Phenotypic non-specificity of transcription factor function in Drosophila melanogaster

花园里鲜艳的花朵、绿色的叶子和五彩缤纷的蝴蝶翅膀是生物学中最基本的过程之一的结果;基因表达的控制。基因表达在沿着将储存在DNA（基因）中的信息转化为信使RNA，然后转化为活性蛋白质的途径上的所有点都受到调节。一个主要的调节机制是控制转录起始的速率;这是信使RNA产生的第一步。转录速率受DNA结合转录因子（TF）控制。三十年来，我一直在研究TF Fushi tarazu（FTZ），Proboscipedia（PB）和Sex combs reduced（SCR）。这些TF对果蝇的身体规划很重要：FTZ决定了形成的片段数量，PB和SCR决定了片段的外观。这三种TF含有共同的DNA结合结构域，同源结构域（HD），并且被称为HOX TF。HOX TF已经分析了三十多年，但是对于作为TF的功能重要的蛋白质区域的映射已经被证明是困难的。近年来，我的研究小组和其他研究小组发现，含HD的蛋白质是由小肽基序组成的，这些小肽基序对整体活性的贡献很小。TF功能组织的这种结构导致差异多效性的遗传现象，差异多效性是TF基因座中突变等位基因的不一致行为。在TF功能的分析中经常提出的中心问题是TF，如PB，如何特异性地调节形成口器所需的基因，而另一个TF，如SCR，特异性地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TF功能的特异性，是不正确的。最近，我描述了一种称为表型非特异性的现象，其中TF只是没有特异性，使得多个TF可以诱导或挽救表型。这与最近描述的另一种表型趋同现象相似，其中TF的不同组合的表达与相同表型相关。我已经解释了表型非特异性使用模型的TF功能的有限特异性和这个赠款测试这个模型的一些中心的期望。将更深入地研究果蝇表型的非特异性，以完善拯救表型的TF的特性。将测试顺式元件旁路的预测，其中拯救相同表型的TF被提议使用不同的调控序列。还将确定表型非特异性情况下的基因表达模式。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.