Mechanisms and dynamics of gene expression during cellular differentiation and development

项目摘要和摘要 适当的细胞分化对于健康的胚胎发育是必不可少的，以及关于 细胞分化将影响癌症、干细胞和再生医学领域。阴沟肠炎 线虫是一个近乎理想的细胞分化模型，因为细胞谱系是可预测的，并且完全被绘制出来。 从受精到成年(Sulston等人，1977；Sulston等人，1984)。为了确定分子特征， 在早期胚胎发育过程中区分细胞，我们已经产生了单细胞分辨率， 线虫早期胚胎的全转录RNA-seq(scRNA-seq)图谱(Osborne Nishimura等， 2015年；Tintori等人，2016年)。许多发育系统(人、鼠等)也适用于单细胞。 RNA-seq检测。然而，在这些生物体中进行下游研究仍然具有挑战性。 旨在剖析细胞分化和发育的关键机制。因为线虫 提供了更易处理的遗传学分析、显微镜和细胞命运变化的量化，我们的目标是开发 识别1)在合子转录之前形成细胞特异性转录模式的机制的系统，2) 信使核糖核酸动态对蛋白质生产和细胞分化的功能影响；3)基因 协调第一波细胞特异性转录和分化的调控网络。 令人惊讶的是，我们发现了令人着迷的亚细胞定位模式(例如，核、细胞皮质、 在极早期胚胎的一些不对称分裂的mRNA中)。这为我们呈现了一种独特的 有机会研究mRNA本地化、翻译控制和发育结局之间的联系 一种不会被新生的转录混淆的系统。我们的目标是阐明系统生物学是如何 方法可以让我们完整地了解细胞分化和发育的功能 活着的有机体。 好了！

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. !