Control and coordination of the maternal-to-zygotic transition

母体向合子转变的控制和协调

基本信息

批准号：
9233196
负责人：
Jan M Skotheim
金额：
$ 32.07万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233196
关键词：
ATAC-seq Address Adult Affect Alpha Cell Amphibia Biological Assay Cell Count Cell Cycle Cell Cycle Checkpoint Cell division Cell-Free System Cells ChIP-seq Chromatin Chromatin Structure Complex Coupled Cytoplasm DNA DNA biosynthesis DNA replication fork Data Development Embryo Event Fertilization Fishes Gene Expression Gene Expression Regulation Genetic Transcription Genome Genomic DNA Growth Histone H3 Histones Human In Vitro Kinetics Label Link Location Measurement Measures Messenger RNA Metabolic Methods Modeling Molecular Chaperones Nuclear Nucleosomes Organism Phase Phenotype RNA RNA Polymerase II Rana Role System Testing Titrations Transcription Initiation Transcriptional Activation Transcriptional Regulation Work Xenopus base blastocyst cell growth cell motility cell type density egg experimental study fly genome-wide in vivo inhibitor/antagonist insight public health relevance temporal measurement transcriptome sequencing vertebrate embryos zygote

项目摘要

DESCRIPTION (provided by applicant): The development of an adult multi-cellular organism from a single fertilized egg requires the proliferation and differentiation of a large number of cells. In many species, the early post-fertilization divisions occur rapidly and synchronously without growth phases and cell cycle checkpoints. These early embryos are almost entirely transcriptionally inactive and therefore driven by maternally supplied RNAs. At the Mid-Blastula Transition (MBT), the embryo initiates large-scale transcription from the zygotic genome and cells gain growth phases and checkpoints. Previous work suggested that the MBT is initiated by the increased DNA-to-cytoplasmic ratio resulting from repeated rounds of DNA replication and cell division without cell growth. This led to the hypothesis that the progressive titration of an inhibitory factor present in the embryo allows the initiation of zygotic transcription. Using a cel free system that recapitulates zygotic genome activation in vitro, we purified the transcriptional inhibitory activity present in the Xenopus egg cytoplasm and identified histones H3/H4 as DNA-titrated inhibitors of the MBT. Manipulating histone levels quantitatively shifts the onset of zygotic transcription and cell cycle lengthening in vivo, demonstrating a specific role for chromatin state in MBT initiation. This raises the question as to how histone titration and chromatin state are mechanistically linked to transcription and cell cycle duration. To address this, we will measure zygotic transcription and nucleosome occupancy genome wide at unprecedented temporal resolution through early development in control and histone manipulated embryos. We will determine mechanism linking DNA replication and histone levels. Successful completion of these aims will identify the mechanism through which global histone levels can be used to coordinate transcription and cell division with development. Since activating zygotic transcription is the first major transition after fertilization in human embryos our work determining how chromatin based mechanisms regulate the initiation of transcription will also provide insight global gene regulation and developmental reprogramming in the early vertebrate embryo.

描述（通过应用证明）：单个受精卵的成年多细胞生物的发展需要大量细胞的增殖，并在许多物种中进行了较早的细胞。细胞周期检查点。先前的工作通过增加的DNA到胞质的态度，导致了DNA复制的重复和EL分裂，而没有细胞生长ACT中存在于Xenopus卵细胞质和MBT的抑制剂中，定量会移动合子转录的发作，并在体内提出循环延长，以解决组蛋白滴定和染色质状态。将通过L和组蛋白操纵的胚胎的早期发育来测量未经预科的时间分辨率的核小体卵子体。在人类胚胎中，我们的胚胎中，确定基于染色质转录的启动如何也将在早期脊椎动物胚胎中洞悉全球基因和发育重编程。