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.

项目概要 转座元件 (TE) 是基因组寄生虫，会对宿主活力和生育力产生负面影响。 尽管 TE 具有有害影响，但它们在几乎所有真核生物中都占了相当大的比例。 调查的基因组。真核生物基因组在细胞学上可分为常染色质和异染色质， 后者是紧密包装的 DNA，通常与抑制表达有关。虽然 大多数物种的异染色质都充满了退化的TE，宿主常染色质的比例 潜在活性 TE 所占据的基因组在不同物种之间存在显着差异（例如，人类、 45%；果蝇，5.4%）。该提案旨在了解分子和进化 导致广泛观察到但知之甚少的 TE 物种间差异的机制 内容，这对于理解真核基因组进化和遗传学至关重要 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，并消除强度的变化 选择的不同预计会导致宿主基因组之间 TE 含量的差异。之前的大部分工作 TE 的有害影响集中在 TE 引起的 DNA 物理破坏的后果上。 相反，该提案重点关注 TE 很大程度上尚未探索的表观遗传效应。本构型 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色区域的空间相互作用。在常染色质中， 活性 TE 可以通过宿主定向富集抑制性表观遗传标记来沉默，这也被 观察到顺式扩散到邻近基因中，从而在表观遗传上损害基因功能。通过使用 以果蝇为模型，本提案将结合Hi-C分析和细胞生物学实验来 研究常染色质 TE 是否通过空间相互作用对邻近基因产生表观遗传影响 组成型异染色质，这将识别以前未知的 TE 表观遗传效应（目标 1）。主持人 已知基因型和环境条件可以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 将测试常染色质中的 TE（目标 2）。最后，该提案将使用比较功能基因组学和 系统发育分析来检验调节宿主成分的物种间变异的假设 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含量的不同 跨越果蝇系统发育。