Mechanisms and evolutionary consequences of transposon strategies to counteract host silencing

对抗宿主沉默的转座子策略的机制和进化后果

• 批准号: 10744339
• 负责人: Christopher Eugene Ellison
• 金额: $ 6.8万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10744339
• 关键词: Address; Affect; Agreement; Biological Assay; Candidate Disease Gene; Clustered Regularly Interspaced Short Palindromic Repeats; Codon Nucleotides; Conflict (Psychology); DNA; DNA Insertion Elements; DNA Transposable Elements; Data; Drosophila genus; Drosophila melanogaster; Elements; Equation; Eukaryota; Event; Gene Expression; Gene Expression Regulation; Gene Silencing; Gene Targeting; Genes; Genetic; Genome; Goals; Health; Homologous Gene; Host Defense; Human; Intervention; Knowledge; Laboratories; Measures; Mediating; Mendelian disorder; Mission; Modeling; Mutation; Organism; Outcome; Ovary; Pathway interactions; Phenotype; RNA Interference; Repression; Research; Selfish Genes; Side; Small RNA; Sterility; Testing; Transcriptional Silencer Elements; United States National Institutes of Health; Untranslated RNA; Up-Regulation; arms race; comparative genomics; fitness; genome editing; histone acetyltransferase; innovation; insight; knock-down; mutant; novel; piRNA; telomere; theories; transcriptome sequencing

PROJECT SUMMARY Harboring active transposable elements (TEs) imposes a substantial mutational burden on the host genome. To reduce this burden, most organisms have evolved sophisticated, and often multi-layered, mechanisms for identifying and inactivating TEs. In spite of these defenses, active TEs are found in the genomes of almost all eukaryotes. One explanation for the evolutionary persistence of TEs is that they are in an “arms race” with their host genome: TEs are constantly evolving novels ways to block or evade host silencing while the host genome is continuously evolving to re-establish TE suppression. While this theory is appealing, there is a gap in knowledge because the mechanisms by which TEs could block or evade host defenses are largely unknown. The long-term goal of this applicant’s laboratory is to understand the evolutionary dynamics of TE/host co- evolution. The overall objective of this project is to understand and functionally validate a novel TE strategy, discovered in the applicant’s laboratory, that involves TEs using their own piRNAs to target host silencing factors for suppression. Preliminary data produced in the applicant’s laboratory suggests that the Drosophila melanogaster telomeric transposon TART-A captured a portion of the host TE silencing factor nxf2, which allows TART-A to produce piRNAs targeting nxf2 for suppression. The rationale for the proposed research is that it will provide critical insight into the mechanisms of host-TE conflict and how TE counter-defense strategies can impact host gene expression and fitness. The objective of this project will be achieved by pursuing three specific aims: 1) Identify genes acquired by telomeric TEs across Drosophila; 2) Determine whether non-telomeric transposons also use a piRNA-mediated counter-silencing strategy; and 3) Disrupt TE counter-silencing using CRISPR in D. melanogaster. Telomeric TEs will be identified in 28 species of Drosophila and assayed to determine whether they have acquired host gene fragments. The applicant’s laboratory has identified 45 candidate genes in D. melanogaster that share homology with TE-derived piRNAs and are known to play a role in TE suppression. These genes will be tested to determine if they suppress the same TE with which they share homology. Candidate TE/gene pairs will be validated using CRISPR genome editing to erase their shared homology, which should result in upregulation of the gene in question. The proposed research is innovative because it represents a substantial departure from the status quo: instead of the host-centric view of previous studies, which examine how the genome responds to TE activity, this project will study the TE side of the equation by investigating how TEs respond to and counteract host defenses. One of the major goals of the field is to understand why host genes involved in TE silencing are rapidly evolving. The proposed research is significant because it will support this goal by characterizing and functionally validating a specific TE counter-defense strategy, which will provide empirical support for the arms race theory, while also increasing understanding of the co-evolutionary dynamics between host genomes and their TE associates.

项目总结