Gene Expression Variability and Nuclear Territory Autonomy in Syncytia

合胞体的基因表达变异性和核域自主性

• 批准号: 10537843
• 负责人: Ameya Pranav Jalihal
• 金额: $ 3.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10537843
• 关键词: Algae; Behavior; Biochemical; Biochemical Process; Biological Process; Biology; Blood; Cell Cycle; Cell Nucleus; Cell Polarity; Cell physiology; Cells; Cellular biology; Conceptions; Cues; Cytoplasm; Cytosol; Diffusion; Disease; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Giant Cells; Global Change; Growth; Heterogeneity; Human; Image; Learning; Life; Malignant Neoplasms; Measures; Mediating; Membrane; Mission; Modeling; Morphology; Muscle; Muscle Cells; Nuclear; Pattern; Physical condensation; Physiology; Placenta; Population; Prevalence; Process; Proteins; Public Health; RNA; Regulation; Research; Ribosomes; Role; Shapes; Signal Transduction; Source; Testing; Transcript; Transcription Process; Transcriptional Regulation; Translating; Translations; Trees; United States National Institutes of Health; Variant; Work; cell type; embryo tissue; fungus; human tissue; insight; nuclear division; optogenetics; response; statistics; transcriptome sequencing

Title Gene expression variability and nuclear territory autonomy in syncytia Project Summary Syncytia are large, multinucleate cells that are found widely across biology. Algae, fungi, protists, and human tissues like muscle and placenta are all composed of syncytia. Such organization has even been proposed to be the ancestral eukaryotic state. Despite its prevalence across kingdoms of life, the organization and regulation of syncytial cells remain understudied. How do multiple nuclei shape the composition and function in syncytia? Syncytial algal and mammalian muscle cells show distinct gradients of local composition. Nuclei sharing the same cytoplasm in these cells show distinct transcriptional profiles. Work in the Gladfelter lab showed that in the syncytial fungus Ashbya gossypii, nuclei show asynchronous nuclear division, suggesting that cell-cycle signals are not shared in neighboring nuclei in these cells. Overall, these pieces of evidence suggest that the cytosolic composition in syncytial cells is highly heterogeneous despite lacking physical barriers to diffusion across the cell, and that syncytial nuclei can show autonomy in gene expression. It is unknown how the composition of nuclear-proximal cytosolic territories is regulated in syncytia, and how this impacts nuclear territory function. Extensive work in the Gladfelter lab has revealed that spatial clustering and non-random localization of transcripts underlies nuclear-autonomous division in Ashbya. Such non-random localization is mediated by the formation of RNA-protein condensates consisting of Whi3 protein. Whi3 condensates also modulate proper branching morphology in Ashbya by clustering transcripts involved in polar growth at hyphal tips. How Whi3 localization modulates translation from these transcripts in unknown. In general, it is unknown how nuclear territory composition and function are regulated by local variation in transcription and translation. In this proposal I will examine how local composition is influenced by spatial variability in transcription and translation in the genetically tractable model syncytial fungus Ashbya. In Aim 1 I will investigate sources of transcription variation between nuclei and the consequences of such variation on local territory function. By modulating transcription locally, I expect to establish the role of nuclear autonomous transcription in controlling variation in local biochemical function. In Aim 2 I will investigate the role of Whi3 condensation on spatial biases in translation. I will use manipulate Whi3 condensation locally to study the impact of condensates on local translation. In Aim 3 I will investigate which biochemical processes are globally coordinated versus those that are locally responsive across syncytial nuclei. This will reveal nuclear populations that show active or repressed transcription, and biochemical processes that are locally regulated. Upon the completion of this work, I expect to dissect the contribution of variation in transcription and regulated local translation in shaping the functionality of nucleus-associated cytosolic territories in Ashbya. The rationale for the proposed work is that it will provide insight into how local autonomy of nuclear territories can shape the biology of large multinucleate cells. Overall, this work will provide insights into organization and regulation of a widespread yet poorly understood cell-type.

综合中的标题基因表达变异性和核领土自治 项目摘要 合成性是大型的多核细胞，在生物学之间广泛发现。藻类，真菌，生物和人类 肌肉和胎盘等组织均由合胞体组成。甚至已经提出了这样的组织 成为祖先的真核状态。尽管在生活的王国中盛行，但组织和监管 合成细胞的研究仍在研究。多个核如何塑造合成中的组成和功能？ 合成藻类和哺乳动物肌肉细胞显示出局部组成的不同梯度。核共享 这些细胞中相同的细胞质显示出不同的转录谱。在Gladfelter实验室的工作表明 合成真菌Ashbya gossypii，核显示异步核分裂，表明细胞周期信号 在这些细胞中没有在邻近的核中共享。总体而言，这些证据表明胞质 尽管缺乏扩散跨整个物理障碍，但合成细胞中的组成是高度异质 细胞，该合胞核可以显示基因表达的自主性。未知的成分是如何 核毒性胞质区域受到合成中的调节，以及这如何影响核领土功能。 Gladfelter实验室的大量工作表明，空间聚类和非随机定位 成绩单是阿什比亚（Ashbya）的核自治部门的基础。这种非随机定位是由 由WHI3蛋白组成的RNA蛋白冷凝物的形成。 WHI3冷凝物还适当调制 通过聚集在菌丝尖端的极性生长的转录本中的分支形态。如何WHI3 本地化在未知中调节这些转录本的翻译。通常，尚不清楚如何核 区域组成和功能受转录和翻译的局部变化调节。 在此提案中，我将研究局部组成如何受到转录的空间可变性的影响 在遗传上可触犯的模型合成真菌Ashbya中的翻译。在AIM 1中，我将调查 核与这种变化对局部区域功能的后果之间的转录变化。经过 在本地调节转录，我希望确定核自主转录在控制中的作用 局部生化功能的变化。在AIM 2中，我将调查WHI3凝结对空间偏见的作用 在翻译中。我将在本地使用操纵WHI3凝结来研究冷凝物对局部的影响 翻译。在AIM 3中，我将研究哪些生化过程是全球协调的 在合成核之间局部响应。这将揭示显示活跃或压抑的核种群 局部调节的转录和生化过程。完成这项工作后，我希望 剖析转录变异和调节局部翻译在塑造功能方面的贡献 Ashbya中与核相关的胞质区域。拟议工作的理由是它将提供 深入了解核领土的局部自主权如何塑造大型多核细胞的生物学。全面的， 这项工作将提供有关组织和调节细胞类型的知识和调节的见解。