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.

合胞体的基因表达变异性和核区域自主性 项目摘要 合胞体是一种大的多核细胞，在生物学中广泛存在。藻类、真菌、原生生物和人类 肌肉和胎盘等组织都是由合胞体组成的。这种组织甚至被提议 是真核生物的祖先尽管它在生命王国中普遍存在， 合胞体细胞的研究还不充分。多核如何塑造合胞体的组成和功能？ 合胞藻类和哺乳动物的肌肉细胞显示出明显的局部组成梯度。原子核共享 这些细胞中相同的细胞质显示不同的转录谱。Gladfelter实验室的工作表明， 合胞体真菌棉阿舒囊霉细胞核分裂不同步，提示细胞周期信号 在这些细胞的相邻核中是不共享的。总的来说，这些证据表明， 尽管缺乏物理屏障来扩散穿过细胞，但合胞体细胞中的组成是高度异质的。 细胞，且合胞体核可以显示基因表达自主性。目前尚不清楚的组成是如何的 近核胞质区域在合胞体中受到调节，以及这如何影响核区域功能。 Gladfelter实验室的大量工作表明，空间聚类和非随机定位的 记录是Ashbya核自治区的基础。这种非随机定位是由 形成由Whi 3蛋白组成的RNA-蛋白质缩合物。Whi 3缩合物也调节适当的 分支形态阿舒囊霉通过聚类转录参与极性生长在菌丝尖端。Whi3 定位调节这些转录本的翻译，但未知。总的来说，目前尚不清楚核如何 区域的组成和功能受转录和翻译的局部变异的调节。 在这个建议中，我将研究如何本地组成的影响，空间变异的转录， 在遗传上易于处理的模式合胞真菌阿舒囊菌中的翻译。在目标1中，我将调查 核之间的转录变异以及这种变异对局部区域功能的影响。通过 调节转录局部，我希望建立核自主转录的作用，在控制 局部生化功能的变化。在目标2中，我将研究Whi 3凝聚对空间偏差的作用 在翻译中。我将使用局部操纵Whi 3凝聚来研究凝聚对局部的影响， 翻译.在目标3中，我将研究哪些生化过程是全局协调的， 在合胞体细胞核中有局部反应。这将揭示细胞核中活跃或压抑的细胞群 转录和生物化学过程的局部调节。在完成这项工作后，我希望 剖析转录变化和受管制的本地翻译在塑造功能方面的贡献， 核相关的胞质领土阿舒囊菌。拟议工作的理由是，它将提供 深入了解核区域的局部自治如何塑造大型多核细胞的生物学。总的来说， 这项工作将提供对一种广泛但知之甚少的细胞类型的组织和调节的见解。