Transgenerational epigenetic regulation by Rlim

Rlim 的跨代表观遗传调控

• 批准号: 10632015
• 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/10632015
• 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; transmission process; 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（例如饮食）影响下一代能量代谢 但是这种转化表观遗传的基本机制不是很好 理解齿。而小的RNA，组蛋白的修饰和生殖细胞中的DNA甲基化可以 充当介导转化性表观遗传遗传的信号，在 机制如何调节这些信号。这部分是由于缺乏遗传模型系统， 适合进行详细的调查。 X连锁的基因RLIM编码一个充当主要表观遗传的环手指E3连接酶 雌性小鼠的调节剂，因为它对于印迹X染色体灭活（IXCI）至关重要， 雌性植入植物体的亲属传播X染色体的表观遗传沉默 实现X剂量补偿的胚胎。确实，主要传播的rlim ko等位基因 导致女性的早期胚胎致死性，而缺乏Rlim的男性成年。我们 最近表明，在男性测试中，rlim在Sertoli细胞（SC）和 在圆形精子阶段的精子生成细胞中。尽管肥沃，但有全身性的老鼠 Rlim的消融产生的精子较少，此外还具有功能失调。针对条件 KO（CKO）至有证明的细胞类型，我们已发布的结果表明RLIM活动 正常精子性细胞需要精子细胞，而不是SCS。 我们发现，由父亲系统地缺乏RLIM的后代受到保护免受高脂饮食的保护 （HFD）在转化表观遗传效应中诱导的肥胖症。针对Rlim的CKO 父亲，我们证明SCS中缺乏RLIM可以概括这种效果。作为父亲信号 传播转世效应是在精子中传播的，我们未发表的结果提供了 新型SCSperm的遗传证据HFD反应在后代途径中。 我们未来的研究研究将利用我们独特的RLIM CKO小鼠来调查这一途径 a）阐明SC中RLIM作用的分子机制，b）确定表观遗传信号 精子及其生成方式，c）最终发现后代的下游效应 导致HFD响应的变化。 未来研究的总体目标是将RLIM鼠标模型建立为新颖 转化表观遗传调节的范例。这项研究将定义SCSperm 在较大的生物学环境中的后代途径，使用尖端技术将确定 新的和基本的表观遗传机制。