Molecular Basis of Drosophila Homeotic Gene Regulation

果蝇同源基因调控的分子基础

• 批准号: 7034497
• 负责人: Peter J. Harte
• 金额: $ 40.17万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7034497
• 关键词: DNA binding protein; DNA replication; Drosophilidae; arthropod genetics; binding sites; chromatin; chromatin immunoprecipitation; cytogenetics; developmental genetics; gene expression; gene interaction; gene mutation; genetic enhancer element; genetic mapping; genetic promoter element; genetic regulation; genetic transcription; homeobox genes; molecular cloning; polymerase chain reaction; protein structure function; regulatory gene; transcription factor

DESCRIPTION (provided by applicant): Molecular Basis of Drosophila Homeotic Gene Regulation The long-term goal of this research is to understand the molecular mechanisms underlying stable long-term maintenance of the patterns of homeotic gene expression during Drosophila development. The Trithorax Group (trxG) and Polycomb Group (PcG) proteins are directly involved in this process and are respectively required to maintain active and inactive transcriptional states established in the early embryo. Evidence suggests that they function by promoting stable changes in local chromatin structure. This proposal is to investigate the role of a Polycomb Group complex containing the ESC, E(Z), SU(Z)12 and p55 proteins as well as complexes containing TRX. These proteins have been highly conserved in diverse phyla, suggesting that their fundamental functions are ancient and highly conserved. Understanding how they function will provide new insights into the mechanisms of transcriptional regulation as well as the mechanisms underlying development of normal body plans in animals. Genetic, molecular and biochemical approaches will be used investigate their functions. We have identified ESC/E(Z) complexes associated with the histone deacetylase RPD3, implicating histone deacetylation in the mechanism of ESC/E(Z) action. TRX and PcG proteins act through the same DNA response elements, suggesting that their antagonistic activities must be managed locally at PREs. We are investigating a new protein that may provide some insights into how this regulation occurs. We will continue to investigate a number of newly identified proteins associated with ESC/E(Z) complexes and TRX complexes that are providing new insights into how the enzymatic activities of ESC/E(Z) complexes function in the epigenetic inheritance of repressed and active chromatin states. We are determining how they function in concert with TRX and ESC/E(Z) complexes to promote maintenance of transcriptional states. Mutations in the human TRX homolog MLL are associated with acute leukemias, while several human PeG proteins are implicated in immune system dysfunction and tumorigenesis. Understanding the fundamental mechanism of action of TRX and ESC/E(Z) complexes in the context of development should also provide insights into the role of their human homologs in disease.

描述（由申请人提供）： 果蝇同源基因调控的分子基础 这项研究的长期目标是了解果蝇发育过程中同源基因表达模式长期稳定维持的分子机制。 Trithorax Group (trxG) 和 Polycomb Group (PcG) 蛋白直接参与这一过程，并分别需要维持早期胚胎中建立的活性和非活性转录状态。有证据表明它们通过促进局部染色质结构的稳定变化来发挥作用。 该提案旨在研究包含 ESC、E(Z)、SU(Z)12 和 p55 蛋白的 Polycomb Group 复合物以及包含 TRX 的复合物的作用。这些蛋白质在不同的门中高度保守，表明它们的基本功能是古老且高度保守的。了解它们的功能将为转录调控机制以及动物正常身体计划发育的机制提供新的见解。将使用遗传、分子和生物化学方法研究它们的功能。我们已经鉴定了与组蛋白脱乙酰酶 RPD3 相关的 ESC/E(Z) 复合物，表明组蛋白脱乙酰作用在 ESC/E(Z) 作用机制中。 TRX 和 PcG 蛋白通过相同的 DNA 反应元件发挥作用，这表明它们的拮抗活性必须在 PRE 局部进行管理。我们正在研究一种新的蛋白质，它可能会为这种调节如何发生提供一些见解。我们将继续研究一些新发现的与 ESC/E(Z) 复合物和 TRX 复合物相关的蛋白质，这些蛋白质为 ESC/E(Z) 复合物的酶活性如何在抑制和活性的表观遗传中发挥作用提供新的见解。染色质状态。我们正在确定它们如何与 TRX 和 ESC/E(Z) 复合物协同发挥作用，以促进转录状态的维持。人类 TRX 同源物 MLL 的突变与急性白血病有关，而几种人类 PeG 蛋白则与免疫系统功能障碍和肿瘤发生有关。了解 TRX 和 ESC/E(Z) 复合物在发育过程中的基本作用机制也应该有助于深入了解它们的人类同源物在疾病中的作用。