Replication-independent DNA methylation dynamics during post-testicular sperm maturation

睾丸精子成熟过程中复制独立的 DNA 甲基化动态

• 批准号: 10219319
• 负责人: Carolina Galan
• 金额: $ 0.51万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-11 至 2021-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219319
• 关键词: Address; Affect; Assisted Reproductive Technology; Binding; Biological; Buffers; Categories; Cells; Child Welfare; Chromatin Structure; Complement; Complex; Cytosine; DNA Methylation; Data Set; Developmental Process; Doctor of Philosophy; Elements; Environment; Enzymes; Epididymis; Epigenetic Process; Fathers; Fertility; Genes; Genetic Transcription; Genome; Haploidy; In Vitro; Lead; Light; Mammals; Meiosis; Methylation; Mitotic; Morphology; Ontology; Oocytes; Population; Process; Proteins; RNA; Regulatory Element; Sorting - Cell Movement; Sperm Maturation; Spermatogenesis; Structure; Testing; Testis; Validation; assisted reproduction; bisulfite sequencing; cell motility; cell type; insight; interest; methylation pattern; novel; offspring; pyrosequencing; sperm cell; targeted delivery; whole genome; zygote

It has become apparent that sperm are extensively remodeled during epididymal transit, with ongoing changes to the protein and RNA content of maturing sperm. In addition, an increasing number of studies have shown that epigenetic information is modified during the process of sperm maturation. During the first year of my PhD studies, I have discovered that cytosine methylation patterns are surprisingly dynamic during sperm maturation in the epididymis. Using whole genome bisulfite sequencing (WGBS), I identified widespread changes in DNA methylation as sperm move from the testes through the caput, corpus, and cauda of the epididymis. Given that sperm are a highly methylated and condensed cell type, it is surprising and novel that epididymal transit results in any DNA methylation reprogramming of sperm. I aim to address the question of how DNA methylation changes occur between different sperm populations. My approach is to recapitulate maturation-associated cytosine methylation dynamics in vitro to understand the mechanism by which these changes are occurring. Resolving what these changes mean for potential offspring and determining the mechanisms and factors leading to changes in methylation will have significant implications for both assisted reproduction, and for understanding how a father's environment impacts his children's well being.

很明显，精子在附睾运输过程中广泛重塑，成熟精子的蛋白质和RNA含量不断变化。此外，越来越多的研究表明，表观遗传信息在精子成熟过程中被修改。在我攻读博士学位的第一年，我发现精子在附睾成熟过程中胞嘧啶甲基化模式是惊人的动态变化。利用全基因组亚硫酸氢盐测序（WGBS），我发现了精子从睾丸通过附睾头、体和尾移动时DNA甲基化的广泛变化。鉴于精子是高度甲基化和浓缩的细胞类型，附睾转运导致精子的任何DNA甲基化重编程是令人惊讶和新颖的。我的目标是解决DNA甲基化变化如何在不同精子群体之间发生的问题。我的方法是在体外概括成熟相关的胞嘧啶甲基化动力学，以了解这些变化发生的机制。解决这些变化对潜在后代的意义，并确定其机制 而导致甲基化变化的因素将对辅助生殖和理解父亲的环境如何影响其子女的健康产生重要影响。