Determinants of genome-wide activity and specificity of SWI/SNF family chromatin remodeling

SWI/SNF 家族染色质重塑的全基因组活性和特异性的决定因素

• 批准号: 10796669
• 负责人: Hamilton Courtney Hodges
• 金额: $ 2.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796669
• 关键词: Address; Biology; Cells; Chemicals; Chromatin; Complex; DNA; Disease; Epigenetic Process; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Heterogeneity; Intervention; Mammals; Microscopy; Outcome Measure; Permeability; Process; Protein Family; Role; Signal Transduction; Site; Specificity; Technology; Variant; chromatin remodeling; epigenomics; genetic manipulation; genome-wide; human disease; improved; live cell microscopy; novel therapeutics; protein complex; tool; Address; Biology; Cells; Chemicals; Chromatin; Complex; DNA; Disease; Epigenetic Process; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Heterogeneity; Intervention; Mammals; Microscopy; Outcome Measure; Permeability; Process; Protein Family; Role; Signal Transduction; Site; Specificity; Technology; Variant; chromatin remodeling; epigenomics; genetic manipulation; genome-wide; human disease; improved; live cell microscopy; novel therapeutics; protein complex; tool

Project Summary Sequencing of genetic and epigenetic variants associated with disease states has revealed that ATP- dependent chromatin remodelers are among the most frequently disrupted genes in a number of diseases. In mammals, BAF (SWI/SNF), PBAF, and GBAF complexes are highly conserved ATP-dependent chromatin remodelers that generate accessibility for DNA-templated processes. Although these complexes have well- documented roles in many contexts, the mechanisms by which BAF-family complexes are regulated by specific signals remains poorly understood. Additionally, accessible sites across the genome respond with extreme heterogeneity to remodeling by these complexes, yet the basis of this heterogeneity, the physical origins of remodeling specificity, as well as the effects on transcription after initiation remain largely unknown. Improved understanding of these principles would provide powerful opportunities to manipulate gene expression in normal and disease states. To address this challenge, we will develop and combine new tools in epigenetics, chemical biology, and microscopy. We will make use of rapid technologies to manipulate BAF activity in living cells using cell-permeable molecules, and measure the outcomes using sensitive, unbiased approaches, including epigenomics and live-cell microscopy. We will use these tools to answer essential questions about ATP-dependent chromatin remodeling specificity, including: (1) How are BAF (SWI/SNF) complexes regulated via cellular signals? (2) Why do sites respond differently to chromatin remodeling? (3) How does chromatin remodeling influence transcription after initiation? Revealing the fundamental mechanisms used by these factors holds great promise to enable powerful intervention strategies for diverse human diseases.

项目摘要 与疾病状态相关的遗传和表观遗传变异的测序表明ATP- 依赖性染色质重塑剂是多种疾病中最常见的基因之一。在 哺乳动物，BAF（SWI/SNF），PBAF和GBAF复合物是高度保守的ATP染色质 为DNA模拟过程产生可访问性的重塑器。尽管这些络合物有很好的 在许多情况下，有记录的角色，即BAF家庭复合物受到特定调节的机制 信号仍然很少理解。此外，整个基因组的可访问地点以极端的反应 这些复合物进行重塑的异质性，但是这种异质性的基础是物理起源 重塑特异性以及开始后对转录的影响仍然在很大程度上未知。改进 对这些原则的理解将为操纵基因表达提供强大的机会 正常和疾病状态。为了应对这一挑战，我们将开发并结合表观遗传学的新工具， 化学生物学和显微镜。我们将利用快速技术来操纵BAF活动 使用细胞可渗透分子的细胞，并使用敏感的，公正的方法测量结果， 包括表观基因组学和活细胞显微镜。我们将使用这些工具回答有关的基本问题 依赖ATP的染色质重塑特异性，包括：（1）BAF（SWI/SNF）配合物如何调节 通过细胞信号？ （2）为什么站点对染色质重塑的反应不同？ （3）染色质如何 重塑会影响开始后的转录？揭示这些使用的基本机制 因素具有巨大的希望，可以为多样化的人类疾病实现强大的干预策略。