Functional and evolutionary consequences of the epigenetic effects of transposable elements

转座元件表观遗传效应的功能和进化后果

• 批准号: 10006836
• 负责人: Grace Yuh Chwen Lee
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006836
• 关键词: 3-Dimensional; Biological; Cancer Etiology; Cell Nucleus; Cells; Colon Carcinoma; Cytology; DNA; DNA Insertion Elements; DNA Transposable Elements; Data; Disease; Drosophila genus; Drosophila melanogaster; Elements; Environmental Risk Factor; Epigenetic Process; Euchromatin; Evolution; Family; Fertility; Gene Silencing; Genes; Genetic; Genetic Diseases; Genome; Genomics; Genotype; Hereditary Disease; Heterochromatin; Human; Human Genome; Impairment; Inherited; Integration Host Factors; Investigation; Location; Malignant Neoplasms; Modeling; Molecular; Natural Selections; Parasites; Phylogenetic Analysis; Phylogeny; Population; Positioning Attribute; Property; Proteins; Publishing; Research; Role; Sulfur; Surveys; Testing; Time; Transgenic Organisms; Variant; Work; comparative; dosage; epigenomics; experimental study; fitness; functional genomics; gene function; insight; leukemia; malignant breast neoplasm; parasite genome; side effect; species difference; transcriptomics; virtual

PROJECT SUMMARY Transposable elements (TEs) are genomic parasites that can negatively impact host viability and fertility. Despite the detrimental effects of TEs, they constitute appreciable proportions of virtually all eukaryotic genomes surveyed. Eukaryotic genomes can be cytologically divided into euchromatin and heterochromatin, with the latter being tightly packaged DNA generally associated with suppressed expression. While the heterochromatin of most species is infested with degenerated TEs, the proportions of host euchromatic genomes that are occupied by potentially active TEs are remarkably different between species (e.g., human, 45%; Drosophila melanogaster, 5.4%). This proposal aims to understand the molecular and evolutionary mechanisms contributing to the widely observed, but poorly understood, between-species differences in TE content, which will be critical for the understanding of eukaryotic genome evolution and the genetics of inherited diseases and cancers caused by TEs. Natural selection can remove deleterious TE insertions from populations, and variation in the strength of selection is expected to result in differences in TE content between host genomes. Most previous work on the deleterious effects of TEs has centered on the consequences of TE-induced physical disruption of DNA. Instead, this proposal focuses on the largely unexplored epigenetic effects of TEs. Constitutive heterochromatin has the potential to influence the epigenetic states of adjacent genes through cis-spreading of repressive epigenetic marks as well as spatial interactions with other heterochromatic regions. In euchromatin, active TEs can be silenced through host-directed enrichment of repressive epigenetic marks, which were also observed to spread in cis into adjacent genes and thereby epigenetically impair gene function. By using Drosophila as a model, this proposal will use a combination of Hi-C analysis and cell biological experiments to investigate if euchromatic TEs epigenetically impact adjacent genes through spatial interactions with constitutive heterochromatin, which will identify previously unknown epigenetic effects of TEs (Aim 1). Host genotypes and environmental conditions are known to modulate the spreading of silencing marks from heterochromatin to adjacent sequences. The influence of these host components on the epigenetic effects of TEs in euchromatin will be tested (Aim 2). Finally, this proposal will use comparative functional genomics and phylogenetic analysis to test the hypothesis that between-species variation of host components that modulate TE's epigenetic effects contributes to different epigenetic effects of TEs, and ultimately divergent TE content across the Drosophila phylogeny.

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。 尽管TE的有害影响，但它们构成了几乎所有真核生物中相当大的比例。 基因组调查。真核生物基因组在细胞学上可分为常染色质和异染色质， 后者是通常与抑制表达相关的紧密包装的DNA。而 大多数物种的异染色质都被退化的TE侵染，宿主常染色质的比例 被潜在活性TE占据的基因组在物种之间显著不同（例如，人类， 黑腹果蝇（Drosophila melanogaster）为5.4%。这项建议旨在了解分子和进化 导致TE中广泛观察到但知之甚少的种间差异的机制 内容，这将是至关重要的真核生物基因组进化和遗传学的理解， 由TE引起的遗传性疾病和癌症。 自然选择可以从种群中去除有害的TE插入， 预期选择的差异会导致宿主基因组之间TE含量的差异。以前的大多数工作 TE的有害影响集中在TE诱导的DNA物理破坏的后果上。 相反，这项建议主要集中在TE的表观遗传效应上。本构 异染色质有可能通过顺式扩散影响相邻基因的表观遗传状态。 抑制性表观遗传标记以及与其他异染色质区域的空间相互作用。在常染色质中， 活性TE可以通过宿主定向的抑制性表观遗传标记的富集而沉默， 观察到顺式扩散到相邻基因中，从而在表观遗传学上损害基因功能。通过使用 以果蝇为模型，本提案将采用Hi-C分析和细胞生物学实验相结合的方法， 研究常染色质TE是否通过空间相互作用在表观遗传上影响相邻基因， 组成性异染色质，这将确定以前未知的表观遗传效应的TE（目的1）。主机 已知基因型和环境条件调节沉默标记的传播， 异染色质与相邻序列。这些宿主成分对表观遗传效应的影响 将检测常染色质中的TE（目标2）。最后，本提案将使用比较功能基因组学， 系统发育分析，以测试的假设，种间变异的主机组件，调节 TE的表观遗传效应导致TE的表观遗传效应不同，最终导致TE含量不同 在果蝇遗传学中的应用