Shared mechanisms regulate transcription-factor activity to control cell fate in neural stem cells and the embryo

共享机制调节转录因子活性以控制神经干细胞和胚胎的细胞命运

• 批准号: 10160968
• 负责人: Melissa Harrison
• 金额: $ 33.44万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160968
• 关键词: 3' Untranslated Regions; Adopted; Adult; Automobile Driving; BRAT gene; Biochemical; Brain; Brain Neoplasms; Cell Fate Control; Cell Lineage; Cell division; Cells; Chromatin; Chromatin Structure; Data; Defect; Development; Drosophila melanogaster; Embryo; Equilibrium; Failure; Fertilization; Genes; Genetic; Genetic Transcription; Genome; Genomics; Germ Cells; Health; Larva; Lead; Mediating; Natural regeneration; Neurons; Organism; Population; Positioning Attribute; Post-Transcriptional Regulation; Process; Proteins; RNA; Regulation; Role; Specific qualifier value; Stress; Structure; System; TRIM Gene; Testing; Tissues; Translations; adult stem cell; base; cell fate specification; daughter cell; embryo cell; nerve stem cell; pluripotency; programs; response to injury; self-renewal; stem cell differentiation; stem cell division; stem cell fate; stem cell population; stem cells; tissue repair; transcription factor; tumorigenesis

ABSTRACT Development requires that cells robustly exit one cell fate and enter another. In the early embryo the specified germ cells must be rapidly reprogrammed to the pluripotent cells that can subsequently generate an entirely new organism. Conversely, following asymmetric stem-cell division the two daughter cells must adopt different fates with one regenerating the stem cell and the other exiting the multipotent state and initiating differentiation. These essential developmental transitions require that the activity of those factors that drive pluripotency be precisely controlled as both too many and too few stem cells are detrimental to the organism. While the transcription factors that drive stem-cell fate have been well characterized in culture, less is known about how the activity of these factors is tightly controlled within the context of a developing organism. Our preliminary data demonstrate a shared role for the transcription factor Zelda (ZLD) as a master regulator of the mulitpotent state in both the early embryo and larval neural stem cells of Drosophila melanogaster. We have recently demonstrated that in both the embryo and the larva ZLD can reprogram cells to a multipotent fate and increased ZLD activity is deleterious. Thus, ZLD activity must be tightly controlled to allow for development to proceed. Our preliminary data suggest that chromatin structure may limit the ability of ZLD to engage the genome and reprogram cell fate. ZLD activity is additionally regulated by post-transcriptional mechanisms that control ZLD levels. Based on these preliminary data we are well positioned to elucidate general mechanisms by which the activities of master regulators of stem-cell fate are precisely controlled to maintain a balance between self-renewal and differentiation. We will use genetic, genomic, and biochemical strategies to (1) identify mechanisms by which chromatin structure influences ZLD activity and (2) determine how post- transcriptional regulation of zld RNA controls ZLD protein levels in both neural stem cells and the early embryo. Together these results will have important implications for understanding how the balance between the multipotent and differentiated states are precisely controlled during development.

抽象的 发育需要细胞强有力地退出一种细胞命运并进入另一种细胞命运。在早期胚胎中指定 生殖细胞必须快速重新编程为多能细胞，随后可以产生完全的 新的有机体。相反，在不对称干细胞分裂之后，两个子细胞必须采用不同的 一种命运是再生干细胞，另一种则退出多能状态并开始分化。 这些重要的发育转变要求那些驱动多能性的因素的活动 精确控制，因为太多和太少的干细胞都对生物体有害。虽然 驱动干细胞命运的转录因子已在培养物中得到很好的表征，但人们对其如何作用知之甚少。 这些因素的活动在发育中的有机体中受到严格控制。我们的初步 数据表明转录因子 Zelda (ZLD) 作为多能的主要调节因子具有共同的作用 果蝇早期胚胎和幼虫神经干细胞的状态。我们最近有 证明在胚胎和幼虫中，ZLD 可以将细胞重编程为多能命运，并且 ZLD 活性增加是有害的。因此，必须严格控制 ZLD 活动，以允许其发展 继续。我们的初步数据表明染色质结构可能限制 ZLD 参与 基因组和重新编程细胞命运。 ZLD 活性还受到转录后机制的调节 控制 ZLD 水平。基于这些初步数据，我们有能力阐明一般机制 通过它精确控制干细胞命运主调节因子的活动以维持平衡 自我更新与分化之间。我们将使用遗传、基因组和生化策略来 (1) 确定染色质结构影响 ZLD 活性的机制，以及 (2) 确定后处理如何 zld RNA 的转录调控控制着神经干细胞和早期胚胎中的 ZLD 蛋白水平。 这些结果将对理解如何平衡两者之间的关系产生重要影响。 多能和分化状态在发育过程中受到精确控制。