Differential expression of selected histone modifier genes in human solid cancers
Differential expression of selected histone modifier genes in human solid cancers
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DOI：
10.1186/1471-2164-7-90
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发表时间：
2006-04-25
期刊：
影响因子：
4.4
通讯作者：
Caldas, Carlos
中科院分区：
文献类型：
--
作者：
Ozdag, Hilal;Teschendorff, Andrew E.;Caldas, Carlos
背景：组蛋白的翻译后修饰导致染色质重塑，在基因表达调控中起着关键作用。在这里，我们报道了3类染色质修饰基因的12个成员在6种不同的癌症类型中的表达特征：组蛋白乙酰转移酶(HATS)-EP300、CREBBP和PCAF；组蛋白去乙酰基酶(HDACs)-HDAC1、HDAC2、HDAC4、HDAC5、HDAC7A和SIRT1；以及组蛋白甲基转移酶(HMTs)-SUV39H1和SUV39H2。对225个样本(135个原发肿瘤、47个癌细胞和43个正常组织)的每个基因的表达进行了QRT-PCR分析，将8个看家基因归一化，并与通用参考RNA进行比较。结果：共进行了13,000次聚合酶链式反应，通过对数据进行线性回归模型进行严格分析。对HDAC1、HDAC2、SUV39H1和SUV39H2的突变分析显示，181个癌症样本(两个细胞系)中只有两个发生了显著的编码序列变化。监督分析和独立成分分析表明，这些基因中的许多表达能够区分肿瘤样本和正常样本。根据12个基因的归一化表达比率进行的聚类也表明，大多数样本是根据组织类型进行分组的。使用线性判别分类器和内部交叉验证表明，仅用12个基因中的5个，即SIRT1、CREBBP、HDAC7A、HDAC5和PCAF，大多数样本被正确分配。结论：HATS、HDACs和HMTs的表达模式表明这些基因在肿瘤转化中起重要作用，并具有取决于来源组织的特征表达模式，具有潜在的临床应用价值。
Background: Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Here we report characteristic patterns of expression of 12 members of 3 classes of chromatin modifier genes in 6 different cancer types: histone acetyltransferases ( HATs)- EP300, CREBBP, and PCAF; histone deacetylases ( HDACs)- HDAC1, HDAC2, HDAC4, HDAC5, HDAC7A, and SIRT1; and histone methyltransferases ( HMTs)- SUV39H1 and SUV39H2. Expression of each gene in 225 samples ( 135 primary tumours, 47 cancer cell lines, and 43 normal tissues) was analysed by QRT-PCR, normalized with 8 housekeeping genes, and given as a ratio by comparison with a universal reference RNA.Results: This involved a total of 13,000 PCR assays allowing for rigorous analysis by fitting a linear regression model to the data. Mutation analysis of HDAC1, HDAC2, SUV39H1, and SUV39H2 revealed only two out of 181 cancer samples ( both cell lines) with significant coding-sequence alterations. Supervised analysis and Independent Component Analysis showed that expression of many of these genes was able to discriminate tumour samples from their normal counterparts. Clustering based on the normalized expression ratios of the 12 genes also showed that most samples were grouped according to tissue type. Using a linear discriminant classifier and internal cross-validation revealed that with as few as 5 of the 12 genes, SIRT1, CREBBP, HDAC7A, HDAC5 and PCAF, most samples were correctly assigned.Conclusion: The expression patterns of HATs, HDACs, and HMTs suggest these genes are important in neoplastic transformation and have characteristic patterns of expression depending on tissue of origin, with implications for potential clinical application.