Transgenerational epigenetic regulation by Rlim

Rlim 的跨代表观遗传调控

• 批准号: 10406547
• 负责人: INGOLF M BACH
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406547
• 关键词: Ablation; Adult; Affect; Alleles; Biological; Biological Models; DNA Methylation; Diet; Dosage Compensation (Genetics); Embryo; Energy Metabolism; Epigenetic Process; Fathers; Female; Genes; Genetic; Genetic Models; Germ Cells; Goals; High Fat Diet; Investigation; Knockout Mice; Link; Mediating; Molecular; Mus; Pathway interactions; Publishing; Regulatory Pathway; Research; Ring Finger Domain; Signal Transduction; Small RNA; Spermatids; Spermatogenesis; Spermatogenic Cell; Technology; Testis; X Chromosome; X Inactivation; blastocyst; cell type; diet-induced obesity; epigenetic regulation; epigenetic silencing; histone modification; imprint; male; mouse model; next generation; novel; offspring; response; sertoli cell; sperm cell; transgenerational epigenetic inheritance; ubiquitin-protein ligase

Project Summary Parental environmental influences such as diet affect energy metabolism in the next generation but the underlying mechanisms for such transgenerational epigenetic inheritance are not well- understood. While small RNAs, histone modifications and DNA methylation in germ cells can function as signals mediating transgenerational epigenetic inheritance, very little is known on the mechanisms how these signals are regulated. This in part due to a lack of genetic model systems, suitable for carrying out detailed investigations. The X-linked gene Rlim encodes a RING finger E3 ligase that functions as a major epigenetic regulator in female mice, as it is crucial for imprinted X chromosome inactivation (iXCI), the epigenetic silencing of the paternally transmitted X chromosome in female preimplantation embryos to achieve X dosage compensation. Indeed, a maternally transmitted Rlim KO allele results in early embryonic lethality in females, while males lacking Rlim grow into adulthood. We recently showed that in testes of males Rlim is highly expressed both in Sertoli cells (SCs) and in spermatogenic cells at the round spermatid stage. Despite being fertile, mice with systemic ablation of Rlim produce less sperm which additionally is dysfunctional. Targeting a conditional KO (cKO) to testicular cell types, our published results demonstrate that Rlim activity in spermatogenic cells but not SCs is required for normal spermatogenesis. We found that offspring sired by fathers systemically lacking Rlim is protected from high fat diet (HFD)-induced obesity in a transgenerational epigenetic effect. Targeting the cKO of Rlim in fathers, we demonstrate that lack of Rlim in SCs recapitulates this effect. As paternal signals transmitting transgenerational effects are transmitted in sperm, our unpublished results provide genetic evidence for a novel SCspermHFD-response in offspring pathway. Our future research research will exploit our unique Rlim cKO mice to investigate this pathway to A) elucidate molecular mechanisms of Rlim action in SCs, B) identify the epigenetic signal in sperm and how it is generated, and C) uncover downstream effects in offspring ultimately leading to changes in HFD-response. The overarching goal of the future research is to establish the Rlim mouse model as a novel paradigm for transgenerational epigenetic regulation. This research will define the SCsperm offspring pathway in a larger biological context and, using cutting edge technologies, will identify new and fundamental epigenetic mechanisms.

项目摘要 父母的环境影响，如饮食，影响下一代的能量代谢 但这种跨代表观遗传的潜在机制并不完善， 明白虽然生殖细胞中的小RNA、组蛋白修饰和DNA甲基化可以 功能作为信号介导跨代表观遗传遗传，很少有人知道， 这些信号是如何被调节的。这部分是由于缺乏遗传模型系统， 适合进行详细的调查。 X连锁基因Rlim编码一种环指E3连接酶，其作为主要的表观遗传调节因子发挥作用。 调节因子在雌性小鼠中的作用，因为它对印记X染色体失活（iXCI）至关重要， 女性植入前父系遗传X染色体的表观遗传沉默 胚胎，以实现X剂量补偿。事实上，母系传播的Rlim KO等位基因 导致雌性的早期胚胎死亡，而缺乏Rlim的雄性则生长到成年。我们 最近的研究表明，在雄性睾丸中，Rlim在支持细胞（SC）和 在圆形精子细胞阶段的生精细胞中。尽管具有生育能力，但全身性 切除Rlim产生更少精子，这另外是功能障碍的。针对条件 KO（cKO）的睾丸细胞类型，我们发表的结果表明，Rlim活性， 正常精子发生需要生精细胞而不是SC。 我们发现，父亲系统性缺乏Rlim的后代可以免受高脂肪饮食的影响。 （HFD）诱导的肥胖症的跨代表观遗传效应。靶向Rlim的cKO， 父亲，我们证明，缺乏Rlim在SC重演这种效果。作为父亲的信号 我们未发表的研究结果表明， 遗传学证据表明，后代途径中存在一种新的SC精子HFD应答。 我们未来的研究将利用我们独特的Rlim cKO小鼠来研究这一途径 为了A）阐明Rlim在SC中作用的分子机制，B）鉴定在SC中的表观遗传信号， 精子及其产生方式，以及C）最终揭示对后代的下游影响 导致HFD反应的变化。 未来研究的总体目标是建立Rlim小鼠模型， 跨代表观遗传调节的范例。这项研究将确定SC精子的数量， 后代途径在更大的生物背景下，并利用尖端技术，将确定 新的和基本的表观遗传机制。