Regulation of Chromatin by Phase Separation

通过相分离调节染色质

• 批准号: 9911981
• 负责人: Bryan A Gibson
• 金额: $ 6.53万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-16 至 2021-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911981
• 关键词: Address; Architecture; Binding Proteins; Biochemical; Biological; Biological Assay; Biological Models; Biology; Carcinoma; Cell Nucleolus; Cell Nucleus; Cells; Cellular Structures; Cellular biology; Chromatin; Chromatin Structure; Complex; DNA; Data; Dependence; Enhancers; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic approach; Genomics; Grant; Growth; Heterochromatin; Histones; In Vitro; Liquid substance; Literature; Malignant Neoplasms; Mammalian Cell; Membrane; Modeling; Molecular; Normal Cell; Nuclear; Nuclear Structure; Nucleosome Core Particle; Nucleosomes; Oncogenes; Oncogenic; Phase; Play; Post-Translational Protein Processing; Proteins; Reader; Regulation; Research; Role; Signal Transduction; Structure; System; Tail; Testing; Text; Work; base; cancer cell; cell growth; design; experimental study; human disease; in vitro Model; insight; novel therapeutic intervention; reconstitution

Project Summary Transcription and genome organization play important roles in cellular signaling, where both can amplify and reinforce cancer-specific gene expression. While significant advances have been made in understanding how chromatin is organized within the nucleus, the exact mechanisms mammalian cells use to organize their genome both in normal cells as well as in cancer remains unclear. Many cellular structures have recently been found to be phase separated bodies known as biomolecular condensates. Biomolecular condensates are membrane-less sub-organellar bodies driven to form by constituents with multivalent architecture. These condensates concentrate particular molecular constituents, altering their localization and biochemical activities in cells. The nucleolus, heterochromatin foci, and PML bodies are all nuclear biomolecular condensates, but whether any other micron-scale nuclear structures are similarly organized remains to be seen. Using biochemical, cell biological, and genomic approaches, the research proposed here aims to understand the portions of the genome undergo phase separation, focusing in particular on the “enhancer” regions that direct gene expression in cancer cells. Through two specific aims, the proposed experiments will (1) determine the molecular components necessary to promote phase separation of chromatin, as well as (2) elucidate the contribution of multivalent proteins BRD4 and BRD4-NUT to oncogenic phase separation of chromatin at super- and mega-enhancers. This proposed research should advance understanding of nuclear organization, specifically addressing how phase separation might contribute to gene expression control in cancer cells. Moreover, the work proposed here may uncover new therapeutic strategies for cancer, focused on approaches that modulate phase separation and genome organization in the nucleus.

项目摘要 转录和基因组组织在细胞信号传导中发挥重要作用， 扩增和加强癌症特异性基因表达。虽然在这方面取得了重大进展， 了解染色质是如何在细胞核内组织的，哺乳动物细胞用来 在正常细胞和癌症中组织它们的基因组仍然不清楚。许多细胞结构具有 最近发现它们是被称为生物分子凝聚物的相分离体。生物分子 凝聚物是无膜的亚细胞器体，由具有多价的组分驱动形成。 架构这些冷凝物浓缩了特定的分子成分，改变了它们的定位， 细胞中的生化活动。核仁、异染色质灶和PML小体均为细胞核 生物分子凝聚物，但是否有任何其他微米级的核结构类似组织 还有待观察。利用生物化学、细胞生物学和基因组学方法， 旨在了解基因组的部分经历相分离，特别是集中在 在癌细胞中指导基因表达的“增强子”区域。通过两个具体目标， 实验将（1）确定促进相分离所需的分子组分， （2）阐明多价蛋白BRD 4和BRD 4-NUT对致癌基因的贡献。 在超级和巨型增强子处染色质的相分离。这项拟议中的研究应该会取得进展， 了解核组织，特别是解决相分离如何对基因做出贡献 在癌细胞中的表达控制。此外，这里提出的工作可能会发现新的治疗策略 对于癌症，专注于调节细胞核中的相分离和基因组组织的方法。