How transposable elements drive genome evolution through epigenetic mechanisms

转座元件如何通过表观遗传机制驱动基因组进化

• 批准号: 10272742
• 负责人: Grace Yuh Chwen Lee
• 金额: $ 38.23万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272742
• 关键词: 3-Dimensional; Affect; Biochemical; Cellular biology; Colon Carcinoma; DNA; DNA Insertion Elements; DNA Sequence; DNA Transposable Elements; Disease; Drosophila genus; Epigenetic Process; Evolution; Exhibits; Fertility; Genes; Genetic; Genetic Processes; Genome; Genomics; Goals; Health; Hereditary Disease; Human; Human Genome; Inherited; Laboratories; Malignant Neoplasms; Mediating; Modeling; Molecular; Nuclear; Organism; Parasites; Positioning Attribute; RNA; Research; Role; Salamander; Selfish DNA; Shapes; Structure; Tetraodontidae; Transgenic Organisms; Variant; chromatin modification; comparative; epigenetic silencing; fitness; genome-wide; leukemia; malignant breast neoplasm; novel; programs; species difference; vertebrate genome

PROJECT SUMMARY Transposable elements (TEs) are genomic parasites that can negatively impact host viability and fertility. They have been identified as the causes of inherited human disorders and cancers. Despite their detrimental effects, TEs are prevalent across eukaryotic genomes and exhibit dramatic variation in abundance and genomic positions within and between species. For instance, the proportion of vertebrate genomes occupied by TEs ranges from only 6% in pufferfish to 65% in salamander. Over 45% of the human genome harbors TEs, and any two people differ by at least a thousand TE insertions. However, it remains unclear what evolutionary forces drive TE variation and how that influences functions and, thereby, host health. Most studies of the harmful effects of TEs have centered on TE-mediated physical disruption of DNA and changes in DNA sequences. While such genetic disturbances have important consequences, this paradigm overlooks the detrimental epigenetic effects mediated by TEs, including biochemical modifications of chromatin and reorganization of three-dimensional (3D) genome structures. My recent pioneering studies revealed, on a genome-wide scale, that epigenetically silenced TEs can perturb the function of neighboring genes through cis spreading of silencing marks (cis epigenetic effects of TEs) and alter 3D genome organization (3D epigenetic effects of TEs). These exciting observations offer a possibility to answer long-unresolved questions about why there are between-species differences in TE content and how these differences affect genome function and evolution—the overarching goals of my research program. My laboratory uses Drosophila as a primary model and integrates evolutionary genomics and cell biology to decipher the functional and evolutionary significance of TE variation. One major goal of my research program is to determine how TE variation influences genome evolution through my newly discovered 3D epigenetic effects of TEs. My research group will use integrative genomic analysis at multiple levels (DNA, RNA, epigenetics, and 3D genome structures) to investigate our hypothesis that the 3D epigenetic effects mediated by TEs can produce varying 3D genome organization. We further predict that this TE-mediated variation in 3D genome structures can shape genome evolution by affecting fundamental genetic processes. In addition, my laboratory seeks to identify the molecular and evolutionary mechanisms contributing to between-species differences in TE content. We will use Drosophila genetics and transgenics to identify host genetic factors that modulate the epigenetic effects of TEs in cis and in 3D nuclear space. Furthermore, we will combine comparative evolutionary genomics and experimental evolution to investigate our hypothesis that between-species variation in these host genetic factors contributes to varying epigenetic effects of TEs and ultimately drives the evolution of divergent TE content across Drosophila species. Our discoveries will provide a novel basis for understanding eukaryotic genome evolution and open new perspectives for TEs' roles in human health and disease.

项目摘要 转座因子（TE）是基因组寄生虫，可以对宿主的生存力和生育力产生负面影响。他们 已被确定为遗传性人类疾病和癌症的原因。尽管它们有有害的影响， TE在真核生物基因组中普遍存在，并且在丰度和基因组遗传多样性方面表现出显著的变化。 物种之间和物种之间的关系。例如，脊椎动物基因组中被TE占据的比例 从河豚的6%到蝾螈的65%。超过45%的人类基因组含有TE， 任何两个人都至少有一千个TE插入不同。然而，目前还不清楚进化的原因是什么。 力驱动TE变化，以及如何影响功能，从而影响宿主健康。大多数研究 TE的有害影响集中在TE介导的DNA物理破坏和DNA的变化 序列的虽然这种遗传干扰具有重要的后果，但这种范式忽视了 TE介导的有害表观遗传效应，包括染色质的生化修饰， 三维（3D）基因组结构的重组。我最近的开创性研究表明， 在全基因组范围内，表观遗传沉默的TE可以通过顺式干扰邻近基因的功能， 沉默标记的扩散（TE的顺式表观遗传效应）和改变3D基因组结构（3D表观遗传效应 的影响）。这些令人兴奋的观察结果为回答长期悬而未决的问题提供了可能性， TE含量存在物种间差异，这些差异如何影响基因组功能， 进化-我的研究计划的首要目标。我的实验室用果蝇作为主要模型 并整合了进化基因组学和细胞生物学， 的变化。我的研究计划的一个主要目标是确定TE变异如何影响基因组 通过我新发现的TE的3D表观遗传效应进行进化。我的研究小组将使用综合方法 多层次的基因组分析（DNA，RNA，表观遗传学和3D基因组结构），以研究我们的 假设TE介导的3D表观遗传效应可以产生不同的3D基因组组织。我们 进一步预测，这种TE介导的3D基因组结构变异可以通过以下方式塑造基因组进化： 影响基本的遗传过程此外，我的实验室试图确定分子和 导致TE含量物种间差异的进化机制。我们会用果蝇 遗传学和转基因学，以确定调节顺式TE的表观遗传效应的宿主遗传因子， 在3D核空间中。此外，我们将结合联合收割机比较进化基因组学和实验 进化来研究我们的假设，即这些宿主遗传因素的种间变异有助于 不同的表观遗传效应的TE，并最终推动不同的TE内容的演变， 果蝇属。我们的发现将为理解真核生物基因组进化提供新的基础 并为TE在人类健康和疾病中的作用开辟了新的视角。