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.

项目总结 转座因子(TES)是一种基因组寄生虫，可以对寄主的生存能力和生育能力产生负面影响。 尽管TES有有害的影响，但它们在几乎所有真核生物中占相当大的比例。 基因组调查。真核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。而当 大多数物种的异染色质上都寄生着退化的TES，寄主的比例常染色质 由潜在活性TES占据的基因组在物种之间显著不同(例如，人类， 45%；果蝇，5.4%)。这一提议旨在理解分子和进化 导致TE的物种间差异的机制被广泛观察到，但了解得很少 内容，这将是理解真核基因组进化和人类基因组遗传学的关键 由TES引起的遗传性疾病和癌症。 自然选择可以从种群中移除有害的TE插入，并在强度上发生变化 预计选择的差异将导致寄主基因组之间TE含量的差异。大多数以前的工作是关于 TES的有害影响集中在TE诱导的DNA物理破坏的后果上。 相反，这项提案关注的是TES在很大程度上尚未被探索的表观遗传效应。构成要素 异染色质有可能通过顺式传播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， 活跃的TES可以通过宿主定向的抑制性表观遗传标记的富集化来沉默，这些标记也是 观察到顺式基因扩散到相邻的基因，从而在表观上损害基因功能。通过使用 以果蝇为模型，本方案将采用Hi-C分析和细胞生物学实验相结合的方法 研究常染色质TES是否通过空间相互作用影响邻近基因 构成异染色质，它将识别以前未知的TES的表观遗传效应(目标1)。寄主 已知的基因类型和环境条件调节沉默标记的传播。 相邻序列的异染色质。这些寄主成分对表观遗传效应的影响 将测试常染色质中的TES(目标2)。最后，这项提案将使用比较功能基因组学和 进行系统发育分析，以检验调节寄主成分的物种间变异假设 TE的表观遗传效应导致TES的表观遗传效应不同，最终导致TE含量的差异 跨越果蝇的系统发育。