Mechanisms and dynamics of gene expression during cellular differentiation and development

细胞分化和发育过程中基因表达的机制和动态

• 批准号: 9750065
• 负责人: Erin Osborne Nishimura
• 金额: $ 37.87万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750065
• 关键词: Adult; Biological Assay; Caenorhabditis elegans; Cell Lineage; Cell model; Cell physiology; Cells; Cytoplasmic Granules; Development; Embryo; Embryonic Development; Fertilization; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Human; Link; Maps; Messenger RNA; Microscopy; Molecular; Mus; Nematoda; Nuclear; Organism; Outcome; Pattern; Production; Proteins; Regenerative Medicine; Regulator Genes; Research; Resolution; System; Systems Biology; Technology; cancer stem cell; cancer therapy; cell cortex; cell growth regulation; cohort; fascinate; novel; single-cell RNA sequencing; stem cell therapy; transcriptome; transcriptome sequencing; tumor progression

PROJECT SUMMARY AND ABSTRACT Proper cellular differentiation is essential for healthy embryonic development, and new discoveries regarding cellular differentiation will impact the cancer, stem cell, and regenerative medicine fields. Caenorhabditis elegans is a nearly ideal model of cellular differentiation because the cell lineage is predictive and fully mapped from fertilization to adulthood (Sulston et al., 1977; Sulston et al., 1984). To determine molecular hallmarks that distinguish cells as they progress through early embryogenesis, we have generated a single-cell-resolution, whole-transcriptome RNA-seq (scRNA-seq) map of the C. elegans early embryo (Osborne Nishimura, et al., 2015; Tintori et al, 2016). Many developmental systems (human, mouse, etc) are also amenable to single-cell RNA-seq assays. However, it remains challenging in those organisms to conduct downstream research efforts aimed at dissecting the mechanisms critical for cellular differentiation and development. Because C. elegans affords more tractable genetics assays, microscopy, and quantification of cell fate changes, we aim to exploit the system to identify 1) mechanisms that pattern cell-specific transcriptomes prior to zygotic transcription, 2) the functional impact of mRNA dynamics on protein production and cellular differentiation, and 3) gene regulatory networks that orchestrate the first waves of cell-specific transcription and differentiation. Surprisingly, we have discovered fascinating sub-cellular localization patterns (e.g. nuclear, cell cortex, granules) in some asymmetrically partitioned mRNAs of the very early embryo. This presents us with a unique opportunity to study the link between mRNA localization, translational control, and developmental outcome in a system that is not confounded by nascent transcription. Our goal is to illuminate how systems biology approaches can inform our functional understanding of cellular differentiation and development in an intact living organism. !

项目总结和摘要 适当的细胞分化对健康的胚胎发育至关重要， 细胞分化将影响癌症、干细胞和再生医学领域。Caenorhabditis elegans是细胞分化的一个近乎理想的模型，因为细胞谱系是可预测的，并且是完全映射的。 从受精到成年（Sulston等，1977; Sulston等人，1984年）。为了确定分子特征， 区分细胞，因为他们通过早期胚胎发生的进展，我们已经产生了一个单细胞分辨率， 全转录组RNA测序（scRNA-seq）图谱。线虫早期胚胎（Osborne Nishimura，et al.， 2015; Tintori等人，2016）。许多发育系统（人类、小鼠等）也适合单细胞 RNA-seq测定。然而，在这些生物体中进行下游研究工作仍然具有挑战性 旨在剖析细胞分化和发育的关键机制。因为C. elegans 提供了更易处理的遗传学测定，显微镜和细胞命运变化的定量，我们的目标是利用 该系统用于鉴定1）在合子转录之前使细胞特异性转录组形成图案的机制，2） mRNA动态对蛋白质产生和细胞分化的功能影响，以及3）基因 调控网络，协调细胞特异性转录和分化的第一波。 令人惊讶的是，我们已经发现了迷人的亚细胞定位模式（例如核，细胞皮层， 颗粒）在一些不对称分配的mRNA的非常早期胚胎。这为我们提供了一个独特的 有机会研究mRNA定位，翻译控制和发育结果之间的联系， 不受新生转录干扰的系统。我们的目标是阐明系统生物学 这些方法可以告知我们对完整细胞中细胞分化和发育的功能性理解。 活的有机体 !