existence of an unexpectedly intricate network of CSB-protein and protein-protein interactions. Lymphoid-specific as well as T lineage-specific nuclear factors are involved to differentially form CSB-bound complexes in extracts of various tissues and cell lines. In addition, certain CSB-binding factors were shown to be expressed in a developmental stage-specific fashion. These factors were easily detected in adult thymic extracts but barely in fetal thymic extracts, or vise versa. Similarly, certain factors involved in forming CSB-bound complexes were expressed in CD4+CD8+ immature T cell as well as CD4+ and CD8+ mature lymphocytes, but were barely detectable in immature CD4-CD8- thymocytes. Furthermore, CSB - bound complexes were formed in extracts of mouse fetal brain and liver tissues; however they were absent in extracts of adult''s brain and liver tissues. The results obtained from these studies also showed that transcription factor Oct-1 as well as lymphoid-specific DNA-binding factors Oct-2 and GATA-3 were indeed involved in interacting with CSB both in vivo as demonstrated by a chromatin immunoprecipitation assay and in vitro as evidenced by electrophoretic mobility shift assays in the mouse thymus. Finally, nuclear extracts from chicken tissues were shown to contain the activity of forming tissue-specific CSB-bound complexes similar to that observed in mouse, and the transcription factors GATA-3 and Oct-2 that have been highly conserved during vertebrate evolution were shown to be involved in forming in vitro CSB-bound complexes in chicken. These findings strongly suggest that CSB is a cis-regulatory element which may play a role of regulating the chromatin structure in the TCR Jα region flanking CSB, so that the V to Jα rearrangement in this region could be temporally regulated during T cell development. These results also suggest that further identification of these CSB-interacting factors would help understand the molecular mechanism involved in regulating the rearrangement and expression of genes in TCR α/δ locus during T cell development.

封面
目錄
圖表目錄
中文摘要
英文摘要
縮寫表
壹、緒論
第一節T細胞及T細胞接受器之簡介
一、T細胞的功能與特性
二、T細胞接受器(T cell receptor;TCR)之簡介
第二節V(D)J重組(V(D)J recombination)
一、簡介
二、反應機制(Reaction Mechanism)
三、酵素機構(Enzymatic Machinery)
第三節T細胞接受器基因的重組和表現(Rearrangement and Ezpression of T Cell Receptor Genes)
一、基因重組及表現具血源特異性(Lineage-Specificity)
二、T細胞接受器基因重組及表現具發育時期特異性(Developmental Stage Specificity)
三、有次序性的基因重組及表現(Ordered Rearrangement and Expression)
第四節T細胞接受器α/δ基因座(α/δlocus)與其基因重組及表現
一、α/δ基因座簡介
二、α/δ基因座基因重組及表現的特性
第五節T細胞接受器基因表現之調控
一、T細胞接受器基因之轉錄調控(Transcriptional Regulation of T Cell Receptor Genes)
二、T細胞接受器基因組合之調控(Regulation of rhe Assembly of TCR Genes)
第六節CSB(Conserved Sequence Block)之簡介
第七節研究方向與策略
貳、實驗材料與方法
參、實驗結果
第一部份CSB生化特性之研究
一、CSB與T細胞接受器α加強子(TCR α enhancer)之交互作用
二、與CSB專一性交互作用的細胞核反式作用因子(Nuclear Trans-Acting Factors)之鑑定(Identification)
三、CSB序列中蛋白質因子結合部位之剖析
四、肝臟具有會抑制胸腺CSB-蛋白質複合體生成的因子
五、DNase I腳印(DNase I Footprinting)分析之結果
第二部份CSB結合因子之研究
一、胚胎時期的肝臟、大腦及胸腺具有參與CSB─結合複合體(CSB─binding complexes)形成之蛋白因子
二、胚胎時期的大腦、肝臟及胸腺具有可辨識並結合CSB分段DNA的細胞核因子
三、Gel overlay試驗(gel overlay assays)分析CSB結合因子之表現
四、T細胞的不同發育時期細胞核萃取液CSB結合活性之觀察
五、胚胎時期肝臟細胞核萃取液不會抑制胸腺CSB結合複合體的生成
六、Oct-1、Oct-2、GATA-3等因子參與CSB結合複合體的生成
第三部份小雞CSB結合因子之研究
一、CSB與小雞組織細胞核因子之交互作用
二、CSB分段DNA與小雞組織細胞核因子交互作用
三、Gel Overlay試驗分析小雞CSB結合因子之表現
四、In vitro DNase I腳印試驗之結果
五、GATA-3及Oct-2參與小雞in vitro CSB結合複合體的生成
第四部份未完成實驗部份之初步結果
肆、結論與討論
伍、未來的研究與方向
陸、參考文獻
柒、圖表及附錄p1

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