Phenotypic non-specificity of transcription factor function in Drosophila melanogaster

果蝇转录因子功能的表型非特异性

• 批准号: RGPIN-2021-03673
• 负责人: PercivalSmith, Anthony
• 金额: $ 2.62万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745847
• 关键词: Phenotypic; non; specificity; transcription; factor

The vivid colour of flowers, the green leaves and the multicoloured butterfly wings seen in a garden are the outcome of one of the most fundamental processes in Biology; the control of gene expression. Gene expression is regulated at all points along the pathway that converts the information stored in DNA (genes) into messenger RNA and then active protein. One major mechanism of regulation is the control of the rate of initiation of transcription; the first step in the production of messenger RNA. The rate of transcription is controlled by DNA-binding transcription factors (TFs). For thirty years, I have been studying the TFs Fushi tarazu (FTZ), Proboscipedia (PB) and Sex combs reduced (SCR). These TFs are important for laying out the body plan of Drosophila: FTZ determines the number of segments that form and PB and SCR determine what the segments will look like. These three TFs contain a common DNA-binding domain, the Homeodomain (HD), and are referred to as HOX TFs. HOX TFs have been analyzed for over thirty years, but the mapping of the regions of the protein important for function as a TF has proven difficult. In recent years, my group and other groups have found that HD¬-containing proteins are composed of small peptide motifs that make small contributions to overall activity. This architecture of TF functional organization results in the genetic phenomenon of differential pleiotropy, which is the non-uniform behavior of mutant alleles in a TF locus. The central question often posed in the analysis of TF function is how a TF, like PB, specifically regulates the genes required for the formation of the mouthparts while another TF, like SCR, specifically regulates the genes required for sex comb formation. I found that the foundation of this central question, which assumes specificity of TF function, is incorrect. Recently I described a phenomenon termed phenotypic non--specificity where TFs are just not specific such that multiple TFs can induce or rescue a phenotype. This is similar to another recently described phenomenon of phenotypic convergence where the expression of different combinations of TFs is associated with the same phenotype. I have explained phenotypic non--specificity using a model of limited specificity of TF function and this grant tests some of the central expectations of this model. Drosophila phenotypic non-specificity will be investigated in more depth to refine the properties of TFs that rescue a phenotype. The prediction of cis--element bypass where the TFs that rescue the same phenotype are proposed to use different regulatory sequences will be tested. The patterns of gene expression in cases of phenotypic non-specificity will also be determined. Phenotypic non--specificity may provide important insights into the control of gene expression. Understanding the control of gene expression is important for studies on how a single celled fertilized egg develops into a multicellular organism composed of distinct cell types.

在花园里看到的鲜艳的花朵、绿叶和五颜六色的蝴蝶翅膀，都是生物学中最基本的过程之一的结果；基因表达的控制。基因表达在将存储在DNA（基因）中的信息转化为信使RNA然后是活性蛋白质的过程中受到调控。调控的一个主要机制是对转录起始速率的控制；这是信使RNA产生的第一步。转录速率由dna结合转录因子（TFs）控制。三十年来，我一直在研究TFs Fushi tarazu (FTZ), Proboscipedia （PB）和Sex combs reduced （SCR）。这些tf对于果蝇的身体结构很重要：FTZ决定了形成的片段数量，PB和SCR决定了这些片段的样子。这三种tf包含一个共同的dna结合域，Homeodomain (HD)，被称为HOX tf。HOX TF已经被分析了30多年，但是作为TF重要功能的蛋白质区域的定位被证明是困难的。近年来，我的研究小组和其他研究小组发现，含HD蛋白是由小肽基序组成的，对整体活性的贡献很小。这种TF功能组织的结构导致了差异多效性的遗传现象，这是一个TF位点上突变等位基因的不均匀行为。在分析TF功能时经常提出的中心问题是，像PB这样的TF如何专门调节口器形成所需的基因，而另一个TF，如SCR，如何专门调节性梳形成所需的基因。我发现这个中心问题的基础，假设了TF函数的特殊性，是不正确的。最近我描述了一种被称为表型非特异性的现象，即tf不具有特异性，以至于多个tf可以诱导或挽救一种表型。这类似于最近描述的另一种表型趋同现象，即tf的不同组合的表达与相同的表型相关。我已经使用TF功能的有限特异性模型解释了表型非特异性，并且该资助验证了该模型的一些核心期望。果蝇表型非特异性将被更深入地研究，以完善拯救表型的tf的特性。将测试顺式元件旁路的预测，其中建议使用不同的调控序列来挽救相同表型的tf。基因表达模式的情况下，表型非特异性也将确定。表型非特异性可能为基因表达的控制提供重要的见解。了解基因表达的控制对于研究单细胞受精卵如何发育成由不同细胞类型组成的多细胞生物是非常重要的。