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: 9925281
• 负责人: Melissa Harrison
• 金额: $ 33.37万
• 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/9925281
• 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.

摘要 发育需要细胞稳健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， 生殖细胞必须迅速重编程为多能细胞，随后可以产生完全的 新的有机体。相反，在不对称的干细胞分裂之后，两个子细胞必须采用不同的 其中一个细胞再生干细胞，另一个退出多能状态并启动分化。 这些重要的发育转变要求驱动多能性的那些因子的活性被 因为太多或太少的干细胞对生物体都是有害的。而 驱动干细胞命运的转录因子已经在培养中得到了很好的表征，但对如何驱动干细胞命运的转录因子知之甚少。 这些因子的活性在发育中的生物体中受到严格控制。我们的初步 数据表明转录因子Zelda（ZLD）作为多能性细胞的主调节因子的共同作用。 在果蝇早期胚胎和幼虫神经干细胞中的状态。我们最近 证明在胚胎和幼虫中，ZLD可以将细胞重新编程为多能命运， 增加的ZLD活性是有害的。因此，必须严格控制ZLD活性，以允许开发， 继续.我们的初步数据表明，染色质结构可能会限制ZLD的能力，从事 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。基于这些初步的数据，我们很好地阐明了一般机制 干细胞命运的主要调节者的活动被精确地控制以保持平衡 自我更新和分化之间的关系。我们将使用遗传学、基因组学和生物化学策略来（1） 确定染色质结构影响ZLD活性的机制，以及（2）确定后染色质结构如何影响ZLD活性。 Zld RNA的转录调节控制神经干细胞和早期胚胎中的ZLD蛋白水平。 总之，这些结果将对理解如何平衡 多能和分化状态在发育过程中得到精确控制。