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.

项目摘要 已经提出了由本质上无序区域（IDR）介导的蛋白质的弱多价相互作用 要将转录机械组织到多组分群集中，但我们对如何如何了解 这些IDR与特定合作伙伴互动以实现功能结果。因为这些互动很高 传统策略鉴定蛋白质 - 蛋白质蛋白 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 弱的多价相互作用能够具有高度特异性的异质相互作用，从而导致功能 核组织。我们的长期目标是了解弱的多价互动如何组织 转录机械的特定成分，以实现基因激活。目的 父授予是为了研究群集介导的IDR相互作用的机理和功能 转录共激活因子。多样性补充剂的拟议工作重点是研究心肌素 （MyOCD），平滑肌细胞特异性共激活剂。拟议的工作与父母的目标3直接相关 格兰特（Grant）提议研究共激活因子IDR在各种基因激活模型中的功能作用 包括报告基因分化的记者测定和细胞模型。 MyOCD是一种平滑的肌肉细胞 共激活因子，我们将研究其IDR在记者测定和平滑肌细胞中的作用 分化。这些研究的完成将促进父母赠款的目标和目标，并将 教我们有关基因激活中普遍但经常被忽略的IDR的功能。