Molecular mechanisms of the maternal to zygotic transition

摘要 母体向受精卵的转变是动物发育的普遍步骤，胚胎 从母性驱动的程序过渡到合子程序。这需要清空 母亲提供的mRNAs，以及合子基因的转录。事实上，这两个过程是 紧密相连的母性因素驱动合子基因的激活，合子 产品积极针对母体mRNAs进行去烯基化、抑制和清除。 虽然最近的研究已经确定了调节信使核糖核酸稳定性和激活的单个因素 合子基因组，我们对1)不同的调控机制缺乏主要了解 整合来指导胚胎中的mRNA翻转和翻译调节，2)什么是 调节蛋白质输出和基因组激活的机制，以及3)什么是调节密码 (序列、结构和RNA修饰)塑造基因组激活和转录后 监管。通过将高通量测序、蛋白质-RNA相互作用图与新的 方法为了检测转录组在早期胚胎中的调节活性，我们将定义 被招募到基因组中以激活合子程序的因子，即激活机制 染色质，决定母体mRNA命运的序列/结构基序(密码)，读者 在活体内解释代码和触发这些步骤的机制。把这些放在一起 拟议中的实验将定义控制早期脊椎动物的基因调控网络 发展。 拟议的项目在不同层面上与公共卫生有关。第一，从人的立场出发 疾病和癌症，控制mRNA稳定性的途径(包括miRNAs)在 癌基因在癌症中的异常激活，并与细胞需要改变的细胞命运有关 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，不孕不育估计影响15%的生殖健康。 年龄、妇女和早孕丢失相当于所有怀孕的25%，其中高达70% 体外受精后怀孕。对合子基因组激活机制的认识 母体信使核糖核酸的衰变可以提供对人类不孕症的基本见解和评估工具 早期失去受精卵。 这个项目得出的结果将帮助我们理解基因表达是如何在 早期胚胎在母体向合子的转变过程中最终会触发不同的激活 胚胎发育过程中的发育途径。

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.