Molecular Basis of Drosophila Homeotic Gene Regulation

果蝇同源基因调控的分子基础

• 批准号: 7531569
• 负责人: Peter J. Harte
• 金额: $ 43.13万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531569
• 关键词: ASCL1 gene; Acetylation; Affect; Binding; Binding Sites; Biological Assay; Biological Process; CREB-binding protein; Cell Cycle; Cell Maintenance; Cell division; Cells; Cellular biology; Chromatin; Chromatin Modeling; Chromosomes; Collaborations; Complex; DNA; DNA biosynthesis; Dependence; Depth; Development; Drosophila genus; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genetic; Genome; Goals; Histone Acetylation; Histones; Homeobox Genes; In Vitro; Investigation; Lead; Lysine; Maintenance; Malignant Neoplasms; Maps; Mediating; Methylation; Modification; Molecular; Mutation; N-terminal; Numbers; PRC1 Protein; Pattern; Polycomb; Proteins; Public Health; RNA Interference; Regulation; Reporter; Research; Response Elements; Role; Source; Staging; Staining method; Stains; Stem cells; Tail; Transcriptional Regulation; Transgenes; Tumor Suppressor Genes; Work; X Inactivation; base; cancer stem cell; daughter cell; enzyme activity; in vivo; insight; mutant; origin recognition complex; pluripotency; prevent; programs; promoter; protein E; research study; self-renewal; tissue regeneration; transmission process; tumor

DESCRIPTION (provided by applicant): The experiments described in this proposal are focused on understanding the mechanisms underlying the maintenance of stable heritable states of gene expression during development by the Polycomb Group (PcG) and Trithorax Group (trxG) proteins. PcG and trxG proteins are now implicated in many biological processes, including genome-wide control of transcriptional programs, maintenance of cell fates, stem cell self-renewal, X- inactivation, tissue regeneration, and reprogramming of gene expression patterns at the onset of differentiation. Polycomb silencing mechanisms are also directly implicated in the aberrant silencing of tumor suppressor genes and others in cancer. The underlying mechanisms that regulate Polycomb silencing are little understood. The Drosophila homeotic genes remain a preeminent source of new insights into these mechanisms. The aims of proposed work are 1) to further investigate the regulation of the TRX-dependent acetylation of histone H3K27 by CBP, the key mechanism by which the TRX prevents Polycomb silencing. 2) investigate the collaboration of the histone demethylase UTX in TRX-dependent H3K27 acetylation and its role during different developmental stages, including involvement in reversing Polycomb silencing at the onset of differentiation 3) investigate whether ASH1 also mediates H3K27 acetylation through its known association with CBP. We also plan to investigate the mechanism underlying the heritable transmission of Polycomb silencing during the cell division cycle, which occurs with high fidelity throughout development. Understanding the role of these new factors in regulating Polycomb silencing will provide new insights into the mechanisms underlying the epigenetic inheritance of stable chromatin states during development. PUBLIC HEALTH RELEVANCE: This proposal focuses on understanding the mechanisms underlying the maintenance of stable states of gene expression by the Polycomb and Trithorax complexes. It explores the role of newly identified proteins and enzyme activities associated with Polycomb and Trithorax complexes in regulating transcriptionally active and silent chromatin states. It also explores the basis of the remarkable fidelity with which Polycomb silencing is "epigenetically" transmitted to daughter cells during cell division. Polycomb silencing mechanisms have recently been implicated in stem cell self-renewal and pluripotency. Abnormal over-expression of Polycomb proteins, which occurs in many tumors, also underlies the widespread aberrant silencing of critical tumor suppressor genes. This research will lead to a deeper understanding of the fundamental mechanisms underlying Polycomb silencing and the mechanisms that regulate it. It will provide new insights into the maintenance of cell fates, genome reprogramming for differentiation, and have broad implications for cancer and stem cell biology.

描述（由申请人提供）：本提案中描述的实验重点是了解 Polycomb 组 (PcG) 和 Trithorax 组 (trxG) 蛋白在发育过程中维持基因表达稳定可遗传状态的机制。 PcG 和 trxG 蛋白现在涉及许多生物过程，包括转录程序的全基因组控制、细胞命运的维持、干细胞自我更新、X-失活、组织再生以及分化开始时基因表达模式的重新编程。多梳沉默机制也直接涉及癌症中肿瘤抑制基因和其他基因的异常沉默。调节 Polycomb 沉默的基本机制尚不清楚。果蝇同源基因仍然是这些机制新见解的重要来源。拟议工作的目的是 1) 进一步研究 CBP 对组蛋白 H3K27 的 TRX 依赖性乙酰化的调节，这是 TRX 防止 Polycomb 沉默的关键机制。 2) 研究组蛋白去甲基化酶 UTX 在 TRX 依赖性 H3K27 乙酰化中的协作及其在不同发育阶段的作用，包括参与逆转分化开始时的 Polycomb 沉默 3) 研究 ASH1 是否也通过其已知的与 CBP 的关联介导 H3K27 乙酰化。我们还计划研究细胞分裂周期中 Polycomb 沉默可遗传传递的机制，该过程在整个发育过程中以高保真度发生。了解这些新因素在调节 Polycomb 沉默中的作用将为了解发育过程中稳定染色质状态的表观遗传机制提供新的见解。 公共健康相关性：该提案的重点是了解 Polycomb 和 Trithorax 复合体维持基因表达稳定状态的机制。它探讨了新发现的与 Polycomb 和 Trithorax 复合物相关的蛋白质和酶活性在调节转录活性和沉默染色质状态中的作用。它还探讨了 Polycomb 沉默在细胞分裂过程中“表观遗传”传递给子细胞的非凡保真度的基础。多梳沉默机制最近被认为与干细胞的自我更新和多能性有关。 Polycomb 蛋白的异常过度表达发生在许多肿瘤中，也是关键肿瘤抑制基因广泛异常沉默的基础。这项研究将有助于更深入地了解 Polycomb 沉默的基本机制及其调节机制。它将为细胞命运的维持、分化的基因组重编程提供新的见解，并对癌症和干细胞生物学产生广泛的影响。