Mechanism Underlying the Transduction of Epimutations from the Soma to the Male Germline

表观突变从体细胞向雄性种系转导的机制

基本信息

批准号：
10615592
负责人：
Wei Yan
金额：
$ 26.54万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615592
关键词：
Adipocytes Adult Cell Transplantation Data Embryo Encapsulated Epididymis Epigenetic Process Epithelial Cells Fathers Generations Genetic Genome Glucose Intolerance Glucose tolerance test Hepatocyte Heritability High Fat Diet Inherited Injections Insulin Resistance Islet Cell Islets of Langerhans Knowledge Lead Liquid substance Metabolic Diseases MicroRNAs Molecular Mus Obesity Pathway interactions Phenotype Production RNA Regulation Reproducibility Seminiferous tubule structure Series Shapes Somatic Cell Spermatocytes Spermatogenesis Spermatogenic Cell Structure of efferent ductule of testis Test Result Testing Testis blastomere structure dietary disease phenotype embryo cell epigenetic memory epigenome epigenomics experimental study extracellular vesicles insulin tolerance intergenerational male mouse model neuronal cell body offspring paracrine reproductive reproductive tract sertoli cell sperm cell trait transmission process

项目摘要

Project Summary Most of the studies on epigenetic inheritance focus on the identification of sperm-borne factors that carry the epigenetic memory and how they act on the epigenome/genome of the embryos so that the specific epigenetic memory can be recalled and manifested as a specific phenotype in offspring. However, one fundamental question remains unanswered: given that the effects of exposures, either environmental or dietary, are presumably initially manifested as epigenetic changes in directly exposed somatic cells (e.g. pancreatic islet cells, adipocytes, hepatocytes, etc.), how do the phenotype-specific epimutations in somatic cells get transduced into spermatozoa? Using a highly reproducible mouse model for intergenerational epigenetic inheritance of a high fat diet (HFD)-induced metabolic disorders, we here propose a series of experiments to tackle this critical question. Our central hypothesis is that HFD- induced epimutations in somatic cells can lead to production of specific sncRNAs that are either encapsulated in extracellular vesicles (EVs), or present as mobile RNAs, which act as the carrier of epigenetic memory once internalized by spermatozoa through either 1) the intra-testicular mechanism (i.e., Sertoli cell HDF-specific epigenetic information transmitted to all developing male germ cells or directly to spermatozoa during spermatogenesis in the testis), or 2) the post-testicular pathway (i.e., HFD-specific epigenetic information transmitted from male reproductive tract epithelial cells to spermatozoa), or 3) a combination of both. To test our hypothesis, we propose to identify when and where male germ cells gain the ability to transmit the HDF-induced metabolic disorder phenotype (Aim1), to study how the intra-testicular pathway contributes to the HFD-specific sperm epigenome (Aim2), to study how the post-testicular pathway influences HFD-specific sperm epigenome (Aim3). Data to be obtained will help fill the knowledge gap in our understanding of the molecular mechanisms underlying the intergenerational epigenetic inheritance of paternally acquired traits in general.

项目概要大多数关于表观遗传的研究都集中在鉴定精子携带的因子上。表观遗传记忆以及它们如何作用于胚胎的表观基因组/基因组，以便特定的表观遗传记忆可以在后代中被回忆并表现为特定的表型。然而，一基本问题仍未得到解答：鉴于暴露的影响，无论是环境还是饮食，可能最初表现为直接暴露的体细胞的表观遗传变化（例如，胰岛细胞、脂肪细胞、肝细胞等），表型特异性表突变是如何发生的？体细胞转化为精子吗？使用高度可重复的小鼠模型高脂肪饮食（HFD）引起的代谢紊乱的代际表观遗传，我们在这里提出一系列实验来解决这个关键问题。我们的中心假设是 HFD- 体细胞中诱导的表观突变可以导致特定 sncRNA 的产生，这些 sncRNA 可以是封装在细胞外囊泡 (EV) 中，或作为移动 RNA 存在，充当载体表观遗传记忆一旦被精子通过以下任一方式内化： 1) 睾丸内机制（即支持细胞 HDF 特异性表观遗传信息传递给所有发育中的雄性生殖细胞或睾丸精子发生过程中直接到达精子），或 2）睾丸后途径（即， HFD 特异性表观遗传信息从男性生殖道上皮细胞传递到精子），或 3）两者的组合。为了检验我们的假设，我们建议确定何时和雄性生殖细胞获得传播 HDF 诱导的代谢紊乱表型的能力 (Aim1)，研究睾丸内通路如何影响 HFD 特异性精子表观基因组 (Aim2)，研究睾丸后通路如何影响 HFD 特异性精子表观基因组 (Aim3)。数据待所获得的成果将有助于填补我们对潜在分子机制理解的知识空白一般而言，父系获得性状的代际表观遗传。