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Regulatory Elements and Gene Expression in Primates and Diverse Human Cell-types.

机译：灵长类动物和多种人类细胞类型的调控元件和基因表达。

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摘要

After finishing a human genome reference sequence in 2002, the genomics community has turned to the task of interpreting it. A primary focus is to identify and characterize not only protein-coding genes, but all functional elements in the genome. The effort has identified millions of regulatory elements across species and in hundreds of human cell-types. Nearly all identified regulatory elements are found in non-coding DNA, hypothesizing a function for previously unannotated sequence. The ability to identify regulatory DNA genome-wide provides a new opportunity to understand gene regulation and to ask fundamental questions in diverse areas of biology.;One such area is the aim to understand the molecular basis for phenotypic differences between humans and other primates. These phenotypic differences are partially driven by mutations in non-coding regulatory DNA that alter gene expression. This hypothesis has been supported by differential gene expression analyses in general, but we have not yet identified specific regulatory variants responsible for differences in transcription and phenotype. I have worked to identify regulatory differences in the same cell-type isolated from human, chimpanzee, and macaque. Most regulatory elements were conserved among all three species, as expected based on their central role in regulating transcription. However, several hundred regulatory elements were gained or lost on the lineages leading to modern human and chimpanzee. Species-specific regulatory elements are enriched near differentially expressed genes, are positively correlated with increased transcription, show evidence of branch-specific positive selection, and overlap with active chromatin marks. Species-specific sequence differences in transcription factor motifs found within this regulatory DNA are linked with species-specific changes in chromatin accessibility. Together, these indicate that species-specific regulatory elements contribute to transcriptional and phenotypic differences among primate species.;Another fundamental function of regulatory elements is to define different cell-types in multicellular organisms. Regulatory elements recruit transcription factors that modulate gene expression distinctly across cell-types. In a study of 112 human cell-types, I classified regulatory elements into clusters based on regulatory signal tissue specificity. I then used these to uncover distinct associations between regulatory elements and promoters, CpG-islands, conserved elements, and transcription factor motif enrichment. Motif analysis identified known and novel transcription factor binding motifs in cell-type-specific and ubiquitous regulatory elements. I also developed a classifier that accurately predicts cell-type lineage based on only 43 regulatory elements and evaluated the tissue of origin for cancer cell-types. By correlating regulatory signal and gene expression, I predicted target genes for more than 500k regulatory elements. Finally, I introduced a web resource to enable researchers to explore these regulatory patterns and better understand how expression is modulated within and across human cell-types.;Regulation of gene expression is fundamental to life. This dissertation uses identified regulatory DNA to better understand regulatory systems. In the context of either evolutionary or developmental biology, understanding how differences in regulatory DNA contribute to phenotype will be central to completely understanding human biology.
机译：在2002年完成人类基因组参考序列后，基因组学界开始着手解释它。主要重点是不仅要识别和表征蛋白质编码基因，而且要鉴定和表征基因组中的所有功能元件。这项工作已经确定了跨物种和数百种人类细胞类型的数百万个调控元件。几乎所有已鉴定的调控元件都存在于非编码DNA中，从而推测了先前未注释序列的功能。在整个基因组范围内识别调节性DNA的能力为理解基因调节和提出生物学各个领域的基本问题提供了新的机会。其中一个领域是旨在了解人类与其他灵长类动物之间表型差异的分子基础。这些表型差异部分由改变基因表达的非编码调控DNA突变驱动。通常，差异基因表达分析支持了该假设，但我们尚未鉴定出负责转录和表型差异的特定调控变异体。我已经努力确定从人类，黑猩猩和猕猴分离出的同一细胞类型的调控差异。正如预期的那样，大多数调节元件在这三个物种中均是保守的，因为它们在调节转录中起着核心作用。但是，在导致现代人类和黑猩猩的血统中获得或失去了数百种调节元素。物种特异性调控元件在差异表达基因附近富集，与转录增加呈正相关，显示分支特异性阳性选择的证据，并与活性染色质标记重叠。在该调节DNA中发现的转录因子基序中的物种特异性序列差异与染色质可及性的物种特异性变化有关。总之，这些表明物种特异性调控元件促成灵长类物种之间的转录和表型差异。调控元件的另一基本功能是定义多细胞生物中的不同细胞类型。调节元件募集转录因子，这些转录因子可在不同细胞类型之间显着调节基因表达。在对112种人类细胞类型的研究中，我根据调节信号组织的特异性将调节元件分为几类。然后，我用它们揭示了调控元件和启动子，CpG-岛，保守元件和转录因子基序富集之间的独特联系。母题分析在细胞类型特异性和普遍存在的调节元件中鉴定出已知和新颖的转录因子结合基序。我还开发了一种分类器，该分类器仅基于43种调控元件即可准确预测细胞类型谱系，并评估癌细胞类型的起源组织。通过关联调节信号和基因表达，我预测了超过500k调节元件的靶基因。最后，我介绍了一个网络资源，以使研究人员能够探索这些调控模式并更好地理解人类细胞内和跨人类细胞类型的表达调控。基因表达的调控是生命的基础。本文利用已鉴定的调控DNA更好地理解调控系统。在进化生物学或发育生物学的背景下，了解调节性DNA的差异如何影响表型将是完全了解人类生物学的核心。

著录项

  • 作者

    Sheffield, Nathan C.;

  • 作者单位

    Duke University.;

  • 授予单位 Duke University.;
  • 学科 Biology Cell.;Biology Bioinformatics.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 164 p.
  • 总页数 164
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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