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Epigenetic Programming of Health and Disease in the Preimplantation Embyro

植入前胚胎健康和疾病的表观遗传编程

基本信息

批准号：
8999931
负责人：
PAOLO RINAUDO
金额：
$ 32.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8999931
关键词：
Adult Affect Animals Assisted Reproductive Technology Atlases Barker Hypothesis Candidate Disease Gene Cataloging Catalogs Cell Count Cells ChIP-seq Child Chromatin Clinical Collaborations Conceptions DNA Methylation Data Data Set Databases Defect Deposition Development Disease Embryo Embryonic Development Environment Environmental Risk Factor Epigenetic Process Evaluation Fatty acid glycerol esters Female Fertilization Fertilization in Vitro Gene Expression Generations Genes Genomics Glucose Intolerance Goals Growth Growth and Development function Health Heritability Histones Human In Vitro Infertility Inner Cell Mass Insulin Laboratories Lead Light Link Liver Metabolic Metabolism Methods Mining Mission Mouse Strains Mus Outcome Partner in relationship Patients Pattern Phenotype Physiological Physiology Placentation Positioning Attribute Process Protocols documentation Qualifying Research Resources Sampling Specimen Staging Stress Testing Time Tissue Sample Tissues Variant Work blastocyst blood glucose regulation career cohort embryo culture epigenetic regulation epigenome epigenomics genome-wide glucose tolerance improved in vivo male mature animal metabolomics mouse development offspring postnatal preimplantation programs public health relevance repository response sex transcriptomics

项目摘要

DESCRIPTION (provided by applicant): It is becoming increasingly clear that the preimplantation period is a time of genomic reprogramming. Preimplantation embryos may respond to an environmental factor by altering their developmental trajectory with the net results that their adult phenotype is altered. This observation has wide clinical implications, since in vitro fertilization (IVF) and preimplantation embryo culture are routinely used to treat patients with infertility and as of today, more than 5 million children have been conceived with assisted reproductive technologies (ART). The laboratory of the PI (Rinaudo) has devoted extensive resources to define the phenotype of mice following ART. We have found that 1) preimplantation embryos are sensitive to the culture conditions they are exposed to; 2) culture conditions more dissimilar to the physiologic in vivo conditions are associated with a more significant alteration of long term phenotypes; 3) glucose intolerance is a common phenotypic change present in adults generated by IVF; 4) using a candidate gene approach, selected chromatin alterations are present in preimplantation embryos and maintained in adult animals in a tissue specific and sexual dimorphic fashion. Although these data are valuable, multiple questions still remain unresolved. We still do not know what global epigenomic changes are present in embryos following ART and if these epigenetic changes persist in the adult. The laboratory of the co-PI (Ramalho-Santos) has an established track record on epigenetic regulation of early mouse development and the germline, with expertise in analyses of histone variants, histone marks and DNA methylation. They have recently developed methods for genome-wide analyses of histone marks using low numbers of cells. This proposal, in response to PAR 13-385, aims to leverage the expertise of both laboratories to determine how ART may program adult physiology. Our long term goal is to define how preimplantation culture conditions affect embryo development and postnatal growth, as a direct test to the Barker hypothesis. The specific goal of this application is to assess epigenetic changes in preimplantation embryos and adult tissues of control and IVF mice. The central hypothesis is that culturing preimplantation embryos in vitro will result in epigenetic changes in the blastocyst; these changes will persist in selected adult tissues in a sexual dimorphic fashion; the identified epigenetic changes might explain the observed adult phenotype. We plan to test our central hypothesis and thereby accomplish the objective of this application by analyzing DNA methylation and describing selected histone marks in the inner cell mass (ICM) of preimplantation embryos of different mouse strains generated in vivo or in vitro. Further, we will confirm if selected epigenetic marks persist in adult tissues. With respect to the expected outcomes, the work proposed is expected to provide a detailed reference epigenome of 1) preimplantation embryos and 2) adult tissue of mice conceived in vitro and in vivo.

描述（由申请人提供）：越来越清楚的是，植入前阶段是基因组重编程的时间。植入前胚胎可能通过改变其发育轨迹来响应环境因素，最终结果是其成年表型发生改变。这一观察结果具有广泛的临床意义，因为体外受精（IVF）和植入前胚胎培养通常用于治疗不孕症患者，截至今天，已有500多万儿童通过辅助生殖技术（ART）受孕。PI（Rinaudo）实验室投入了大量资源来确定ART后小鼠的表型。我们发现：1）植入前胚胎对它们所暴露的培养条件敏感; 2）与体内生理条件更不相似的培养条件与更显著的长期表型改变相关; 3）葡萄糖耐受不良是IVF产生的成人中存在的常见表型变化; 4）使用候选基因方法，选定的染色质改变存在于植入前胚胎中，并以组织特异性和性二态性方式维持在成年动物中。虽然这些数据很有价值，但仍有许多问题没有得到解决。我们仍然不知道ART后胚胎中存在哪些整体表观基因组变化，以及这些表观遗传变化是否会持续到成年。co-PI（Ramalho-Santos）的实验室在早期小鼠发育和生殖系的表观遗传调控方面有着良好的记录，在组蛋白变体，组蛋白标记和DNA甲基化分析方面具有专业知识。他们最近开发了使用少量细胞进行组蛋白标记的全基因组分析的方法。该提案是对PAR 13-385的回应，旨在利用两个实验室的专业知识来确定ART如何编程成人生理学。我们的长期目标是确定植入前培养条件如何影响胚胎发育和出生后生长，作为对Barker假说的直接检验。本申请的具体目标是评估对照和IVF小鼠的植入前胚胎和成年组织中的表观遗传变化。核心假设是体外培养植入前胚胎将导致胚泡的表观遗传变化;这些变化将持续到植入后。选择成年组织中的性二态的方式;确定的表观遗传变化可能解释观察到的成年表型。我们计划通过分析DNA甲基化和描述体内或体外产生的不同小鼠品系的植入前胚胎的内细胞团（ICM）中的选定组蛋白标记来测试我们的中心假设，从而实现本申请的目的。此外，我们将确认所选择的表观遗传标记是否在成人组织中持续存在。关于预期的结果，所提出的工作预计将提供1）植入前胚胎和2）体外和体内受孕小鼠成年组织的详细参考表观基因组。