MOLECULAR BASIS OF DROSOPHILA HOMEOTIC GENE REGULATION

果蝇同源基因调控的分子基础

• 批准号: 6012434
• 负责人: Peter J. Harte
• 金额: $ 33.72万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6012434
• 关键词: DNA binding protein; Drosophilidae; chromatin; cytogenetics; developmental genetics; gel mobility shift assay; gene expression; gene interaction; gene mutation; genetic enhancer element; genetic mapping; genetic promoter element; genetic regulation; genetic transcription; homeobox genes; immunofluorescence technique; in situ hybridization; molecular cloning; polymerase chain reaction; protein structure function; regulatory gene; transcription factor

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 for the maintenance of active and inactive transcriptional states established in the early embryos. Evidence increasingly suggests that they function by promoting stable changes in local chromatin structure. This proposal is to investigate the role of the Trithorax protein (TRX) and Polycomb Group protein Extra sex combs (ESC). TRX and ESC 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. We have shown that the natural response elements for both TRX and PcG proteins are intimately associated on the same DNA elements, including promoters, and that at least one PcG protein binds directly to TRX, suggesting that TRX and PcG proteins may directly modulate each other's activity. We will further characterize TRX and ESC response elements in the Ubx gene. We will investigate how TRX and ESC exert their positive and negative regulatory effects by tethering them near promoters and enhancers to see if they possess intrinsic transcriptional activation or repression activity. We will continue to investigate the function of a number of other proteins that are physically associated with TRX and ESC and initiate genetic investigations of a number of newly identified proteins associated with both. We will determine how they function in concert with TRX and ESC to promote maintenance of transcriptional states. Mutations in the human TRX homolog MLL are associated with acute leukemias, while several human PcG proteins are implicated in immune system dysfunction and tumorigenesis. Understanding the fundamental mechanism of TRX and ESC action should also provide insights into the role of their human homologs in disease.

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的长期稳定的长期维持的分子机制。 Trithorax组（TRXG）和PolyComb组（PCG）蛋白直接参与此过程，并且分别是维持早期胚胎中建立的主动和非活动转录状态所必需的。证据越来越多地表明，它们通过促进局部染色质结构的稳定变化而发挥作用。该建议是研究Trithorax蛋白（TRX）和Polycomb蛋白额外的性梳子（ESC）的作用。 TRX和ESC在不同的门中高度保守，这表明它们的基本功能是古老和高度保守的。了解它们的功能将为转录调节机制以及动物正常身体计划的发展的机制提供新的见解。我们已经表明，TRX和PCG蛋白的自然反应元件在包括启动子在内的相同DNA元素上密切相关，并且至少一种PCG蛋白直接与TRX结合，这表明TRX和PCG蛋白可能直接调节彼此的活性。我们将进一步表征UBX基因中的TRX和ESC响应元素。我们将通过将它们绑在启动子和增强子附近，以查看它们是否具有固有的转录激活或抑制活性来研究TRX和ESC如何发挥其正和负调节作用。我们将继续研究与TRX物理相关的许多其他蛋白质的功能，并启动了许多与两者相关的新鉴定的蛋白质的遗传研究。我们将确定它们如何与TRX和ESC协同工作以促进转录状态的维持。人TRX同源物中的突变与急性白血病有关，而几种人PCG蛋白与免疫系统功能障碍和肿瘤发生有关。了解TRX和ESC动作的基本机制也应提供有关其人类同源物在疾病中的作用的见解。