Sperm Prions: A Mechanism of Epigenetic Inheritance

精子朊病毒：表观遗传机制

基本信息

批准号：
8616632
负责人：
Gail A Cornwall
金额：
$ 22.48万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-15 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616632
关键词：
Affect Amyloid Androgen Receptor Antibodies Asparagine Biological Process Cell Nucleus Cell Survival Cells Cellular Stress Centrosome Cytosol DNA DNA Methylation DNA Sequence DNA-Binding Proteins Defect Development Disease Embryonic Development Endocrine Disruptors Environment Environmental Exposure Epigenetic Process Exposure to Fathers Female Fertility Fertilization Gene Expression Generations Genetic Genome Germ Cells Glutamine Greek Head Health Human Immunofluorescence Immunologic Incidence Incubated Inherited Label Lead Length Ligand Binding Ligands Link Male Infertility Malignant Neoplasms Malignant neoplasm of prostate Mammals Modeling Modification Molecular Conformation Mus N Domain Neck Nuclear Nutrient Oocytes Partner in relationship Perinatal Exposure Phenotype Play Population Prions Protein p53 Proteins RNA-Binding Proteins Rattus Reagent Regulation Role Site Sperm Head Stress Structure Testing Western Blotting Yeasts base chromatin remodeling daughter cell embryo cell genetic regulatory protein histone modification human disease in utero male monomer non-genomic novel novel strategies offspring prion-based prion-like protein aggregate protein aggregation protein function research study sperm cell sperm protein trait translation factor transmission process vinclozolin yeast prion

项目摘要

DESCRIPTION (provided by applicant): There is growing evidence that environmental exposures to the father can affect the phenotype of his offspring and in some cases these effects can be adaptive. Indeed, in utero exposure of male rats to the endocrine disruptor vinclozolin resulted in decreased fertility and increased rates of cancer over several generations. Although classic epigenetic mechanisms such as changes in DNA methylation have been observed, to date no clear mechanism has been established for how these transgenerational effects were transmitted by spermatozoa. Epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. While in mammals epigenetics currently refers to modifications of the genome such as DNA methylation or histone modifications, it is possible that nongenomic means of inheritance may also occur. We hypothesize that sperm prions are a novel mechanism for transgenerational inheritance in mammals. Prions are self-aggregates of proteins in highly ordered structures known as amyloids that can convert native forms of the protein to the self-aggregated state and thus are self-perpetuating. Our hypothesis is based on an established mechanism for prion-based inheritance in yeast. Many regulatory proteins in yeast contain Q/N rich prion domains that, when exposed to cell stress, switch the protein from its native fold into a self-aggregated prion resulting in changed protein function and cell phenotype that can be heritable and passed on to daughter cells. Remarkably, several mammalian regulatory proteins including the DNA binding proteins TDP43 and androgen receptor (AR) contain Q/N domains and form prions that alter normal protein function that is linked to human disease. The tumor suppressor p53 has also been shown to form prions. While the significance of the prion forms of TDP43, AR and p53 is not known, the similarities between these mammalian proteins and the yeast prions suggest a common mechanism for regulation of protein function and possibly generation of new phenotypes. We have made the exciting observation that prions are present in mouse and rat spermatozoa including the head and the centrosomal region which plays critical roles in embryonic development. Although the identity of these prions is not known, we have determined that TDP43 localizes to the sperm head and centrosome and that a proportion of TDP43 in sperm is in a prion state. We hypothesize that sperm proteins, possibly TDP43, AR, p53 and others, may be induced to form prions (or more prions) following environmental stress and that these prions are involved in the transgenerational inheritance of new phenotypes. To test our hypothesis, we will use an established model for transgenerational inheritance and expose rats in utero to vinclozolin and carry out the following studies: 1) Identify and characterize prions including TDP43 in spermatozoa from F1-F3 males; 2) Determine if sperm prions are present in fertilized oocytes.

描述（由申请人提供）：越来越多的证据表明，向父亲的环境暴露会影响其后代的表型，在某些情况下，这些影响可能是适应性的。实际上，在雄性大鼠对内分泌干扰物的子宫内暴露于几代人的生育能力和癌症发生率降低。尽管已经观察到了经典的表观遗传机制，例如DNA甲基化的变化，但迄今为止，尚未确定这些转世效应如何通过精子传播的明确机制。表观遗传学是对基因表达或细胞表型的可遗传变化的研究，而不是基础DNA序列的变化而引起的。尽管在哺乳动物的表观遗传学中目前是指基因组（例如DNA甲基化或组蛋白修饰）的修饰，但可能还会发生非原核遗传方法。我们假设精子王是哺乳动物跨代遗传的新型机制。王室是高度有序结构中蛋白质的自聚集，可以将蛋白质的天然形式转化为自聚集状态，因此是自我持久的。我们的假设是基于建立的基于酵母菌的基于prion的遗传的机制。酵母中的许多调节蛋白都包含Q/N丰富的prion域，当暴露于细胞应激时，将蛋白质从其天然折叠转换为自构的prion，导致蛋白质功能和细胞表型变化，并且可以传播并传递给子细胞。值得注意的是，几种包括DNA结合蛋白TDP43和雄激素受体（AR）的哺乳动物调节蛋白包含Q/N结构域，并形成了改变与人类疾病相关的正常蛋白功能的prions。肿瘤抑制p53也已显示形成王室。虽然尚不清楚TDP43，AR和p53的Prion形式的意义，但这些哺乳动物蛋白质与酵母菌prions之间的相似性表明了调节蛋白质功能以及可能产生新表型的共同机制。我们已经对小鼠和大鼠精子中存在的prions存在于包括头部和中心体区域，在胚胎发育中起着关键作用。尽管这些王室的身份尚不清楚，但我们已经确定TDP43定位于精子头和中心体，并且精子中TDP43的比例处于prion状态。我们假设可能诱使精子蛋白（可能是TDP43，AR，p53和其他）在环境压力下形成王室（或更多的prions），并且这些prions涉及新表型的跨代遗传。为了检验我们的假设，我们将使用既定模型来用于转世遗传，并将子宫内的大鼠暴露于vinclozolin中，并进行以下研究：1）识别和表征来自F1-F3男性精子中TDP43在内的王牌； 2）确定受精卵母细胞中是否存在精子王。