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Resolving genome-wide views of chromatin structure to identify fundamental principles of genome organization.

机译：解析染色质结构的全基因组视图，以确定基因组组织的基本原理。

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摘要

Chromatin, the collection of DNA and proteins found in eukaryotic nuclei, is organized into a distinct structure to facilitate the compaction of genomic DNA. Chromatin structure is highly conserved across eukaryotic species and the organization of chromatin is known to have far-reaching implications on the accessibility and functionality of genetic information stored in nucleotide sequences.;The purpose of this research is to improve our understanding of the global principles controlling chromatin structure. Work in this thesis utilizes the genetic model of Saccharomyces cerevisiae because of its high experimental tractability, strong conservation of eukaryotic transcription machinery, and extensive genome annotation. This thesis begins with a study defining the technical biases present in genome-wide chromatin mapping experiments and outlining the development and validation of an improved methodology that standardizes the collection and analysis of genome-wide maps of chromatin structure. This standardized collection and analysis of chromatin structures ultimately enables unbiased comparisons between genome-wide chromatin states, which help to expand our understanding of chromatin biology. Accordingly, global principles of genome organization are explored by using this improved methodology to map and compare genome-wide chromatin structures in various experimentally perturbed chromatin states.;First, genome-wide chromatin structures are compared in the presence and absence of a conserved transcriptional repressor protein that is known to act through chromatin, Tup1p. Analysis of wild-type and tup1Delta ; chromatin structures enabled identification of a dominant role for Tup1p in establishing nucleosome positioning and occupancy at -1 and -2 promoter nucleosomes directly upstream of transcription start sites as part of is repressive mechanism. Additionally, analysis of chromatin organization at Tup1-regulated genes suggests a link between Tup1 regulation and transcriptional plasticity, whereby more open promoter structures are targeted by a larger number of regulatory factors with distinct patterns, to enable more variable gene expression across different environments.;Finally, genome-wide chromatin structures are mapped and compared following an experimental depletion of nucleosomes to explore the role of histone dosage in chromatin organization. Structural responses to nucleosome depletion suggest alternative mechanisms for the establishment of the 5' barrier against which nucleosomes are packed and the spacing between 5' nucleosomes. Packing barriers at the 5' ends of genes are established through a mechanism that is sensitive to histone dosage, whereas spacing between 5' nucleosomes is maintained more resiliently in response to nucleosome depletion, suggesting a histone dose-independent mechanism. Loss of nucleosomes also occurs in a non-random fashion and with distinct structural changes that appear to relate to differences in transcriptional machinery and promoter elements at gene classes. Overall, this behavior is consistent with the active placement of nucleosomes surrounding transcription start sites and suggests that statistical packing principles, once thought to organize a large portion of the genome, may not be as prominent.
机译：染色质是在真核中发现的DNA和蛋白质的集合，被组织成一个独特的结构以促进基因组DNA的紧缩。染色质结构在真核生物中高度保守，染色质的组织对核苷酸序列中存储的遗传信息的可及性和功能性具有深远的影响。这项研究的目的是增进我们对控制全球原则的理解染色质结构。本文的工作利用了酿酒酵母的遗传模型，因为它具有较高的实验可操作性，强大的真核转录机制保守性和广泛的基因组注释。本论文以定义全基因组染色质图谱实验中存在的技术偏见并概述标准化的染色质结构全基因组图谱的收集和分析的改进方法的开发与验证为开始。标准化的染色质结构收集和分析最终实现了全基因组染色质状态之间的无偏比较，这有助于扩展我们对染色质生物学的理解。因此，通过使用这种改进的方法来绘制和比较在各种实验上受干扰的染色质状态下的全基因组染色质结构，探索了基因组组织的总体原理。首先，在存在和不存在保守转录阻遏物的情况下比较了全基因组染色质结构已知通过染色质起作用的蛋白质Tup1p。野生型和tup1Delta分析；染色质结构能够确定Tup1p在建立核小体定位和在转录起始位点上游直接位于-1和-2启动子核小体中的占主导地位的显性作用，这是抑制机制的一部分。此外，对Tup1调控基因上的染色质组织的分析表明，Tup1调控与转录可塑性之间存在联系，从而更多开放的启动子结构被大量具有不同模式的调控因子所靶向，从而能够在不同环境中实现更多可变的基因表达。最后，在实验性核小体耗竭之后，对全基因组染色质结构进行定位和比较，以探索组蛋白剂量在染色质组织中的作用。对核小体耗竭的结构反应提示了建立5'壁垒的替代机制，核小体针对该壁垒进行了包装，并确定了5'核小体之间的间隔。通过对组蛋白剂量敏感的机制来建立基因5'端的包装障碍，而5'核小体之间的间隔可响应核小体耗竭而更有弹性地保持，这表明了组蛋白剂量独立的机制。核小体的损失也以非随机的方式发生，并具有明显的结构变化，这些变化似乎与基因类别上转录机制和启动子元件的差异有关。总的来说，这种行为与围绕转录起始位点的核小体的主动定位是一致的，并表明统计包装原理，曾经被认为可以组织大部分基因组，但可能并不那么重要。

著录项

  • 作者

    Rizzo, Jason Michael.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Biochemistry.;Bioinformatics.;Genetics.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 163 p.
  • 总页数 163
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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