Molecular mechanisms of the maternal to zygotic transition

母体向合子转变的分子机制

• 批准号: 9277085
• 负责人: Antonio J Giraldez
• 金额: $ 70.5万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277085
• 关键词: Advanced Development; Affect; Age; Animals; Biological Assay; Cells; Chromatin; Code; Development; Embryo; Embryonic Development; Fertilization; Fertilization in Vitro; Gene Expression; Genes; Genetic Transcription; Genome; Goals; High-Throughput Nucleotide Sequencing; Hour; Human; Individual; Infertility; Instruction; Malignant Neoplasms; Maps; Maternal Messenger RNA; Messenger RNA; Methods; MicroRNAs; Modification; Molecular; Oncogene Activation; Output; Pathway interactions; Play; Post-Transcriptional Regulation; Pregnancy; Pregnancy loss; Process; Proteins; Public Health; RNA; RNA-Protein Interaction; Reader; Recruitment Activity; Regulation; Regulator Genes; Repression; Reproductive Health; Role; Shapes; Structure; System; Translations; Woman; egg; experimental study; human disease; in vivo; insight; mRNA Decay; mRNA Stability; novel; programs; reproductive; tool; transcriptome; vertebrate embryos; zygote

SUMMARY The maternal to zygotic transition is a universal step in animal development, where the embryo transitions from a maternally driven program to a zygotic program. This requires the clearance of the maternally provided mRNAs, and transcription of the zygotic genes. Indeed, these two processes are intimately interconnected, 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 identified individual factors regulating mRNA stability and activation of the zygotic genome, we lack major understanding on 1) how different regulatory mechanisms are integrated to instruct mRNA turn over and translation regulation in the embryo, 2) what are the mechanisms that regulate protein output and genome activation, and 3) what is the regulatory code (sequences, structures and RNA modifications) that shape genome activation and post-trasncriptional regulation. By combining high throughput sequencing, protein-RNA interaction maps, with novel methods to assay the regulatory activity of the transcriptome in the early embryo, we will define the factors that are recruited to the genome to activate the zygotic program, the mechanisms that activate the chromatin, the sequence/structural motifs (code) that determine maternal mRNA fate, the readers that interpret the code and the mechanisms that trigger each of these steps in vivo. Together these proposed experiments, will define the gene regulatory network that controls early vertebrate development. The proposed project is relevant for public health at different levels. First, from the stand point of human disease and cancer, pathways that control mRNA stability (including miRNAs) play an important role in aberrant oncogene activation in cancer, and are relevant to changes in cell fate where the cells need to install a new program and remove the previous cellular program through post-transcriptional regulation. Second, from the stand point 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 of 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 derived from this project will help us understand how gene expression is regulated in the early embryo during the maternal to zygotic transition to ultimately trigger the activation of the different developmental pathways during embryogenesis.

概括 孕产妇至二型过渡是动物发育的普遍步骤，胚胎 从母体驱动的计划过渡到合子计划。这需要清除 母体提供了mRNA和二元基因的转录。确实，这两个过程是 紧密互连的母体因子驱动二吻合基因的激活和二吻合 产品积极靶向母体mRNA，以降低甲基化，抑制和清除率。 尽管最近的研究已经确定了调节mRNA稳定性和激活的个体因素 合子基因组，我们对1）不同的调节机制缺乏重大了解 集成以指示mRNA翻转和翻译调节，2） 调节蛋白质输出和基因组激活的机制，以及3）法规代码是什么 （序列，结构和RNA修饰）塑造基因组激活和后刻录后 规定。通过将高吞吐量测序，蛋白-RNA相互作用图与新颖 分析转录组在早期胚胎中的调节活性的方法，我们将定义 募集到基因组以激活二吻合程序的因素，即激活的机制 染色质，确定母体mRNA命运的序列/结构基序（代码），读者 这解释了触发这些步骤的代码和体内每个步骤的机制。在一起 提出的实验将定义控制早期脊椎动物的基因调节网络 发展。 拟议的项目与不同级别的公共卫生有关。首先，从人类的角度来看 疾病和癌症，控制mRNA稳定性（包括miRNA）的途径在 癌症中异常的致癌基因激活，并且与细胞命运的变化有关 安装新程序，并通过转录后法规删除先前的蜂窝程序。 第二，从生殖健康的立场上，不育估计会影响15％的生殖 年龄妇女和早期怀孕损失对应于所有怀孕的25％，最多70％ 体外受精后的怀孕。理解二元基因组激活的机制 产妇mRNA衰减可以提供人类不育症和工具的基本见解来评估 早期失去受精卵。 从该项目得出的结果将有助于我们了解基因表达如何调节 在母体到合子过渡期间的早期胚胎，最终触发不同的激活 胚胎发生过程中的发育途径。