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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：
9889155
负责人：
OLIVER J RANDO
金额：
$ 66.89万
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889155
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 Quality of life RNA RNA Interference Regulation Reproductive Biology Rodent Role Signal Transduction Small RNA Surveys Time Toxic Environmental Substances Transfer RNA blastocyst embryo culture embryonic stem cell 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.

项目总结/文摘