Global Repression of Cancer Gene Expression in a Zebrafish Model of Melanoma Is Linked to Epigenetic Regulation
Global Repression of Cancer Gene Expression in a Zebrafish Model of Melanoma Is Linked to Epigenetic Regulation
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DOI：
10.1089/zeb.2009.0612
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发表时间：
2009-12-01
期刊：
影响因子：
2
通讯作者：
Mione, Marina
中科院分区：
文献类型：
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作者：
Anelli, Viviana;Santoriello, Cristina;Mione, Marina
我们已经建立了斑马鱼黑色素瘤进展的模型，通过产生在黑色素细胞谱系中特异性表达致癌人类HRAS的转基因系。在这些肿瘤中，我们从已知的和预测的癌症基因列表中对几个假定的癌症基因进行了定量表达分析。特别是，我们分析了101个假定的癌症基因中的39个，用生物信息学方法鉴定，并选择了重复频率低和蛋白质网络中高连通性的基因。通过对斑马鱼黑色素瘤组织进行实时聚合酶链反应分析得到的数据显示，斑马鱼黑色素瘤中许多癌基因表达下调，而只有细胞周期基因表达上调。为了了解这种趋势是否由于与抑制染色质状态相关的基因表达的全球抑制，我们研究了在我们的黑色素瘤模型中是否可以检测到组蛋白甲基化的变化。我们发现，与正常皮肤相比，黑色素瘤组织中H3K9me3、H4K20me2、H3K27me3、H3K4me3和H3R2me2a免疫染色水平存在显著差异。因此，我们的分析表明，在我们的模型中，就像在人类黑色素瘤中一样，组蛋白的甲基化状态发生了重要变化。尽管这些变化的结果尚不清楚，但它们可能是本研究显示的通过表观遗传调控抑制基因表达的原因。
We have established a model of melanoma progression in zebrafish through the generation of transgenic lines specifically expressing oncogenic human HRAS in the melanocytic lineage. In these tumors we have carried out quantitative expression analysis of several putative cancer genes, from known and predicted cancer gene lists. In particular, we analyzed 39 out of 101 putative cancer genes identified with a bioinformatics approach and selected for the low frequency of duplication and the high connectivity in protein networks. Data obtained by real-time polymerase chain reaction analysis from zebrafish melanoma tissue shows that the expression of many cancer genes is downregulated in zebrafish melanomas, whereas only cell cycle genes are upregulated. To understand whether this trend is due to global repression of gene expression associated to a repressive chromatin state, we investigated whether changes of histone methylation were detectable in our melanoma model. We found substantial differences in the levels of H3K9me3, H4K20me2, H3K27me3, H3K4me3, and H3R2me2a immunostaining in melanoma tissue when compared with normal skin. Thus our analysis suggests that in our model, like in human melanoma, important changes occur to the methylation status of histones. Although the outcome of these changes is still unknown, they could be responsible for the global repression of gene expression through epigenetic regulation shown in this study.