Analysis of the gene networks regulating the maternal to zygotic transition

调节母体向合子转变的基因网络分析

• 批准号: 8343531
• 负责人: Antonio J Giraldez
• 金额: $ 44.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8343531
• 关键词: 3' Untranslated Regions; Address; Advanced Development; Affect; Age; Animals; Behavior; Chromatin; Clip; Computer Analysis; Congenital Abnormality; Development; Electrophoretic Mobility Shift Assay; Embryo; Embryonic Development; Event; Family; Fertilization; Fertilization in Vitro; Gene Expression; Gene Expression Profile; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Goals; Hour; Human; Hybrids; Infertility; Instruction; Label; Malignant Neoplasms; Mass Spectrum Analysis; Maternal Messenger RNA; Mediating; Messenger RNA; MicroRNAs; Nucleotides; Oncogene Activation; Oncogenic; Pathway interactions; Phenotype; Play; Pregnancy; Pregnancy loss; Process; Protein Binding; Protein Binding Domain; Proteins; Public Health; RNA Splicing; Regulation; Regulator Genes; Regulatory Element; Repression; Reproductive Health; Role; Transcriptional Activation; Translations; Untranslated Regions; Validation; Vertebrates; Woman; Work; Yeasts; cis acting element; computerized tools; egg; gastrulation; human disease; in vivo; insight; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; mutant; novel; programs; promoter; reproductive; research study; tool; transcription factor; zygote

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. PUBLIC HEALTH RELEVANCE: In all animals, the fertilized egg depends on the "instructions" provided by the mom to the egg to undergo the first hours of development. Upon fertilization the egg undergo two universally conserved steps. First, it needs to activate the expression of its own instructions (genome), and second, it needs to eliminate the maternal instructions (mRNAs and proteins) to proceed into advanced development. This proposal studies how the vertebrate embryos organize multiple players to undertake these tasks.

描述（由申请人提供）：母体到合子的转变是动物发育中的一个普遍步骤，其中胚胎从母体驱动的程序转变为合子程序。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进行去腺苷化、抑制和清除。该建议旨在表征介导母体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（目的1）和合子激活（目的2）的不同波。使用计算分析和实验验证，我们将确定介导这种调节在转录和转录后水平的基序，确定负责这种调节的因素的最终目标。这些实验将共同定义控制脊椎动物早期发育的基因调控网络。拟议的项目与各级公共卫生有关。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miRNA）在癌症中的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，该提议为癌症中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% 早孕流产占所有怀孕的25%，体外受精后怀孕的比例高达70%。了解合子基因组激活和母体mRNA衰变的机制可以为人类不育提供基本的见解，并提供评估受精卵早期丢失的工具。来自该项目的结果将帮助我们了解在母体向合子过渡期间早期胚胎中基因表达是如何调节的，以最终触发原肠胚形成和轴形成期间不同发育途径的激活，从而导致合子发育。 公共卫生相关性：在所有动物中，受精卵都依赖于母亲提供给卵的“指令”来进行最初的发育。受精时，卵子经历两个普遍保守的步骤。首先，它需要激活自身指令（基因组）的表达，其次，它需要消除母体指令（mRNA和蛋白质）以进入高级发育。该提案研究了脊椎动物胚胎如何组织多个参与者承担这些任务。