Transcriptional regulation in mammalian cells

哺乳动物细胞的转录调控

• 批准号: 10668974
• 负责人: RICHARD YOUNG
• 金额: $ 79.85万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668974
• 关键词: Affect; Affinity; Architecture; Behavior; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biology; Cell Nucleus; Cell physiology; Cells; Chemicals; Chemistry; Chromatin; Code; Collaborations; Drug Design; Educational process of instructing; Environment; Future; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Heterochromatin; Investments; Maintenance; Mammalian Cell; Mentors; Nuclear; Output; Physical condensation; Physics; Process; Property; Proteins; RNA; Regulation; Research; Scientist; Specificity; Testing; Training; Transcriptional Regulation; Untranslated RNA; cell type; insight; programs; small molecule

Project Summary/Abstract  Transcription is a fundamental cellular process whose proper regulation is essential to establishment and maintenance of healthy cell states. As with many regulatory processes in the cell, transcription is now understood to involve the dynamic formation and dissolution of large assemblies of protein and RNA molecules called biomolecular condensates. Our research program is focused on three goals at the intersection of transcription and condensates that we believe will provide important new insights into gene regulation and fill important gaps in our understanding of condensates and their regulation. Goal 1) We will test the hypothesis that many long noncoding RNAs (lncRNAs) regulate transcriptional condensates at nearby genes. Condensates are formed by an ensemble of low-affinity molecular interactions and RNA can be a powerful regulator of condensate dynamics. Thousands of lncRNA species are expressed in any one cell type, but the functions of the vast majority of these RNA molecules are not known. Most lncRNAs are transcribed within 10kb of protein coding genes and appear to accumulate at those loci, suggesting that many of these RNAs function to tune the expression of local protein coding genes by affecting the dynamics of local condensate formation and dissolution. Goal 2) We will test the hypothesis that condensate immiscibility contributes to the functional separation of active and silent chromatin. The nuclear architecture of a cell involves transcriptionally active and inactive compartments, and current evidence indicates that the two compartments form separate condensates. We have observed that condensates formed by regulators of active and silent genes are immiscible and postulate that this property contributes to the functional separation of active and inactive compartments in the nucleus of mammalian cells. Goal 3) We will explore the physicochemical environments of nuclear condensates with the goal of determining the types of chemistries that distinguish diverse condensates. A major issue in condensate biology is the extent to which the chemical environments of diverse condensates enable biological specificity. Our evidence indicates that small molecules can be used to probe the internal chemical environment that governs the behavior of condensates and thus teach us about the internal chemistry of diverse condensates that may enable biological specificity. This information may also provide insights into the chemical features that selectively concentrate small molecules in specific condensates, which may enable future advances in drug design for targets that reside in specific condensates. While conducting these studies, we will continue to identify protein and RNA components of euchromatic and heterochromatin condensates and to invest in assays of condensate dynamics and transcriptional output. We will also continue to train and mentor diverse young scientists in an environment that facilitates collaboration with leading experts in biochemistry, chemistry and physics.

项目总结/摘要 转录是一个基本的细胞过程，其适当的调节对于建立和 维持健康的细胞状态。与细胞中的许多调节过程一样，转录现在是 它被理解为涉及蛋白质和RNA大集合体的动态形成和溶解 称为生物分子凝聚物的分子。我们的研究计划集中在三个目标， 我们相信，转录和缩合物的交叉将为基因组学提供重要的新见解， 调节和填补了我们对冷凝物及其调节的理解的重要空白。目标1：我们将 测试假设，许多长的非编码RNA（lncRNA）调节转录缩合物， 附近的基因缩合物是由低亲和力分子相互作用的集合体形成的，RNA可以 成为凝析动力学的强大调节器。任何一种lncRNA都表达数千种lncRNA 细胞类型，但这些RNA分子的绝大多数功能尚不清楚。大多数lncRNA 在蛋白质编码基因的10 kb内转录，并似乎在这些位点积累，这表明， 这些RNA中的许多通过影响细胞内的蛋白质， 局部凝析油形成和溶解的动力学。目标2）我们将检验假设， 凝聚物的不分散性有助于活性和沉默染色质的功能分离。核 细胞的结构包括转录活性和非活性区室，目前的证据表明， 表明两个隔室形成单独的冷凝物。我们已经观察到， 由活性和沉默基因的调节器形成的基因是不混溶的，并假设这种特性有助于 涉及哺乳动物细胞核中活性区室和非活性区室的功能分离。目标3） 我们将探索核凝聚物的物理化学环境，目的是确定 区分不同冷凝物的化学类型。冷凝物生物学的一个主要问题是 不同冷凝物的化学环境使生物特异性得以实现的程度。我们 有证据表明，小分子可用于探测内部化学环境， 控制着冷凝物的行为，从而教会我们各种物质的内部化学。 可以使生物特异性成为可能的浓缩物。这些信息还可以提供对 选择性地将小分子浓缩在特定冷凝物中的化学特征， 针对特定凝聚物中靶点的药物设计的未来进展。在进行这些 研究，我们将继续确定常染色质和异染色质的蛋白质和RNA成分 并投资于冷凝物动力学和转录输出的测定。我们还将 继续在促进与以下方面合作的环境中培训和指导不同的青年科学家： 生物化学、化学和物理学方面的顶尖专家。