Analysis of the gene networks regulating the maternal to zygotic transition

描述（由申请人提供）：母体到合子的转变是动物发育的一个普遍步骤，胚胎从母体驱动程序过渡到合子程序。这需要清除母体提供的mrna，并转录合子基因。事实上，这两个过程是密切相关的，母体因素驱动合子基因的激活，合子产物主动靶向母体mrna进行死蛋白化、抑制和清除。本研究旨在描述介导母体mrna清除和合子基因组激活的基因调控网络。通过将高通量测序与早期胚胎的实验操作相结合，我们将定义mRNA衰变（aim 1）和合子激活（aim 2）的不同波。通过计算分析和实验验证，我们将确定在转录和转录后水平介导这种调控的基序，最终目标是确定负责这种调控的因素。这些拟议的实验将共同定义控制早期脊椎动物发育的基因调控网络。拟议的项目与不同层次的公共卫生有关。首先，从人类疾病和癌症的角度来看，控制mRNA稳定性的途径（包括miRNAs）在癌症中异常癌基因激活中发挥重要作用。通过评估早期胚胎中控制mRNA稳定性和转录激活的网络，该建议为癌症的致癌表型提供了新的机制见解。第二，从生殖健康的角度来看，不孕症估计影响15%

DESCRIPTION (provided by applicant): 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. This proposal aims to characterize the gene regulatory networks that mediate clearance of the maternal mRNAs and activation of the zygotic genome. By combining high throughput sequencing with experimental manipulation of the early embryo, we will define distinct waves of mRNA decay (aim 1) and zygotic activation (Aim 2). Using computational analysis and experimental validation we will identify the motifs that mediate this regulation at the transcriptional and post-transcriptional level, with the ultimate goal of identifying the factors responsible for this regulation. 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. By assessing the networks that control mRNA stability and transcriptional activation in the early embryo, this proposal provides novel mechanistic insights into the oncogenic phenotype in cancer. 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 thi 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 gastrulation and axis formation resulting in zygote development.