Organization of transcriptional machinery by weak multivalent interactions

通过弱多价相互作用组织转录机制

• 批准号: 10758297
• 负责人: Benjamin Sabari
• 金额: $ 2.55万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10758297
• 关键词: Biological Assay; Biological Process; Cell Differentiation process; Cell Nucleus; Cell model; Data; Defect; Development; Developmental Process; Disease; Educational process of instructing; Gene Activation; Genes; Genetic Transcription; Goals; Investigation; Mediating; Modeling; Process; Protein Region; Reporter; Role; Smooth Muscle Myocytes; Time; Transcription Coactivator; Work; functional outcomes; genomic locus; human disease; insight; myocardin; novel; parent grant; protein protein interaction; recruit

Project Summary Weak multivalent interactions mediated by intrinsically disordered regions (IDRs) of proteins have been proposed to spatially organize the transcriptional machinery into multi-component clusters, yet we know little about how these IDRs interact with specific partners to enable functional outcomes. As these interactions are highly dynamic and cluster-dependent they have been overlooked by conventional strategies to identify protein-protein interactions. Our preliminary data support our overarching hypothesis that in the context of higher-order clusters weak multivalent interactions are capable of highly specific hetero-typic interactions leading to functional organization of the nucleus. Our long-term objective is to understand how weak multivalent interactions organize specific components of the transcriptional machinery in order to enable gene activation. The objective of the parent grant is to investigate the mechanism and function of cluster-mediated interactions of IDR of found on transcriptional coactivators. The proposed work in the diversity supplement focusses on investigating myocardin (MYOCD), a smooth muscle cell specific coactivator. The proposed work is directly related to Aim 3 of the parent grant, which proposes to investigate the functional role of coactivator IDRs in various models of gene activation including reporter assays and cell models of cellular differentiation. MYOCD is a smooth muscle cell specific coactivator, and we will be investigating the role of its IDR in reporter assays and smooth muscle cell differentiation. Completion of these studies will advance the goals and objectives of the parent grant and will teach us about how the function of prevalent yet often overlooked IDRs in gene activation.

项目概要 已提出由蛋白质本质无序区域 (IDR) 介导的弱多价相互作用 在空间上将转录机制组织成多组分簇，但我们对如何将其组织成多组分簇知之甚少 这些 IDR 与特定合作伙伴互动以实现功能性成果。由于这些相互作用高度 动态且依赖于簇的它们已被识别蛋白质-蛋白质的传统策略所忽视 互动。我们的初步数据支持我们的总体假设，即在高阶集群的背景下 弱多价相互作用能够产生高度特异性的异型相互作用，从而导致功能性 细胞核的组织。我们的长期目标是了解弱多价相互作用如何组织 转录机制的特定组件，以实现基因激活。该计划的目标 家长资助的目的是研究 IDR 的簇介导相互作用的机制和功能 转录共激活因子。多样性补充中拟议的工作重点是调查心肌素 (MYOCD)，一种平滑肌细胞特异性共激活剂。拟议的工作与母公司的目标 3 直接相关 拨款，提议研究共激活剂 IDR 在各种基因激活模型中的功能作用 包括报告基因检测和细胞分化的细胞模型。 MYOCD 是平滑肌细胞特异性的 共激活剂，我们将研究其 IDR 在报告基因检测和平滑肌细胞中的作用 差异化。完成这些研究将推进家长补助金的目的和目标，并将 教我们了解普遍但经常被忽视的 IDR 在基因激活中的功能。