Developmental Functions of SNR1 and the BRM Chromatin Remodeling Complex in Drosophila

果蝇中 SNR1 和 BRM 染色质重塑复合体的发育功能

• 批准号: 0516386
• 负责人: Andrew Dingwall
• 金额: --
• 依托单位: Loyola University Stritch School of Medicine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0516386&HistoricalAwards=false
• 关键词: Developmental; Functions; SNR1; BRM; Chromatin

In most living cells, chromosomes are formed from highly condensed DNA and basic proteins that function to compact the chromosomes into a structure called chromatin. This research is focused on understanding the multitude of critically important roles chromatin structure plays in normal development. In particular, the work focuses on a highly conserved group of proteins that form a complex whose main function is to regulate gene expression through direct effects on chromatin structure. This complex uses energy to alter the contacts between chromosomal DNA and histones (basic proteins that wrap DNA in the cell) to allow for specific changes in gene expression. This energy driven process is called 'chromatin remodeling'. When components of this complex are missing or mutated, cells lose the ability to properly control their fates and growth, leading to a variety of defects in proper body patterning and unregulated cellular proliferation. This project utilizes molecular genetics and biochemical assays to explore important connections between hormone signaling and chromatin remodeling during development. Hormone signaling directs the development of tissues to adopt certain fates. Using both classical and 'reverse' (making specific mutations in the genes under study) genetics and cell-culture based studies, the mechanisms are being defined by which hormone receptors select the genes they will regulate and how they cooperate with chromatin remodeling complexes to either turn genes on or off in response to the presence of hormone signals. Genetic interactions are being examined between genes important for hormone signaling and the genes that help convey those signals to the proper cellular targets. The genes important in this process are also being selectively silenced in cultured cells where it is possible to directly address how the chromatin remodeling complexes help to determine whether certain genes will be activated or repressed. The project utilizes molecular, genetic and biochemical analyses of the Drosophila melanogaster (fruitfly) Brahma (Brm) chromatin remodeling complex. Research efforts are primarily focused on one of the most highly conserved and critically important components, known as SNR1. This subunit is crucial in both flies and humans for coordinating or targeting specific protein interactions between the complex and a variety of transcription factors and cell cycle regulatory proteins. The broader scientific impacts of these studies are: (1) teaching and training of graduate and undergraduate students in fundamental concepts of systems biology, including molecular genetics, biochemistry, and bioinformatics/structural biology; and (2) a better understanding of the functional relationships among subunits of a large and extremely important chromatin remodeling complex. This project also provides new insights into the biological significance of chromatin remodeling in normal developmental processes, including hormone-dependent gene regulation and control of cell growth.

在大多数活细胞中，染色体是由高度浓缩的DNA和基本蛋白质组成的，这些蛋白质的作用是将染色体紧密结合成一种叫做染色质的结构。这项研究的重点是了解染色质结构在正常发育中发挥的众多至关重要的作用。特别是，这项工作集中在一组高度保守的蛋白质上，这些蛋白质形成了一个复合体，其主要功能是通过直接影响染色质结构来调节基因表达。这种复合物利用能量改变染色体DNA和组蛋白（细胞中包裹DNA的基本蛋白质）之间的接触，从而允许基因表达的特定变化。这种能量驱动的过程被称为“染色质重塑”。当这种复合物的组成部分缺失或发生突变时，细胞就会失去适当控制其命运和生长的能力，从而导致机体正常模式的各种缺陷和不受调节的细胞增殖。本项目利用分子遗传学和生化分析来探索发育过程中激素信号和染色质重塑之间的重要联系。激素信号引导组织发育，使其适应特定的命运。利用经典和“反向”（在研究基因中产生特定突变）遗传学和基于细胞培养的研究，这些机制正在被定义为激素受体选择它们将调节的基因，以及它们如何与染色质重塑复合体合作，根据激素信号的存在打开或关闭基因。对激素信号重要的基因和帮助将这些信号传递到适当的细胞目标的基因之间的遗传相互作用正在被研究。在这一过程中重要的基因也被选择性地在培养细胞中沉默，这有可能直接解决染色质重塑复合体如何帮助确定某些基因是被激活还是被抑制。该项目利用果蝇Brahma （Brm）染色质重塑复合体的分子、遗传和生化分析。研究工作主要集中在一个高度保守和至关重要的组成部分，被称为SNR1。该亚基在果蝇和人类中都是至关重要的，用于协调或靶向复合物与各种转录因子和细胞周期调节蛋白之间的特定蛋白质相互作用。这些研究的更广泛的科学影响是：(1)教授和培训研究生和本科生系统生物学的基本概念，包括分子遗传学、生物化学和生物信息学/结构生物学；(2)更好地理解一个巨大而极其重要的染色质重塑复合体的亚基之间的功能关系。该项目还为染色质重塑在正常发育过程中的生物学意义提供了新的见解，包括激素依赖性基因调控和细胞生长的控制。