Molecular mechanisms of the maternal to zygotic transition

总结 从母体到合子的转变是动物发育中的一个普遍步骤， 从母源驱动程序到合子程序的转变。这需要清除 母体提供的mRNA和合子基因的转录。事实上，这两个过程是 密切相关的，母系因素驱动合子基因的激活，合子基因的激活是由母系因素驱动的。 产物主动靶向母体mRNA进行去腺苷化、抑制和清除。 虽然最近的研究已经确定了调节mRNA稳定性和激活的单个因素， 合子基因组，我们缺乏主要的了解1）如何不同的调控机制， 整合来指导胚胎中的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）什么是调节代码 （序列，结构和RNA修饰），塑造基因组激活和转录后 调控通过将高通量测序、蛋白质-RNA相互作用图谱与新的 方法测定转录组在早期胚胎中的调节活性，我们将定义 这些因子被募集到基因组中以激活合子程序，激活合子程序的机制， 染色质，决定母体mRNA命运的序列/结构基序（代码），阅读器 解释这些代码以及触发体内这些步骤的机制。综合这些 提出的实验，将确定控制早期脊椎动物的基因调控网络， 发展 拟议的项目与各级公共卫生有关。第一，从人的角度 在疾病和癌症中，控制mRNA稳定性的途径（包括miRNA）在 癌基因的异常激活，并与细胞命运的变化有关， 安装一个新的程序，并通过转录后调节删除以前的细胞程序。 其次，从生殖健康的角度来看，不孕症估计影响15%的生殖健康。 年龄妇女和早孕流产占所有怀孕的25%， 体外受精后怀孕合子基因组激活机制的认识 和母体mRNA衰变可以提供人类不育的基本见解和评估工具， 受精卵早期丢失。 该项目的结果将帮助我们了解基因表达是如何调节的， 在母体向合子过渡的早期胚胎中， 胚胎发生过程中的发育途径。

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.