Dietary effects on the sperm epigenome

项目摘要/摘要 尽管DNA序列的遗传是大多数遗传性的基础 生物学，越来越清楚的是，基因组以外的信息--众所周知的 表观遗传信息-也传递给下一代，有大量的 对健康和发展的影响。在过去的十年里，我们已经 在小鼠身上开发了几种父系效应范例来解决表观遗传 配子中的信息影响后代的表型，以及 动物的环境条件会影响可遗传的表观遗传信息， 从而对后代的表型进行“重新编程”。我们发现当父亲的 环境暴露可以重复地改变后代的生理，而我们正在 揭示这种信息传递背后的分子机制，专注于 精子RNA在控制早期哺乳动物中的作用尚未被发现 发展。 小RNA在具有良好特征的跨代 玉米和RNA中的表观遗传范式，如参数突变 对线虫的干扰，越来越明显的是，在线虫中的小RNA 哺乳动物精子在早期胚胎中起着关键的功能作用。不仅是因为 总体精子小RNA有效载荷对早期发育至关重要，但水平 精子中许多特定的小RNA已经被证明会随着反应的改变而改变 父亲的环境条件。这些早期和令人兴奋的研究激发了 更全面地描述小RNA在哺乳动物中的作用 发展。 在这里，我们建议采取三个部分的方式来监管和 精子小RNA在着床前胚胎中的作用在第一部分中，我们 建议对精子RNA的早期功能进行系统的表征 胚胎，操纵受精卵中的小RNA水平并测量结果 单胚胎RNA序列的调控后果。接下来，我们计划调查 环境对精子RNA的影响，建立了大多数 同样条件和测量条件下的可信父权效应范式 精子RNA水平和由此导致的早期胚胎调控后果 对这些环境扰动的反应。最后，我们试图揭开 5‘tRNA片段功能的潜在机制，一个研究不足的 一类调节分子，构成占主导地位的小RNA物种 由成熟的哺乳动物精子携带。 总而言之，这些研究将提供前所未有的洞察 哺乳动物精子中小RNA水平的调节及其在精子中的功能 植入前胚胎。这些对表观遗传信号的系统分析 精子不仅将揭示生物遗传的新原理，而且还将 使我们能够预测和潜在地操纵后代的表型 促进健康。

Project Summary/Abstract Although inheritance of DNA sequence underpins the majority of heritability in biology, it is increasingly clear that information beyond the genome – known as epigenetic information – is also transmitted to the next generation, with vast implications for health and development. Over the past decade, we have developed several paternal-effect paradigms in mice to address how epigenetic information in gametes affects the phenotype of offspring, and whether an animal's environmental conditions can affect heritable epigenetic information, thereby “reprogramming” the offspring's phenotype. We discovered that paternal environmental exposures can reproducibly alter offspring physiology, and we are uncovering molecular mechanisms underlying this information transfer, focusing on the largely unexplored role for sperm RNAs in control of early mammalian development. Small RNAs play central roles in well-characterized transgenerational epigenetic inheritance paradigms such as paramutation in maize and RNA interference in C. elegans, and it is increasingly clear that small RNAs in mammalian sperm play key functional roles in the early embryo. Not only is the overall sperm small RNA payload essential for early development, but the levels of many specific small RNAs in sperm have been shown to change in response to paternal environmental conditions. These early and exciting studies motivate a more thorough characterization of the role of small RNAs in mammalian development. Here, we propose to take a three part approach to the regulation and function of sperm small RNAs in preimplantation embryos. In the first part, we propose to systematically characterize the functions of sperm RNAs in the early embryo, manipulating small RNA levels in zygotes and measuring resulting regulatory consequences by single-embryo RNA-Seq. Next, we plan to survey the landscape of environmental effects on sperm RNAs, establishing most of the credible paternal effect paradigms under the same conditions and measuring sperm RNA levels and resulting early embryonic regulatory consequences in response to these environmental perturbations. Finally, we seek to uncover the mechanisms underlying the functions of 5' tRNA fragments, an understudied class of regulatory molecules which comprise the dominant small RNA species carried by mature mammalian sperm. Together, these studies will provide unprecedented insights into the regulation of small RNA levels in mammalian sperm, and their functions in the preimplantation embryo. These systematic analyses of epigenetic signals in sperm will not only reveal new principles of biological inheritance, but will also enable us to predict and potentially manipulate offspring phenotypes in ways that promote health.