染色質折疊為能夠將大量的基因資訊納入僅數微米之細胞核中之程序，且被認為是具有階級性之組裝機制，然而，此一折疊程序目前僅有第一級之核小體結構及第二級之染色質之串珠結構被詳盡闡明，其接續之折疊機制與結構卻仍未被釐清。本研究旨在藉由解析DNA-樹狀體錯合物及核小體等模型系統之結構與交互作用力，進一步瞭解染色質折疊的可能機制，主要包括三個重點： (1) 組蛋白八聚體與DNA間之交互作用力 (即核小體內之交互作用力) 、 (2) 核小體間的交互作用力以及連結DNA在核小體系統中扮演之角色及 (3) 人工重組染色質之折疊機制，包含鹽類誘導之染色質構形轉換及折疊結構探討。
我們利用DNA與樹狀體形成之靜電錯合物做為核小體之簡化模型，探討藉由純粹靜電作用力是否可以重現核小體之主要結構特徵，並進而了解核小體內之交互作用力。研究發現質子化之樹狀體與組蛋白八聚體皆可吸引DNA纏繞於其上形成超螺旋結構，並具有相似之螺旋週期；然而，纏繞在樹狀體之DNA螺旋軌跡相對於其在核小體內之固定纏繞構形卻較為鬆散且擾動。此外，被纏繞的樹狀體為緊密的一維排列，而在染色質系統中，核小體被相對較長之連結DNA所分隔，形成著名之串珠結構。此研究成果表明組蛋白八聚體與DNA之間具有額外之交互作用力，因而能夠維持與固定DNA於核小體內之纏繞軌跡以及選擇特定DNA序列與組蛋白結合成為核小體。
經由比較具有及不具有連結DNA之核小體 (即核小體與核小體核心粒) 之結構與交互作用力，可了解各獨立核小體間的交互作用力以及連結 DNA 在於核小體系統中所扮演的角色。研究結果指出連結DNA可令纏繞在組蛋白八聚體上的DNA解纏繞約 25 鹼基對之長度，進而稍微改變核小體之構形。此外，藉由改變樣品濃度以及摻雜鹽類改變系統中的離子強度，可以觀察帶電粒子間交互作用力之變化。研究成果揭露連結DNA不但可減緩核小體間之靜電排斥力，更進一步避免了核小體在高鹽類濃度時進行高密度的規則排列，此成果揭露連結DNA不僅只具有連結核小體的功用，更在染色質折疊程序中扮演舉足輕重之角色。
為了更進一步探討控制離子強度所誘發之染色質折疊過程，本研究在人工重組染色質系統中加入二價鹽類，氯化鈣，並探討其誘導此染色質之構形變化。 藉由比較實驗觀察所得以及經由理論模型 (包含自由連接鏈之珍珠項鍊模型、螺線模型以及之字曲折模型) 計算所得之小角度X光散射圖譜，發現在未加鹽類時，染色質主要具自由連接鏈之特性，在鹽類濃度增加過程，其構形將轉換成為螺線結構或曲折結構。此外，隨著離子強度上升，染色質間將會互相吸引聚集並使得核小體間不只進行染色質內堆疊，更會形成染色質間堆疊。根據此研究成果，我們提出染色質折疊機制是形成由螺線結構或曲折結構做為基本單元所組成之大尺度之緻密碎形球結構。

The folding of chromatin fiber to form chromosome has been considered as a hierarchical process which allows abundant genetic information written in the DNA sequence to be stored into the cell nucleus. So far, only the first two levels of the folding process, which are the conformation of the nucleosome core particle and the 10-nm chromatin fiber, have been resolved unambiguously. The subsequent higher-order folding mechanism and structure still remain elusive. Aiming at understanding the underlying mechanism of chromatin folding, three topics covering the local to global structure associated with chromatin have been studied in this dissertation, including (1) the intra-nucleosome interaction between the histone proteins and DNA, (2) the inter-nucleosome interaction and the role linker DNA plays in the nucleosome system and (3) the folding mechanism of the reconstituted nucleosome array induced by salt addition.
The intra-nucleosome interaction between histone octamer (HO) and DNA was investigated using the electrostatic complex of DNA and poly(amidoamine) (PAMAM) G6 dendrimer (called “dendriplex”) as the model system to resolve whether the pure electrostatic interaction can lead to the exactly key structural features of nucleosome. Both dendrimer and HO are found to attract DNA to wrap helically around them with comparable pitch lengths; however, the DNA superhelix trajectory in dendriplex is loose and fluctuating, whereas that in nucleosome array is tight and rigid. Moreover, the DNA-wrapped dendrimer particles are closely spaced along the dendriplex fiber, while the nucleosome core particles (NCPs) in the nucleosome array are separated by relatively long linker DNA. The clear contrasts in structural features attests that DNA-HO interaction is beyond electrostatics, as additional specific interactions exists to fix DNA superhelical trajectory and select the favored DNA sequence for constituting the NCP.
The inter-nucleosome interaction as well as the role that linker DNA plays in nucleosome system have been studied through studying the structures and interactions of the NCPs with and without linker DNA mediated by ionic strength and the nucleosome concentration. Linker DNA was found to partially dewrap the nucleosomal DNA in NCP by 25 bp irrespective of the length of linker DNA; moreover, linker DNA alleviated the electrostatic repulsion between the NCPs and prevented them from stacking into columns under high ionic strength. The latter two effects demonstrate in particular that linker DNA plays an active role in chromatin folding via facilitating the intimate contact of NCPs while preventing them from dense stacking.
The mechanism of the folding of reconstituted chromatin fiber consisting of 36 nucleosomes induced by divalent salt (CaCl2) addition has been explored in vitro by means of SAXS. The 36-mer nucleosome array was found to transform from the freely jointed chain-like conformation before salt addition to the compact structure with either the solenoid or the zigzag conformation upon increasing the ionic strength. Furthermore, the 36-mer nucleosome arrays containing the solenoid and zigzag motifs are hypothesized to aggregate and interdigitate with each other, leading to the formation of a fractal globule with compact structure at large scale.

摘要 I
Abstract III
致謝辭 V
Table of Contents VII
List of Tables X
List of Figures XI
Chapter 1. Introduction 1
1.1 General Background 1
1.2 Chromatin Compaction 5
1.2.1 Introduction of DNA 5
1.2.2 Nucleosome Core Particle (NCP) 9
1.2.3 Chromatin Fiber with Beads-On-String Structure 11
1.2.4 Hypotheses of Further Chromatin Compaction 18
1.3 Dendrimer and DNA-Dendrimer Complexes 25
1.3.1 Introduction of Dendrimer 25
1.3.2 Introduction of Polyamidoamine (PAMAM) Dendrimer 25
1.3.3 Structure of DNA-Dendrimer Complex ( Dendriplex) 35
1.4 Small Angle X-ray Scattering (SAXS) 48
1.4.1 Introduction 48
1.4.2 Scattering Intensity Calculation from Real-Space Model 49
1.4.3 Relationship between Structure Factor and Interparticle Interaction Potential 50
1.4.4 Screened Coulombic Interaction between Particles 52
1.5 Motivations and Objectives of the Research 55
1.6 Overview of the Thesis 55
1.7 Reference 57
Chapter 2. Elucidating the DNA-Histone Interaction in Nucleosome from the DNA-Dendrimer Complex 67
2.1 Introduction 67
2.2 Experimental Section 70
2.2.1 Dendriplexes Preparation 70
2.2.2 Nucleosome Core Particle (NCP) Reconstitution and Nucleosome Array Assembly 70
2.2.3 Small Angle X-ray Scattering (SAXS) 71
2.3 Results 71
2.4 Discussion 81
2.5 Conclusions 87
2.6 Appendix 89
2.7 References 93
Chapter 3. Linker DNA: the Hidden Figure Mediating the Structure and Interaction of Nucleosome Core Particles 99
3.1 Introduction 99
3.2 Experimental Section 102
3.2.1 Nucleosome Core Particle (NCP) Reconstitution 102
3.2.2 Small Angle X-ray Scattering (SAXS) 103
3.2.3 Model Fitting 103
3.3 Results and Discussion 103
3.3.1 Linker DNA induced dewrapping of nucleosomal DNA 103
3.3.2 Linker DNA alleviated the electrostatic repulsion between nucleosome particles 105
3.3.3 Linker DNA prevents NCPs from close stacking at high salt concentration 109
3.4 Conclusions 112
3.5 Appendix 115
3.6 References 117
Chapter 4. Salt-induced Conformational Transition of Nucleosome Array: From Pearl Necklace to Fractal Globule 121
4.1 Introduction 121
4.2 Experimental Section 124
4.2.1 177 Nucleosome and 36-mer Nucleosome Array Reconstitution 124
4.2.2 Small Angle X-ray Scattering (SAXS) 125
4.2.3 Structure Factor of the Pearl Necklace Model 125
4.3 Results 126
4.4 Discussion 132
4.5 Conclusions 136
4.6 References 138
Chapter 5. Overall Conclusions and Suggestions for Future Work 144
5.1 Overall Conclusions 144
5.2 Suggestions for Future Works 145
5.2.1 PAMAM-DNA Dendriplex with Specific DNA Sequence and Length 145
5.2.2 Dendriplex with Rigid-Body Dendrimer 145
5.2.3 Ionic Strength Alteration of Dendriplex System 146
5.2.4 Nucleosome Array Compaction 146
5.3 References 147
List of Publication 148

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