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 父母的饮食等环境影响会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是很好- 明白了。而生殖细胞中的小RNA、组蛋白修饰和DNA甲基化可以 作为信号调节跨代表观遗传的功能，对 这些信号是如何被调控的机制。这在一定程度上是由于缺乏遗传模型系统， 适合开展详细调查。 X连锁基因Rlim编码环指E3连接酶，其功能是主要的表观遗传学 在雌性小鼠中，由于它对印记X染色体失活(IXCI)至关重要，所以 女性植入前父系传递X染色体的表观遗传学沉默 胚胎实现X剂量补偿。事实上，一种母性传播的Rlim KO等位基因 导致雌性胚胎早期死亡，而缺乏Rlim的雄性发育到成年。我们 最近的研究表明，在男性的睾丸中，Rlim在支持细胞(SCs)和 在圆形精细胞期的生精细胞中。尽管有生育能力，但患有系统性疾病的小鼠 切除Rlim会产生更少的精子，这也是功能障碍。目标是有条件的 KO(CKO)对睾丸细胞类型的影响，我们发表的结果表明，Rlim在 正常的精子发生需要的是生精细胞，而不是干细胞。 我们发现，父亲系统性缺乏林姆的后代不会受到高脂肪饮食的影响 高脂血症(HFD)导致的肥胖是一种跨代表观遗传效应。瞄准Rlim的CKO in 父亲们，我们证明了干细胞中Rlim的缺失概括了这一效应。作为父亲的信号 传递跨代效应是通过精子传递的，我们未发表的结果提供了 一种新的SC精子-hfd反应在后代途径中的遗传学证据。 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 A)阐明Rlim在SCs中作用的分子机制，B)鉴定表观遗传信号 精子及其产生方式，以及C)最终发现后代的下游效应 导致HFD反应的变化。 未来研究的首要目标是将Rlim小鼠模型建立为一种新颖的 跨代表观遗传调控范式。这项研究将定义SC精子 在更大的生物学背景下的后代途径，并使用尖端技术，将识别 新的和基本的表观遗传机制。