Genetic and Molecular Definition of Histone Modifying Enzyme Functions

组蛋白修饰酶功能的遗传学和分子定义

• 批准号: 10364649
• 负责人: SHARON Y. R. DENT
• 金额: $ 40万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364649
• 关键词: Address; Affect; Alleles; Biochemical; Biological; Bromodomain; Cell Nucleus; Cells; Cerebellar Ataxia; Cerebellum; Chromatin; Complex; Development; Disease; Embryo; Enzymes; Foundations; Funding; Gene Expression; Gene Expression Regulation; Genetic; Genetic Transcription; Genome; Genomics; Goals; Growth; Histones; Human; Knowledge; Link; LoxP-flanked allele; Malignant Neoplasms; Mammalian Cell; Molecular; Mutant Strains Mice; Mutate; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Pathway interactions; Proteins; Research; Role; SAGA; Spinal; Tissues; Work; XCL1 gene; cell behavior; enzyme activity; flexibility; histone acetyltransferase; histone modification; human disease; insight; novel; novel therapeutics; programs; stem cells

Understanding how histone modifications are regulated is fundamentally important for understanding mechanisms of chromatin organization and gene regulation in both normal and disease states. The overall goal of our research is to address this challenging question, using genetic and molecular approaches to define which histone modifying enzymes, and by extension, which histone modifications, govern specific gene expression programs in particular biological contexts. Our work is focused largely on the Gcn5 histone acetyltransferase (HAT) and the USP22 histone deubiquitylase (DUB), which are both components of a large multiprotein assembly termed SAGA. Gcn5, USP22 and other SAGA components have been implicated in human maladies, including cancer and neurodegeneration, but the molecular mechanisms underlying such effects are not known. Over the past 20 years, we have created a novel toolkit of Gcn5 and USP22 mutant mice and cells, including null alleles, conditional (floxed) alleles, and point mutated alleles (in the Gcn5 HAT domain, the Gcn5 bromodomain, or the USP22 DUB domain) that affect the activity of these enzymes. Our studies of Gcn5 mutations revealed key insights to both transcriptional and non-transcriptional functions for this HAT during development, and most recently, they revealed important connections between Gcn5 and Myc functions both in normal stem cells and in cancer. Our USP22 mutant mice revealed that this DUB is also critical for embryo survival, but through different pathways than those affected by Gcn5 loss. Despite these advances, many significant gaps in knowledge still remain. We have only a partial view of which transcription programs require Gcn5 in mammalian cells. Moreover, Gcn5 is now known to be part of a second histone modifying complex called ATAC, but we do not know how Gcn5 is apportioned between these complexes or their relative roles in development or disease. We also have an incomplete understanding of the roles of USP22 and the SAGA DUB module in specific tissues such as the cerebellum, which is especially relevant since specific components of the SAGA DUB module are linked to a debilitating neurodegenerative disease, spinal cerebellar ataxia type 7 (SCA7). This MIRA will provide us stable and flexible funding to continue our genetic, biochemical, and molecular studies to address these critically important questions. In the longer term, definition of the normal functions of Gcn5 and USP22 will provide molecular foundations for development of new therapeutic options for diseases in which these factors are mis-regulated.

了解组蛋白修饰是如何被调控的对于