Boily Gino, Beaulieu Patrick, Healy Jasmine, Sinnett Daniel
Division of Hematology-Oncology, Charles-Bruneau Cancer Center, Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada.
Cancer Inform. 2008;6:183-201. doi: 10.4137/cin.s556. Epub 2008 Apr 21.
Accumulating genetic and functional evidence point to ETV6 as being the tumour suppressor gene targeted by the deletions at chromosome 12p12-13 found in various cancers, particularly childhood leukemia. ETV6 is a ubiquitously expressed transcription factor (TF) of the ETS family with very few known targeted genes. We recently compiled a list of 87 ETV6-modulated genes that can be classified into a number of subgroups based on their coordinated expression patterns. In the present report, we hypothesized that genes presenting a similar profile of modulation could also share biological features, promoter sequence similarities and/or, common transcription factor binding sites (TFBSs). Using an exploratory approach based on hierarchical clustering of expression data, Gene Ontology (GO) terms, sequence similarity and evolutionary conserved putative TFBSs, we found that many genes presenting a similar expression profile also share biological features and/or conserved predicted TFBSs but rarely show detectable promoter sequence similarities. We also calculated the proportion of ETV6-modulated genes that have any conserved TFBSs of the Jaspar database in their regulatory sequence and compared these proportions to those calculated for two other gene lists, ETV6 non-modulated and ETS-regulated. We found that the NF-kB, c-REL and p65 TFBSs, which all bind TFs of the REL class, were under-represented among the ETV6-modulated genes compared to the ETV6-non-modulated genes, while the Broad-complex 1 TFBS appeared to be over-represented. NF-Y and Chop/cEBP TFBSs were over-represented in the promoters of ETV6-modulated genes compared to ETS-regulated genes. These analyses will help direct further studies intending to understand the role of ETV6 as a transcriptional regulator and aid in constructing the ETV6-regulatory gene network.
越来越多的遗传学和功能学证据表明，ETV6是在多种癌症，尤其是儿童白血病中，位于12p12 - 13染色体上发生缺失所靶向的肿瘤抑制基因。ETV6是ETS家族中广泛表达的转录因子（TF），已知的靶向基因很少。我们最近汇编了一份87个受ETV6调控的基因列表，这些基因可根据其协同表达模式分为若干亚组。在本报告中，我们假设呈现相似调控模式的基因也可能共享生物学特征、启动子序列相似性和/或共同的转录因子结合位点（TFBSs）。通过基于表达数据的层次聚类、基因本体论（GO）术语、序列相似性和进化保守的假定TFBSs的探索性方法，我们发现许多呈现相似表达模式的基因也共享生物学特征和/或保守的预测TFBSs，但很少显示出可检测到的启动子序列相似性。我们还计算了在其调控序列中具有Jaspar数据库任何保守TFBSs的ETV6调控基因的比例，并将这些比例与另外两个基因列表（非ETV6调控基因和ETS调控基因）计算的比例进行比较。我们发现，与非ETV6调控基因相比，所有与REL类转录因子结合的NF - kB、c - REL和p65 TFBSs在ETV6调控基因中代表性不足，而Broad - complex 1 TFBS似乎代表性过高。与ETS调控基因相比，NF - Y和Chop/cEBP TFBSs在ETV6调控基因的启动子中代表性过高。这些分析将有助于指导进一步的研究，以了解ETV6作为转录调节因子的作用，并有助于构建ETV6调控基因网络。
