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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：
10018079
负责人：
Wei Yan
金额：
$ 26.51万
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/10018079
关键词：
Adipocytes Adult Cell Transplantation Data Diet Embryo Encapsulated Epididymis Epigenetic Process Epithelial Cells Fathers Genetic Genome Germ Cells Glucose Intolerance Glucose tolerance test Hepatocyte Heritability High Fat Diet Inherited Injections Insulin Resistance Islet Cell Islets of Langerhans Knowledge Lead Liquid substance Metabolic Metabolic Diseases MicroRNAs Molecular Mus Obesity Pathway interactions Phenotype Production RNA Regulation Reproducibility Seminiferous tubule structure Series Shapes Somatic Cell Spermatogenesis Spermatogenic Cell Structure of efferent ductule of testis Testing Testis 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

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.

项目总结