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.

项目摘要/摘要尽管DNA序列的遗传是大部分遗传力的基础生物学，越来越清楚的是，基因组以外的信息 - 称为表观遗传信息 - 还通过疫苗传输到下一代对健康和发展的影响。在过去的十年中，我们有在小鼠中开发了几种父亲效应范例，以解决表观遗传的方式游戏中的信息会影响后代的表型，以及是否存在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。我们发现父亲环境暴露可以可重复地改变后代生理学，我们是揭示此信息传输的基础的分子机制，聚焦关于精子RNA在控制早期哺乳动物中的意外作用发展。小型RNA在特征良好的转型中扮演着核心角色表观遗传遗传范式，例如玉米和RNA的参数干扰秀丽隐杆线虫，越来越明显的是哺乳动物精子在早期胚胎中扮演关键功能角色。不仅是总体精子小RNA有效载荷对于早期开发至关重要，但是水平精子中许多特定的小RNA中的反应发生了变化到父亲环境条件。这些早期和令人兴奋的研究激发了小RNA在哺乳动物中的作用更彻底的表征发展。在这里，我们建议对法规采取三个部分的方法精子小RNA在植入前胚胎中的功能。在第一部分，我们提出系统地表征精子RNA在早期的功能的提议胚胎，操纵Zygotes中的小RNA水平并测量结果单晶RNA序列的调节后果。接下来，我们计划调查环境对精子RNA的影响，建立大多数在相同条件下的可信父亲效应范例和测量精子RNA水平和产生的早期胚胎调节后果对这些环境扰动的反应。最后，我们试图发现 5'tRNA片段功能的基础机制，一个理解的构成主要小RNA物种的调节分子类由成熟的哺乳动物精子携带。这些研究将共同提供前所未有的见解调节哺乳动物精子中小的RNA水平及其在植入前胚胎。这些对表观遗传信号的系统分析精子不仅会揭示生物遗传的新原则，而且还将使我们能够以方式预测并潜在地操纵后代表型促进健康。