Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms
Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms
复制标题
DOI：
10.1101/gr.249219.119
复制
发表时间：
2019-10-01
期刊：
影响因子：
7
通讯作者：
Arnaud, Philippe
中科院分区：
文献类型：
--
作者：
Court, Franck;Le Boiteux, Elisa;Arnaud, Philippe
在癌细胞中，异常的DNA甲基化通常与转录改变相关，包括肿瘤抑制基因的沉默。然而，多种表观遗传机制，包括多梳抑制标记，有助于癌症中的基因失调。为了剖析DNA甲基化依赖和非依赖机制对癌症中CpG岛/启动子相关基因转录改变的相对贡献，我们研究了70个成人胶质瘤样本，这是一种广泛的脑肿瘤类型，根据其异柠檬酸脱氢酶（IDHI）突变状态进行分类。我们发现肿瘤样本中的大多数转录改变是DNA甲基化无关的。相反，改变组蛋白H3三甲基化在赖氨酸27（H3 K27 me 3）是主要的分子缺陷在失调的基因。我们的研究结果还表明，在干细胞中的CpG岛启动子的二价染色质签名的存在下，不仅易于高甲基化，广泛记录，但更普遍的是所有类型的转化细胞中的转录改变。此外，健康脑细胞中的基因表达强度影响胶质瘤中DNA甲基化和H3 K27 me 3相关沉默之间的选择。高表达的基因更可能被H3 K27 me 3抑制，而不是DNA甲基化。我们的研究结果支持一个模型，其中改变H3 K27 me 3动力学，更具体地说，多梳蛋白复合物和脑特异性转录机制之间的相互作用的缺陷，是神经胶质瘤细胞中转录改变的主要原因。我们的研究首次全面描述了胶质瘤的表观遗传变化及其对转录变化的相对贡献。这可能有助于设计针对癌症相关表观遗传缺陷的药物。
In cancer cells, aberrant DNA methylation is commonly associated with transcriptional alterations, including silencing of tumor suppressor genes. However, multiple epigenetic mechanisms, including polycomb repressive marks, contribute to gene deregulation in cancer. To dissect the relative contribution of DNA methylation-dependent and -independent mechanisms to transcriptional alterations at CpG island/promoter-associated genes in cancer, we studied 70 samples of adult glioma, a widespread type of brain tumor, classified according to their isocitrate dehydrogenase (IDHI) mutation status. We found that most transcriptional alterations in tumor samples were DNA methylation-independent. Instead, altered histone H3 trimethylation at lysine 27 (H3K27me3) was the predominant molecular defect at deregulated genes. Our results also suggest that the presence of a bivalent chromatin signature at CpG island promoters in stem cells predisposes not only to hypermethylation, as widely documented, but more generally to all types of transcriptional alterations in transformed cells. In addition, the gene expression strength in healthy brain cells influences the choice between DNA methylation- and H3K27me3-associated silencing in glioma. Highly expressed genes were more likely to be repressed by H3K27me3 than by DNA methylation. Our findings support a model in which altered H3K27me3 dynamics, more specifically defects in the interplay between polycomb protein complexes and the brain-specific transcriptional machinery, is the main cause of transcriptional alteration in glioma cells. Our study provides the first comprehensive description of epigenetic changes in glioma and their relative contribution to transcriptional changes. It may be useful for the design of drugs targeting cancer-related epigenetic defects.