Epimutations in Offspring Produced by Assisted Reproductive Technologies (ART)

辅助生殖技术 (ART) 产生的后代的表观突变

• 批准号: 8757199
• 负责人: John R MCCARREY
• 金额: $ 62.76万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757199
• 关键词: Address; Age; Appearance; Assisted Reproductive Technology; Clinical; Couples; DNA Methylation; Data Set; Defect; Development; Disease; Embryo; Embryo Transfer; Embryonic Development; Epigenetic Process; Etiology; Frequencies; Future; Gametogenesis; Gene Expression; Gene Expression Profile; Genes; Genome; Genomics; Germ Lines; Gonadotropins; Health; Human; Human Biology; Incidence; Individual; Intracytoplasmic Sperm Injections; Knowledge; Lead; Maintenance; Methodology; Methods; Modification; Mus; Oocytes; Outcome; Pattern; Phenotype; Procedures; Process; Prospective Studies; Protocols documentation; Relative (related person); Reporting; Reproduction; Research; Resolution; Resources; Risk; Safety; Somatic Cell; Staging; Technical Expertise; Technology; Testing; Time; base; blastocyst; design; embryo culture; epigenome; epigenomics; experience; fetal; folliculogenesis; genome-wide; imprint; innovation; novel; offspring; preimplantation; programs; public health relevance; skills

DESCRIPTION (provided by applicant): This project is designed to obtain the first comprehensive assessment of epigenetic defects (epimutations) induced by the use of assisted reproductive technologies (ART) in the offspring produced. The genome-wide occurrence of abnormalities in DNA methylation patterns and gene expression patterns will be assessed in mice produced by intracytoplasmic sperm injection (ICSI) using cutting-edge, high-throughput epigenomic and genomic technologies. In addition, the etiology of ART-induced epimutations will be investigated by determining the precise timing of appearance of epimutations in mice produced by ART, as well as by discerning the relative contribution of each of three specific aspects of the ART process - gonadotropin stimulation of folliculogenesis, prolonged culture of preimplantation embryos, and embryo transfer - to the induction of epimutations. Finally, the fate of ART-induced epimutations will be examined to determine if these are consistently corrected by epigenetic reprogramming during either embryogenesis or gametogenesis. The significance of the research proposed in this application is that it will include high (single-base) resolution, comprehensive analyses of the disruptive effects of ART on epigenetic programming genome-wide, and it will facilitate controlled, prospective studies of the genesis, etiology, extent and fte of epimutations induced by ART, including parallel, simultaneous studies of the relative contribution(s) of multiple different aspects of the ART process to the induction of epimutations in the offspring produced. The proposed research is innovative and timely because we are now able to generate datasets of unprecedented scale and resolution describing abnormal epigenetic programming and gene expression in ART offspring, and we can use these to understand the genesis, consequences and fate of ART-induced epimutations in ways that will have significant implications for basic biology and human health. The resulting enhanced understanding of the etiology of ART-induced epimutations will inform future modifications of clinical ART protocols to minimize the induction of epimutations in ART-derived human offspring and thereby reduce the occurrence of epigenetic disorders in individuals produced by this technology.

描述（由申请人提供）：该项目旨在对使用辅助生殖技术（ART）产生的后代所引起的表观遗传缺陷（表观突变）进行首次全面评估。将使用尖端、高通量表观基因组和基因组技术，在通过胞浆内单精子注射 (ICSI) 产生的小鼠中评估全基因组 DNA 甲基化模式和基因表达模式异常的发生情况。此外，将通过确定 ART 产生的小鼠中表突变出现的精确时间，以及通过辨别 ART 过程的三个特定方面（卵泡生成的促性腺激素刺激、植入前胚胎的延长培养和胚胎移植）中每一个对诱导表突变的相对贡献来研究 ART 诱导的表突变的病因学。最后，将检查 ART 诱导的表观突变的命运，以确定这些表观突变是否在胚胎发生或配子发生期间通过表观遗传重编程得到一致纠正。本申请中提出的研究的意义在于它将包括高分辨率（单碱基）、 全面分析 ART 对全基因组表观遗传编程的破坏性影响，并将有助于对 ART 诱导的表观突变的发生、病因、程度和寿命进行受控、前瞻性研究，包括并行、同时研究 ART 过程的多个不同方面对诱导产生的后代表观突变的相对贡献。这项研究具有创新性和及时性，因为我们现在能够生成规模和分辨率前所未有的数据集，描述 ART 后代中异常的表观遗传编程和基因表达，并且我们可以利用这些数据来了解 ART 诱导的表观突变的起源、后果和命运，这将对基础生物学和人类健康产生重大影响。由此增强对 ART 诱导的表观突变病因学的了解，将为未来临床 ART 方案的修改提供信息，以最大限度地减少 ART 衍生的人类后代中表观突变的诱导，从而减少通过该技术产生的个体中表观遗传疾病的发生。