Kwong Camilla, Adryan Boris, Bell Ian, Meadows Lisa, Russell Steven, Manak J Robert, White Robert
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
PLoS Genet. 2008 Sep 5;4(9):e1000178. doi: 10.1371/journal.pgen.1000178.
Polycomb-group (PcG) and Trithorax-group proteins together form a maintenance machinery that is responsible for stable heritable states of gene activity. While the best-studied target genes are the Hox genes of the Antennapedia and Bithorax complexes, a large number of key developmental genes are also Polycomb (Pc) targets, indicating a widespread role for this maintenance machinery in cell fate determination. We have studied the linkage between the binding of PcG proteins and the developmental regulation of gene expression using whole-genome mapping to identify sites bound by the PcG proteins, Pc and Pleiohomeotic (Pho), in the Drosophila embryo and in a more restricted tissue, the imaginal discs of the third thoracic segment. Our data provide support for the idea that Pho is a general component of the maintenance machinery, since the majority of Pc targets are also associated with Pho binding. We find, in general, considerable developmental stability of Pc and Pho binding at target genes and observe that Pc/Pho binding can be associated with both expressed and inactive genes. In particular, at the Hox complexes, both active and inactive genes have significant Pc and Pho binding. However, in comparison to inactive genes, the active Hox genes show reduced and altered binding profiles. During development, Pc target genes are not simply constantly associated with Pc/Pho binding, and we identify sets of genes with clear differential binding between embryo and imaginal disc. Using existing datasets, we show that for specific fate-determining genes of the haemocyte lineage, the active state is characterised by lack of Pc binding. Overall, our analysis suggests a dynamic relationship between Pc/Pho binding and gene transcription. Pc/Pho binding does not preclude transcription, but levels of Pc/Pho binding change during development, and loss of Pc/Pho binding can be associated with both stable gene activity and inactivity.
多梳家族（PcG）蛋白和三胸节家族蛋白共同构成了一种维持机制，负责基因活性的稳定遗传状态。虽然研究得最透彻的靶基因是触角足复合体和双胸复合体中的Hox基因，但大量关键的发育基因也是多梳（Pc）的靶标，这表明这种维持机制在细胞命运决定中具有广泛作用。我们利用全基因组图谱研究了PcG蛋白结合与基因表达的发育调控之间的联系，以确定果蝇胚胎以及一个更局限的组织——第三胸节的成虫盘——中被PcG蛋白Pc和同源异形框蛋白（Pho）结合的位点。我们的数据支持了Pho是维持机制的一个普遍组成部分这一观点，因为大多数Pc靶标也与Pho结合相关。我们发现，总体而言，Pc和Pho在靶基因上的结合具有相当大的发育稳定性，并且观察到Pc/Pho结合既可以与表达的基因相关，也可以与不活跃的基因相关。特别是在Hox复合体中，活跃和不活跃的基因都有显著的Pc和Pho结合。然而，与不活跃基因相比，活跃的Hox基因显示出结合模式减少和改变。在发育过程中，Pc靶基因并非简单地持续与Pc/Pho结合，我们鉴定出了在胚胎和成虫盘之间具有明显差异结合的基因集。利用现有的数据集，我们表明，对于血细胞谱系的特定命运决定基因，活跃状态的特征是缺乏Pc结合。总体而言，我们的分析表明Pc/Pho结合与基因转录之间存在动态关系。Pc/Pho结合并不排除转录，但Pc/Pho结合水平在发育过程中会发生变化，并且Pc/Pho结合的丧失既可以与稳定的基因活性相关，也可以与基因失活相关。
