Molecular mechanisms of the maternal to zygotic transition

母体向合子转变的分子机制

• 批准号: 10406654
• 负责人: Antonio J Giraldez
• 金额: $ 82.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406654
• 关键词: Affect; Age; Animals; Biological Assay; Cells; Chromatin Structure; Code; DNA; Deposition; Development; Embryo; Embryonic Development; Fertilization in Vitro; Gene Expression; Genes; Genome; Goals; Human; Individual; Infertility; Instruction; Malignant Neoplasms; Maps; Maternal Messenger RNA; Mediating; Messenger RNA; Molecular; Oncogene Activation; Output; Pathway interactions; Play; Post-Transcriptional Regulation; Pregnancy; Process; Proteins; Public Health; RNA; Reader; Regulation; Reporter; Repression; Reproductive Health; Role; Shapes; Structure; System; Transcriptional Regulation; Translations; Woman; early pregnancy loss; embryonic protein; experimental study; gene regulatory network; human disease; imaging approach; in vivo; insight; mRNA Decay; mRNA Stability; novel; programs; reproductive; tool; vertebrate embryos; zygote

SUMMARY The maternal to zygotic transition is a universal step in animal development characterized by the clearance of the maternally provided mRNAs and the activation of the zygotic genome. Indeed, these two processes are intimately interconnected as maternal factors drive the activation of the zygotic genes, and zygotic products actively target maternal mRNAs for deadenylation, repression and clearance. While recent studies have began identifying individual factors regulating mRNA stability and activation of the zygotic genome, we lack major understanding on 1) the regulatory code (sequences, structures and readers) that shapes genome activation and post-transcriptional regulation, 2) the mechanisms that regulate protein output and genome activation, and 3) how different regulatory mechanisms are integrated to instruct mRNA turnover, translation regulation and genome activation in the embryo. We will combine massive parallel reporter assays to determine the regulatory activity of different sequences in the early embryo, protein interaction maps (at the level of the DNA and RNA) to define the factors that mediate transcriptional and post-transcriptional regulation and novel imaging approaches to determine how pioneer factors shape chromatin structure and in turn genome activation. Together these experiments will define the mechanisms that trigger each of these steps in vivo and the gene regulatory network that controls early vertebrate development. This project is relevant for public health at different levels. First, from the standpoint of human disease and cancer, pathways that control mRNA stability play an important role in aberrant oncogene activation in cancer and are relevant to changes in cell fate where the cells need to transition to a new program and remove the previous one through post-transcriptional regulation. Second, from the standpoint of reproductive health, infertility is estimated to affect 15% of reproductive age women and early pregnancy loss corresponds to 25% of all pregnancies with up to 70% in pregnancies after in vitro fertilization. Understanding the mechanisms of zygotic genome activation and maternal mRNA decay can provide fundamental insights in human infertility and tools to evaluate early loss of fertilized eggs. The results we derived here will help us understand how gene expression is regulated in the early embryo to trigger the activation of different developmental pathways during embryogenesis.

总结 母系到合子的转变是动物发育中的普遍步骤，其特征在于： 清除母体提供的mRNA和激活合子基因组。事实上，这些 两个过程密切相关，因为母体因素驱动合子的激活， 基因和合子产物主动靶向母体mRNA进行去腺苷化，抑制和 间隙 虽然最近的研究已经开始确定调节mRNA稳定性和激活的单个因素， 对于合子基因组，我们缺乏对1）调控代码（序列，结构）的主要了解 和读者），塑造基因组激活和转录后调控，2）的机制， 调节蛋白质输出和基因组激活，以及3）不同的调节机制是如何 整合以指导胚胎中的mRNA周转、翻译调节和基因组激活。我们 将结合联合收割机大规模的平行报告分析，以确定不同序列的调节活性 在早期胚胎中，蛋白质相互作用图（在DNA和RNA水平上）定义了 介导转录和转录后调节的新的成像方法， 确定先驱因子如何塑造染色质结构，进而影响基因组激活。一起 这些实验将确定在体内触发这些步骤的机制， 控制脊椎动物早期发育的调节网络。 该项目与各级公共卫生有关。首先，从人类疾病的角度来看 和癌症，控制mRNA稳定性的途径在异常癌基因中起重要作用。 在癌症中激活，并与细胞命运的变化有关，其中细胞需要过渡到新的细胞。 通过转录后调节来编程并删除前一个。二是从 从生殖健康的角度来看，不孕症估计影响到15%的育龄妇女， 早期妊娠丢失占所有妊娠的25%，在体外受精后妊娠中高达70%。 受精了解合子基因组激活和母体mRNA衰变的机制 可以提供人类不孕症的基本见解和评估受精卵早期损失的工具。 我们在这里得到的结果将帮助我们了解基因表达是如何在早期调控的。 在胚胎发生过程中，激活不同的发育途径。