SWING LIGAND-REGULATED ENHANCER-DEPENDENT TRANSCRIPTION

摆动配体调节的增强子依赖性转录

• 批准号: 10446924
• 负责人: Dario Meluzzi
• 金额: $ 11.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-04 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10446924
• 关键词: Acute; Architecture; Award; Binding; Biological Assay; Chromosomes; Complement; Complex; Cytoplasmic Granules; DNA; DNA Damage; DNA Repair; Data; Enhancers; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Event; G22P1 gene; Gene Activation; Genes; Genetic Transcription; Genomic approach; Genomics; Grant; Heterochromatin; Housekeeping Gene; Informatics; Knowledge; Licensing; Ligands; Link; Location; Maps; Mediating; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear; Outcome; Parents; Phase; Positioning Attribute; Property; Proteins; Proteomics; RNA; Research Personnel; Resolution; Role; Shapes; Signal Transduction; Single-Stranded DNA; Structure; Testing; Time; Transcription Elongation; Transcriptional Regulation; Type I DNA Topoisomerases; base; career; cellular imaging; experimental study; genome-wide; insight; novel strategies; parent grant; programs; promoter; protein complex; recruit; response

ABSTRACT In response to estrogen-dependent gene activation, the rapid assembly of the MegaTrans complex at responsive enhancers, is suggested to assemble an RNP condensate with phase separation-like properties. The resultant condensate is required for formation of homotypic cooperative enhancer networks, and initial data suggest that these activated enhancers become rapidly associated with specific sub-nuclear bodies. Further, the enhanced transcription of enhancers located separated by many TADs by linear distance may come into closer proximity response to E2. Here, we hypothesize that by linking new mechanistic principles of ERα-bound enhancer, promoter activation events to roles of transcription at chromosomal boundaries in chromosomal architectures and relocation into specific subnuclear architectural structures, can provide mechanistic insights into the activation of large regulated enhancer programs. First, we will explore a new approach to detect single strand DNA nicking genome-wide to uncover a previously-overlooked, but required, mechanism for ligand- and signal-dependent acute activation of enhancer programs. This would uncover a component of the DNA damage program that here instead serves as required coactivators for regulated enhancer activation. We will test the hypothesis that the strongest chromosomal boundaries harbor universally-expressed genes, and that they interact both intra- and inter- chromosomally, impacting chromosomal architecture. This supports a functional association of active chromosomal boundaries with specific subnuclear architectural structures. This R03 award would permit me to generate the essential data required to establish new principles regarding dynamic enhancer activation programs and interactions with specific subnuclear architectural structures for ligand-regulated gene transcriptional programs, providing a strong experimental basis for subsequent submission of an R01 grant.

抽象的 响应于雌激素依赖性基因激活，大塔群岛复合物的快速组装在反应性时 建议增强子与相分离的特性组装RNP冷凝物。结果 凝结物是形成同型合作增强剂网络所必需的，而初始数据表明 这些激活的增强子与特定的亚核体迅速相关。此外，增强了 通过线性距离分隔的位于许多TAD的增强子的转录可能会更接近 对E2的响应。在这里，我们假设通过链接ERα结合增强子的新机械原理，启动子 激活事件到染色体体系结构中染色体边界处转录的作用，然后迁移到 特定的亚核体系结构可以为大量调节的激活提供机械洞察力 增强程序计划。首先，我们将探索一种新方法，以检测单链DNA划分全基因组到 发现一种以前被忽视但需要的机制，用于配体和信号依赖性的急性激活 增强程序计划。这将揭示DNA损伤程序的组成部分，而这里是 需要进行调节增强子激活的共激活因子。我们将检验以下假设 染色体边界具有普遍表达的基因，并且它们相互作用 染色体，影响染色体建筑。这支持主动的功能关联 具有特定亚核体系结构结构的染色体边界。这个R03奖将使我能够 生成建立有关动态增强器激活程序的新原则所需的基本数据 以及与配体调节基因转录的特定亚核体系结构的相互作用 计划，为随后提交R01赠款提供了强大的实验基础。