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Transcriptome reprogramming in the early embryo

早期胚胎中的转录组重编程

基本信息

批准号：
10673874
负责人：
Miler T. S. Lee
金额：
$ 36.36万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-24 至 2025-07-31
项目状态：
未结题

项目摘要

Early in development, a highly coordinated maternal-to-zygotic transition “reprograms” the embryo to a pluripotent cellular identity, capable of giving rise to all subsequent cell types in the developing organism. How cells are induced to pluripotency is still poorly understood, and yet has enormous implications, not only for understanding fundamental developmental and gene regulatory processes, but also for disease modeling and therapies. The long-term goal is to decipher mechanisms and principles conserved across vertebrates that guide pluripotency induction. To begin to address this question, this proposal aims to elucidate how pluripotency factors provided to the egg activate the first genes from the embryonic genome in the model vertebrate zebrafish. Zebrafish produce large clutches of externally developing embryos and express many key regulators of pluripotency that are conserved with humans, making them an ideal experimental system to discover novel regulatory paradigms that induce vertebrate pluripotency. This proposal has three primary goals. First, the regulatory logic underlying the specificity of embryonic gene activation will be deciphered. Maternal pluripotency factors act on a transcriptionally quiescent embryonic genome to initially activate only a few hundred genes, prior to the activation of thousands of genes hours later. Cutting-edge techniques will be used to map pluripotency factor binding genome wide, at earlier developmental stages than have previously been profiled. Binding patterns will be compared in the vicinity of early- versus later activated genes, and distinguishing properties of their respective gene regulatory sequences will be extracted. Second, novel regulators of embryonic genome activation will be deduced by integrating multiple sources of genomics data. These factors will be evaluated using innovative loss-of-function strategies to measure their contributions to embryonic reprogramming and pluripotency. Third, this proposal will uncover post-transcriptional mechanisms that regulate the maternal pluripotency factors themselves. Biochemical and genetic approaches will be used to discover factors that bind maternal mRNA to positively or negatively affect their expression, and in turn exert precise temporal control over pluripotency induction. Together, these analyses will further elucidate the gene regulatory logic of the early vertebrate embryo and provide a deeper understanding of how pluripotent identities are induced.

在发育的早期，高度协调的母体到合子的转变将胚胎“重新编程”为多能细胞特性，能够在发育中的生物体中产生所有随后的细胞类型。如何细胞被诱导为多能性仍然知之甚少，但具有巨大的影响，不仅对了解基本的发育和基因调控过程，也用于疾病建模，治疗长期目标是破译脊椎动物中保守的机制和原则，引导多能性诱导。为了开始解决这个问题，本建议旨在阐明如何提供给卵子的多能性因子激活了模型中胚胎基因组的第一批基因脊椎动物斑马鱼斑马鱼产生大量外部发育的胚胎，并表达许多关键的多能性的调节因子，这些调节因子在人类中是保守的，使它们成为理想的实验系统，发现诱导脊椎动物多能性的新的调控模式。该提案有三个主要内容目标.首先，胚胎基因激活的特异性背后的调控逻辑将被破译。母体多能性因子作用于转录静止的胚胎基因组，最初仅激活一个转录因子。几百个基因，然后在几个小时后激活数千个基因。尖端技术将是用于在比以前更早的发育阶段对多能性因子结合基因组进行作图被侧写了结合模式将在早期与晚期激活基因附近进行比较，将提取它们各自的基因调节序列的区别性质。二、新颖胚胎基因组激活的调节因子将通过整合多个基因组学数据来源来推导。这些因素将使用创新的功能丧失策略进行评估，以衡量其对胚胎重编程和多能性。第三，这项建议将揭示转录后机制，调节母体多能性因子本身。将采用生物化学和遗传学方法发现与母体mRNA结合的因素，积极或消极地影响其表达，并反过来发挥作用。对多能性诱导的精确时间控制。总之，这些分析将进一步阐明基因早期脊椎动物胚胎的调控逻辑，并提供更深入的了解如何多能身份是诱导的。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hybridization led to a rewired pluripotency network in the allotetraploid Xenopus laevis.

DOI：
10.7554/elife.83952
发表时间：
2023-10-03
期刊：
eLife
影响因子：
7.7
作者：
Phelps WA;Hurton MD;Ayers TN;Carlson AE;Rosenbaum JC;Lee MT
通讯作者：
Lee MT

RNA degradation is required for the germ-cell to maternal transition in Drosophila.

DOI：
10.1016/j.cub.2021.04.052
发表时间：
2021-07-26
期刊：
Current biology : CB
影响因子：
0
作者：
Blatt P;Wong-Deyrup SW;McCarthy A;Breznak S;Hurton MD;Upadhyay M;Bennink B;Camacho J;Lee MT;Rangan P
通讯作者：
Rangan P

Optimized design of antisense oligomers for targeted rRNA depletion.