Phenotypic non-specificity of transcription factor function in Drosophila melanogaster

花园中鲜艳的花朵、绿叶和五颜六色的蝴蝶翅膀是生物学中最基本的过程之一--基因表达控制的结果。在将储存在DNA(基因)中的信息转化为信使RNA，然后再转化为活性蛋白质的过程中，基因表达在整个过程中的各个点都受到调控。调控的一个主要机制是控制转录的启动速度，这是信使RNA生产的第一步。转录速度由DNA结合转录因子(TF)控制。三十年来，我一直在研究FFS福士Tarazu(FTZ)、ProBoscipedia(PB)和Sex Coms Reduced(SCR)。这些TF对于规划果蝇的身体平面很重要：FTZ决定了形成的节段的数量，PB和SCR决定了节段的外观。这三个转录因子包含一个共同的DNA结合域，即同源结构域(HD)，被称为Hox转录因子。HOX转录因子已经被分析了30多年，但事实证明，绘制作为转录因子功能的重要蛋白质区域是困难的。近年来，我的团队和其他团队发现，含有HD的蛋白质是由对整体活性贡献很小的小肽基序组成的。Tf功能组织的这种结构导致了差异多效性的遗传现象，这是Tf基因座上突变等位基因的不一致行为。在分析TF功能时经常提出的中心问题是，TF如何像PB一样，专门调控口器形成所需的基因；而另一种TF，如SCR，如何专门调节性梳子形成所需的基因。我发现这个中心问题的基础是假设TF函数的特殊性，这是不正确的。最近，我描述了一种被称为表型非特异性的现象，其中TF不是特异性的，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，其中不同组合的TF的表达与相同的表型相关。我已经用一个有限特异度的Tf函数模型解释了表型的非特异性，这项授权测试了这个模型的一些中心预期。将对果蝇的表型非特异性进行更深入的研究，以提炼挽救表型的转铁蛋白的特性。如果挽救相同表型的转录因子被提议使用不同的调控序列，那么顺式元件旁路的预测将得到测试。表型非特异性病例的基因表达模式也将被确定。表型的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有机体非常重要。

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.