Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer
Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer
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DOI：
10.1101/gr.107318.110
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发表时间：
2010-10-01
期刊：
影响因子：
7
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
--
作者：
Estecio, Marcos R. H.;Gallegos, Juan;Issa, Jean-Pierre J.
表观遗传沉默在癌症发展中起着重要作用。一个有吸引力的假设是，局部DNA特征可能参与基因超甲基化的差异易感性。我们发现，与甲基化抗性基因相比，甲基化倾向基因在其转录起始位点附近具有较低频率的SINE和LINE反转录转座子。在几个大型测试集中，这种分布高度预测启动子甲基化。全基因组分析表明，22%的人类基因被预测在癌症中具有甲基化倾向;这些基因往往在癌症中下调，并在发育过程中发挥作用。此外，反转录转座子分布标志着更大比例的甲基化倾向的基因相比，Polycomb组蛋白（PcG）标记在胚胎干细胞;事实上，PcG标记和我们的预测模型的基础上反转录转座子频率似乎是相关的，但也是互补的。总之，我们的数据表明，反转录转座子元件，这是广泛存在于我们的基因组中，与基因启动子DNA甲基化在癌症中，实际上可能发挥作用，影响正常和异常的生理状态下的表观遗传调控。
Epigenetic silencing plays an important role in cancer development. An attractive hypothesis is that local DNA features may participate in differential predisposition to gene hypermethylation. We found that, compared with methylation-resistant genes, methylation-prone genes have a lower frequency of SINE and LINE retrotransposons near their transcription start site. In several large testing sets, this distribution was highly predictive of promoter methylation. Genome-wide analysis showed that 22% of human genes were predicted to be methylation-prone in cancer; these tended to be genes that are down-regulated in cancer and that function in developmental processes. Moreover, retrotransposon distribution marks a larger fraction of methylation-prone genes compared to Polycomb group protein (PcG) marking in embryonic stem cells; indeed, PcG marking and our predictive model based on retrotransposon frequency appear to be correlated but also complementary. In summary, our data indicate that retrotransposon elements, which are widespread in our genome, are strongly associated with gene promoter DNA methylation in cancer and may in fact play a role in influencing epigenetic regulation in normal and abnormal physiological states.