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Roles for chromatin remodeler RSC and histone acetyltransferases in regulating chromatin structure and transcription

染色质重塑剂 RSC 和组蛋白乙酰转移酶在调节染色质结构和转录中的作用

基本信息

批准号：
10579529
负责人：
Chhabi K Govind
金额：
$ 42.98万
依托单位：
OAKLAND UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579529
关键词：
ATP phosphohydrolase Acetylation Affect Affinity Animal Model Auxins Binding Biological Process Bromodomain Cells ChIP-seq Chromatin Chromatin Structure Code Coffin-Siris Syndrome Complex Coupled DNA DNA Polymerase II DNA-Directed RNA Polymerase Data Development Developmental Disabilities Disease Dissociation Family Family member Fingers Gene Expression Genes Genetic Transcription Goals Growth HTATIP gene Histone Acetylation Histone H3 Histone H4 Histones Human In Vitro Intellectual functioning disability Length Link Lysine Malignant Neoplasms Mediating Methods Molecular Molecular Chaperones Mutation N-terminal Nucleosome Binding Domain Nucleosomes Open Reading Frames Physiological Positioning Attribute Role Running Saccharomyces cerevisiae Saccharomycetales Sfh1 Slide Stress Surface Plasmon Resonance Syndrome TATA-Box Binding Protein Tail Transcription Elongation Transcription Initiation Site Uracil Yeasts chromatin remodeling disease-causing mutation genome-wide histone acetyltransferase histone modification human disease in vitro activity in vivo member mutant nuclease prevent promoter public health relevance recruit transcriptome sequencing

项目摘要

PROJECT SUMMARY Dynamic changes to chromatin structure are essential for regulating gene expression in cells. These changes are mediated by chromatin-associated factors such as histone modifiers, chaperones, and chromatin remodelers. Mutations in these factors are strongly linked to many human diseases. For example, mutations in the conserved SWI/SNF family of ATP-dependent chromatin remodelers are linked to ~20% of human cancers. Some of these mutations are also linked to developmental and intellectual disability syndrome, such as Coffin-Siris syndrome (CSS). However, we do not fully understand what aspects of SWI/SNF remodeling activities are affected by the disease-causing mutations under physiological conditions. The Remodels the Structure of Chromatin (RSC) complex is a member of the SWI/SNF family, and is the only essential remodeler in budding yeast. RSC regulates many biological processes, including transcription by all three RNA polymerases. It is critically involved in maintaining canonical chromatin structure near gene-promoters. Many domains have been identified within the RSC ATPase subunit Sth1 that modulate its remodeling activity. Additional domains are implicated in interacting with DNA and nucleosomes. However, the contributions of these domains in dictating RSC function in living cells are poorly understood. Furthermore, the mechanisms that regulate the association of RSC with chromatin are also not clear. RSC could bind to specific regions of chromatin using its bromodomains that have been shown to bind acetylated histones in vitro. How RSC exploits histone acetylation for its recruitment or to execute its function under physiological conditions remains to be understood. Using Saccharomyces cerevisiae as a model organism, in the specific AIM 1), we will investigate the impact of mutations in various regulatory and nucleosome-binding domains, and some of the mutations that are linked to developmental abnormalities on chromatin structure, including accessibility and gene expression. We will examine how mutations in these important domains affect the ability of cells to respond to stress. In the specific AIM 2), we will identify the histone tail residues that promote RSC association with chromatin and those that help RSC disengage from chromatin. The extent to which acetylated residues affect RSC ability to make DNA accessible will also be determined, genome-wide. Furthermore, we will examine the role of RSC in regulating transcription during elongation steps. These studies will be valuable in understanding how histone modifiers and chromatin remodelers cooperate to regulate gene expression.

项目总结