权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of genomic reprogramming and transcriptional activation in the embryo

胚胎基因组重编程和转录激活机制

基本信息

批准号：
9894113
负责人：
Melissa Harrison
金额：
$ 13.1万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894113
关键词：
Automobile Driving Behavior Binding Binding Sites Biochemical Biological Cells Characteristics Chromatin Chromatin Remodeling Factor Chromatin Structure Complex Coupled DNA Binding Data Development Disease Drosophila Proteins Drosophila melanogaster Proteins Embryo Embryonic Development Environment Event Fertilization Generations Genes Genetic Genetic Transcription Genome Genomic Segment Genomics Germ Cells Goals Histone Acetylation Mediating Mitosis Modeling Molecular Molecular Conformation NURF Nature Nucleosomes Organism Pattern Population Positioning Attribute Process Proteins Publishing Regulation Research Role Shapes Specific qualifier value Stem cells Testing Therapeutic Totipotency Totipotent Totipotent cell Transcriptional Activation Work Workplace cell population study cell type chromatin remodeling cofactor embryonic stem cell genome-wide genome-wide analysis histone acetyltransferase histone modification in vitro testing in vivo insight protein complex recruit stem cell population transcription factor unpublished works

项目摘要

ABSTRACT Our long-term goal is to elucidate the molecular mechanisms governing the restructuring of the genome that allows for the transition from a specified cell type to a totipotent state. This transition occurs rapidly and efficiently immediately following fertilization, during the initial stages of embryonic development. At this critical developmental stage, the zygotic genome is transcriptionally quiescent. Only when the cells have become totipotent and poised to differentiate does widespread zygotic transcription initiate. Despite the fact that this delayed transcriptional activation of zygotic genome is nearly universal among metazoans, the mechanisms governing this process and how it relates to the coordinated establishment of a totipotent state remain unknown. We have recently demonstrated that the Drosophila protein Zelda (ZLD) acts globally to facilitate the activation of the zygotic genome and propose that it is doing so by establishing a permissive chromatin environment. Through genome-wide binding studies, we have shown that ZLD is bound early in development to thousands of genomic regions that subsequently drive the first wave of zygotic transcription. These loci are later defined as regions of open chromatin and are bound by a large number of transcription factors that govern embryonic patterning. Through our initial studies, we are well positioned to define the mechanisms by which the zygotic genome is remodeled to create an environment permissive to transcriptional activation and cellular differentiation. We will use genetic, genomic, and biochemical strategies to determine the mechanism by which ZLD is acting as a pioneer factor to shape the chromatin environment of the early embryo by: 1) determining the role of ZLD in organizing the chromatin structure of the early embryo and 2) identifying cofactors required for ZLD-mediated genome activation. The mechanistic insights we will gain into ZLD function will advance our understanding of how totipotent genomes are established generally. Ultimately this work will have important implications for the generation of totipotent mammalian stem cells both in culture and in vivo.

摘要我们的长期目标是阐明基因组重组的分子机制，允许从特定细胞类型转变为全能状态。这种转变发生得很快，在胚胎发育的最初阶段，受精后立即有效地进行。在这个关键在发育阶段，合子基因组转录静止。只有当细胞变成全能的和准备分化的广泛合子转录启动。尽管这合子基因组的延迟转录激活在后生动物中几乎是普遍的，管理这一进程以及它与协调建立一个全能国家的关系仍然存在，未知我们最近证明了果蝇蛋白塞尔达（ZLD）在全球范围内发挥作用，以促进合子基因组的激活，并提出它是通过建立一个允许的染色质这样做环境通过全基因组结合研究，我们已经表明ZLD在发育早期就被结合数千个基因组区域，这些区域随后驱动合子转录的第一波。这些位点是后来被定义为开放染色质的区域，并被大量的转录因子结合，支配胚胎模式。通过我们的初步研究，我们能够很好地确定机制，其中合子基因组被重塑以产生允许转录激活的环境，细胞分化我们将使用遗传学、基因组学和生物化学策略来确定其机制 ZLD作为一个先锋因子，通过以下方式塑造早期胚胎的染色质环境：1）确定ZLD在组织早期胚胎的染色质结构中的作用，以及2）鉴定 ZLD介导的基因组激活所需的辅因子。我们将从ZLD中获得的机械见解功能将促进我们对全能基因组如何普遍建立的理解。最终这这项工作对于在培养物中产生全能性哺乳动物干细胞， in vivo.

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optogenetic Inactivation of Transcription Factors in the Early Embryo of Drosophila.

果蝇早期胚胎转录因子的光遗传学失活。

DOI：
10.21769/bioprotoc.3296
发表时间：
2019
期刊：
Bio-protocol
影响因子：
0.8
作者：
McDaniel,StephenL;Harrison,MelissaM
通讯作者：
Harrison,MelissaM

Zelda is differentially required for chromatin accessibility, transcription factor binding, and gene expression in the early Drosophila embryo.

DOI：
10.1101/gr.192682.115
发表时间：
2015-11
期刊：
Genome research
影响因子：
7
作者：
Schulz KN;Bondra ER;Moshe A;Villalta JE;Lieb JD;Kaplan T;McKay DJ;Harrison MM
通讯作者：
Harrison MM

GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo.