Molecular mechanisms of the maternal to zygotic transition

母体向合子转变的分子机制

• 批准号: 10685563
• 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/10685563
• 关键词: Affect; Age; Animals; Biological Assay; Cells; Chromatin Structure; Code; DNA; Deposition; Development; Embryo; Embryonic Development; Fertilization in Vitro; Gene Expression; Genes; Genetic Transcription; 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; Translational Regulation; Woman; early pregnancy loss; experimental study; gene regulatory network; human disease; imaging approach; in vivo; insight; mRNA Decay; mRNA Stability; novel; post pregnancy; 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.

摘要 母体向受精卵的转变是动物发育的普遍步骤，其特征是 母亲提供的mRNAs的清除和合子基因组的激活。事实上，这些 母体因素驱动受精卵的激活，这两个过程紧密相连 基因和合子产物主动靶向母体mRNAs进行去烯化、抑制和 通行证。 虽然最近的研究已经开始识别调节mRNA稳定和激活的个别因素 对于合子基因组，我们缺乏对1)调控密码(序列、结构)的主要了解 和读者)，形成基因组激活和转录后调节，2)机制， 调节蛋白质输出和基因组激活，以及3)调节机制有多不同 整合以指导胚胎中的mRNA周转、翻译调节和基因组激活。我们 将结合大量的平行报告分析来确定不同序列的调控活性 在早期胚胎中，蛋白质相互作用图(在DNA和RNA水平上)定义因素 介导转录和转录后调控以及新的成像方法 确定先锋因子如何塑造染色质结构，进而激活基因组。同舟共济 这些实验将确定在体内触发这些步骤和基因的每一个步骤的机制 控制脊椎动物早期发育的调控网络。 该项目与不同层次的公共卫生有关。第一，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发挥着重要作用 在癌症中的激活，并与细胞命运的变化有关，在细胞命运中，细胞需要过渡到新的 通过转录后调控来编程并移除前一个基因。第二，从 从生殖健康的角度来看，不孕不育估计影响15%的育龄妇女和 早期妊娠丢失相当于所有妊娠的25%，体外受孕后高达70% 受精。理解合子基因组激活和母体mRNA衰变的机制 可以为人类不孕不育提供基本见解，并提供评估受精卵早期丢失的工具。 我们在这里得到的结果将有助于我们理解基因表达在早期是如何调控的。 胚胎在胚胎发生过程中触发不同发育途径的激活。