Sexual dimorphism of piRNA transcription and target silencing mechanisms in C. elegans

线虫 piRNA 转录的性别二态性和靶标沉默机制

• 批准号: 10673887
• 负责人: John Kim
• 金额: $ 47.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673887
• 关键词: Animals; Automobile Driving; Binding; Binding Sites; Biogenesis; Biological; Caenorhabditis elegans; Complex; Computational algorithm; Data; Development; Elements; Ensure; Equilibrium; Exhibits; Family; Female; Fertility; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Goals; Human; Infertility; Maintenance; Organism; Pathway interactions; Phenotype; Process; Publishing; RNA; Regulation; Regulator Genes; Regulatory Element; Repression; Research; Role; Small Nuclear RNA; Small RNA; Specificity; Spermatogenesis; Spliceosomes; System; Testing; Therapeutic; Variant; cofactor; fly; genome integrity; insight; male; male health; molecular scale; mutant; novel; paralogous gene; piRNA; preservation; promoter; recruit; reproductive; sex; sexual dimorphism; transcription factor; transcriptomics; transposon/insertion element

Abstract The Piwi-interacting RNA (piRNA) pathway promotes animal fertility by protecting the germline genome against mobile DNA elements. Despite this well-established paradigm, several critical gaps remain in our understanding of piRNA mechanisms, including the sexual dimorphism of their biogenesis and downstream gene regulatory functions. We discovered that the ancient SNAPc (or SNPC) transcription complex that transcribes small nuclear RNAs (snRNAs) of the spliceosome has diversified in C. elegans to drive the expression of male- and female- specific piRNAs, in addition to its canonical function in snRNA transcription. In the fly and human, the SNPC holocomplex is composed of SNPC-1, SNPC-3, and SNPC-4 subunits, each encoded by a single gene. In contrast, C. elegans expresses several paralogs of SNPC-1 and SNPC-3 that we propose dictate the specificity of three distinct SNPC complexes. In particular, based on our published and preliminary data, we hypothesize that the SNPC-1 paralogs comprise the primary specificity factors that define the unique functions of each SNPC complex for either snRNA or sex-specific piRNA transcription. In this proposal, we will first investigate how this specificity is achieved by identifying the cis-regulatory elements recognized by each SNPC transcription complex (Aim 1). We will also determine the specificity domains, cofactors, and subcellular assembly of the piRNA and snRNA SNPC complexes (Aim 2). Finally, we will characterize the biological phenotypes of the male and female piRNA mutants and leverage these insights to predict and validate endogenous gene targets of sex-specific piRNAs. Collectively, this research will bridge the gaps in our understanding of sexual dimorphism in piRNA transcription and gene targeting mechanisms that ensure proper germline development and robust reproductive capacity of animals. 1

摘要