Dietary effects on the sperm epigenome

饮食对精子表观基因组的影响

基本信息

批准号：
10355482
负责人：
OLIVER J RANDO
金额：
$ 65.55万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-14 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355482
关键词：
Address Affect Animals Behavior Binding Biological Biological Process Biology Caenorhabditis elegans Cells Child DNA Sequence Development Diabetes Mellitus Diet Dissection Embryo Embryo Transfer Environment Environmental Exposure Epidemiology Epididymis Epigenetic Process Exposure to Fertilization Foundations Future Future Generations Generations Genes Genome Genomics Germ Cells Goals Grant Health Health Promotion Heritability Human Individual Injections Intracytoplasmic Sperm Injections Investigation Link Literature Maize Mammals Measures Metabolic Metabolic Control Metabolic Diseases Metabolism Microinjections Molecular Molecular Biology Mus Oocytes Paternal Exposure Pathway interactions Phenotype Physiological Physiology Play Pre-implantation Embryo Development Quality of life RNA RNA Interference Regulation Reproductive Biology Rodent Role Signal Transduction Small RNA Surveys Time Toxic Environmental Substances Transfer RNA blastocyst dietary embryo culture embryonic stem cell environmental disparity epidemiology study epigenome epigenomics human disease innovation insight male next generation nicotine exposure offspring preimplantation public health relevance reproductive tract response small molecule social defeat sperm cell sperm function stem cell model stressor transcriptome sequencing transgenerational epigenetic inheritance zygote

项目摘要

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.

项目概要/摘要尽管 DNA 序列的遗传是大多数遗传力的基础生物学上，越来越清楚的是，基因组之外的信息——称为表观遗传信息 - 也传递给下一代，具有巨大的在过去的十年里，我们已经取得了对健康和发展的影响。在小鼠中开发了几种父系效应范例来解决表观遗传如何配子中的信息影响后代的表型，以及配子是否动物的环境条件会影响可遗传的表观遗传信息，从而“重新编程”后代的表型，我们发现了父系的表现型。环境暴露可以重复地改变后代的生理机能，而我们揭示这种信息传递背后的分子机制，聚焦精子 RNA 在控制早期哺乳动物中的作用尚未被探索发展。小RNA在充分表征的跨代细胞中发挥着核心作用表观遗传范式，例如玉米和 RNA 的副突变线虫中的干扰，并且越来越清楚的是，小RNA 哺乳动物的精子在早期胚胎中发挥着关键的功能作用。总体精子小RNA有效负载对于早期发育至关重要，但水平精子中的许多特定小 RNA 已被证明会因反应而发生变化这些早期且令人兴奋的研究激发了人们对父亲环境条件的兴趣。更全面地表征小RNA在哺乳动物中的作用发展。在此，我们建议采取三部分的监管方法在第一部分中，我们研究了精子小RNA在植入前胚胎中的功能。提出系统地表征早期精子 RNA 的功能胚胎，操纵受精卵中的小 RNA 水平并测量结果接下来，我们计划调查单胚胎 RNA 测序的监管后果。环境对精子 RNA 的影响，建立了大部分相同条件下可信的父子效应范式和测量精子 RNA 水平和由此产生的早期胚胎调控后果最后，我们试图揭示对这些环境扰动的反应。 5' tRNA 片段功能的潜在机制，一个尚未得到充分研究的机制包含主要小 RNA 种类的一类调节分子由成熟哺乳动物的精子携带。总之，这些研究将为我们提供前所未有的见解。哺乳动物精子中小RNA水平的调节及其在精子中的功能这些对植入前胚胎的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并潜在地操纵后代表型促进健康。