The genome integrity and epigenome of sperm from men with recurrent pregnancy loss

反复流产男性精子的基因组完整性和表观基因组

• 批准号: 10556688
• 负责人: Winifred W Mak
• 金额: $ 51.26万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556688
• 关键词: Aberrant DNA Methylation; Address; Affect; Aging; Aniline; Animals; Area; Biological Assay; Candidate Disease Gene; Chromosomal translocation; Classification; Clinical; Couples; DNA; DNA Damage; DNA Fragmentation; DNA Methylation; Data; Data Set; Defect; Development; Diagnosis; Diagnostic; Diagnostic tests; Embryonic Development; Ensure; Epigenetic Process; Exclusion; Female; Genes; Genetic; Genome; Genomic Imprinting; Genomic Instability; Habitual Abortion; Histones; Human; Infertility; Karyotype; Knowledge; Measures; Micrococcal Nuclease; Mission; Molecular; Molecular Analysis; Mosaicism; Multiomic Data; Mutation; National Institute of Child Health and Human Development; Nested Case-Control Study; Nucleotides; Pattern; Phenotype; Play; Pregnancy; Pregnancy Complications; Pregnancy loss; Premature aging syndrome; Public Health; Recurrence; Reproductive Medicine; Research; Research Priority; Risk; Role; Seminal fluid; Spontaneous abortion; Stains; Technology; Testing; Therapeutic; United States; Work; adverse pregnancy outcome; animal data; clinical diagnostics; cohort; diagnostic strategy; early pregnancy loss; epidemiology study; epigenome; experience; experimental study; genetic analysis; genome integrity; genome-wide; genome-wide analysis; genomic locus; healthy pregnancy; imprint; improved; innovation; insight; male; men; methylome; novel; predictive modeling; sperm analysis; sperm cell; sperm quality; treatment strategy; trying to conceive; unethical

PROJECT SUMMARY/ABSTRACT: Miscarriage is the most frequent pregnancy complication, and around 750,000 to 1,000,000 miscarriages occur annually in the United States. Up to five percent of couples will experience two or more miscarriages and have recurrent pregnancy loss (RPL). RPL is a significant clinical problem as even after a diagnostic workup, 50% of couples will not find a cause for their recurrent losses and will be diagnosed with unexplained RPL (uRPL). Therefore, investigating new causes for RPL is crucial to help couples with RPL to identify a cause and, therefore, possible therapeutic options. Male factor causes of uRPL are understudied, and clinically, the only diagnostic testing performed on men with uRPL is a karyotype to exclude chromosomal translocation/inversion. Our proposal is highly significant as it addresses this major gap in our knowledge regarding paternal causes of RPL. Several lines of evidence show that abnormal sperm quality as objectively measured by high DNA fragmentation and aberrant DNA methylation in imprinted genes is associated with uRPL. This project will shift the present clinical diagnostic paradigm for RPL couples from a mainly female-centric approach to a balanced approach, including molecular analysis of sperm. Our project will involve a comprehensive analysis of sperm from a large cohort of uRPL couples to study DNA fragmentation (Aim 1), DNA methylation (Aim 2), and histone patterns (Aim 3). In Aim 1, our experiments will investigate the molecular mechanisms by which increased sperm DNA fragmentation in humans can lead to RPL by investigating the type of DNA damage occurring and the genomic loci affected. One major innovation in our approach is to uniquely study in parallel the genome of the miscarriages resulting from high DNA fragmented sperm to elucidate the underlying defect. Although sperm genomic integrity is one crucial aspect of ensuring a healthy pregnancy, another aspect is the sperm epigenome, which also plays a crucial role in pregnancy viability. Prior studies show that sperm DNA methylation at imprinted loci is perturbed in men with uRPL, and increased retention of histones in sperm from uRPL men has been observed. Building upon these observations, in aim 2, we will pursue both a candidate (imprinted genes) and an unbiased genome-wide approach to studying the sperm methylome using the latest comprehensive DNA methylation array technology. In addition, we will also leverage a prior predictive model using DNA methylation as a marker of paternal aging to assess if there is premature aging in the sperm from uRPL men. This work will identify epimutations in sperm that could play a mechanistic role in RPL. In aim 3, we will expand our epigenetic analysis to perform a genome-wide analysis of sperm histone patterns in uRPL men. Finally, we will combine our multi-omics datasets to compare and contrast the genomic loci affected. In summary, this project will contribute significantly to identifying novel male factor causes of RPL, which will ultimately lead to significant advancements in the diagnosis and treatment of couples with RPL.

项目摘要/摘要：流产是妊娠期最常见的并发症，且围绕在身边