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Combinatorial control of Met4-activated transcription

Met4 激活转录的组合控制

基本信息

批准号：
8036936
负责人：
TRACI A LEE
金额：
$ 28.92万
依托单位：
UNIVERSITY OF WISCONSIN PARKSIDE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-08 至 2016-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Modulation of gene expression is achieved in part by a conserved regulatory mechanism called combinatorial control, in which permutations among a fixed set of transcription factors at a promoter allow different transcriptional responses. One aspect of combinatorial control is how families of transcription factors that bind the same promoter motif behave differently to allow distinct expression outcomes. We study this issue in a well characterized yeast system that modulates expression of sulfur metabolism genes in response to varying environmental cues. Transcription of these genes depends on one activator called Met4. Since Met4 lacks intrinsic DNA binding ability, Met4 relies on interactions with DNA-binding "cofactors" (transcription factors that lack intrinsic activation ability) to target Met4 to specific promoters. There are two classes of DNA-binding cofactors for Met4 with each class binding a distinct DNA motif. One class consists of the basic helix-loop-helix protein Cbf1; the other class consists of two similar and semi-redundant zinc finger proteins: Met31 and Met32. While we have uncovered that Cbf1 is required for a subset of Met4 target genes to be expressed, all Met4 target gene expression is eliminated upon removal of both Met31 and Met32 [1]. The aim of this proposal is to determine the individual roles of Met31 and Met32 in mediating Met4-activated transcription. Using a genome-wide approach, we will identify targets in terms of promoter binding and transcriptional response and calculate DNA consensus motifs that are specific for Met31 and for Met32. We will also examine how loss of either Met31 or Met32 alters the combinatorial components within the Met4 transcriptional system. When comparing the above data with target promoter composition, we hope to provide more detailed insights into how transcription factor families allow a broad range of transcriptional responses for their targets. The general mechanisms uncovered from this study are likely to be conserved in higher eukaryotes, which contain much larger, more complex, transcription factor families that are intractable to these kinds of analyses. PUBLIC HEALTH RELEVANCE: Transcription factor families, whose members bind the same promoter motif, are found throughout eukaryotic gene regulation systems. These families allow a broad range of transcriptional responses for their targets. By manipulating a well-characterized yeast system, we will examine how a simple two-member transcription factor family orchestrates gene expression of its multiple targets in response to different signaling cues.

描述（由申请人提供）：基因表达的调节部分是通过称为组合控制的保守调节机制实现的，其中启动子上一组固定转录因子之间的排列允许不同的转录反应。组合控制的一个方面是结合相同启动子基序的转录因子家族如何表现不同以允许不同的表达结果。我们研究了这个问题在一个很好表征酵母系统，调节硫代谢基因的表达，以响应不同的环境线索。这些基因的转录依赖于一种叫做Met4的激活因子。由于Met4缺乏内在的DNA结合能力，因此Met4依靠与DNA结合“辅因子”（缺乏内在激活能力的转录因子）的相互作用将Met4靶向到特定的启动子上。Met4有两类DNA结合辅因子，每一类结合一个不同的DNA基序。一类是基本的螺旋-环-螺旋蛋白Cbf1；另一类由两个相似且半冗余的锌指蛋白组成：Met31和Met32。虽然我们发现Cbf1是Met4靶基因子集表达所必需的，但在去除Met31和Met32[1]后，所有Met4靶基因的表达都被消除。该提案的目的是确定Met31和Met32在介导met4激活转录中的单独作用。使用全基因组方法，我们将在启动子结合和转录反应方面确定目标，并计算Met31和Met32特异性的DNA共识基序。我们还将研究Met31或Met32的缺失如何改变Met4转录系统中的组合成分。当将上述数据与目标启动子组成进行比较时，我们希望提供更详细的见解，了解转录因子家族如何允许对其目标进行广泛的转录反应。从这项研究中发现的一般机制可能在高等真核生物中保守，其中包含更大，更复杂的转录因子家族，这对这些类型的分析来说是棘手的。