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Molecular mechanisms of the maternal to zygotic transition

母体向合子转变的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

总结