1] CNRS, UMR 144 - Cell Biology Department, Institut Curie, Paris, France [2] Institut Curie, Centre de Recherche, Paris, France.
Chromosome and Gene Expression Section, MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Scotland, UK.
Oncogene. 2015 Feb 5;34(6):741-51. doi: 10.1038/onc.2013.604. Epub 2014 Jan 27.
The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high-H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations.
染色质的大区域通过表观遗传机制沉默在癌症中经常发生。在这些基因座处，表观遗传标记（如组蛋白甲基化和乙酰化）发生改变。然而，形成这种异常基因簇的机制在很大程度上仍然未知。在这里，我们表明，在癌细胞中，染色质重塑为乙酰化程度较低的区域，这些区域覆盖有组蛋白 H3K27 三甲基化，同时伴随着高级染色质结构的变化。通过荧光原位杂交，我们证明了局部表观遗传沉默与形成紧密染色质结构域相对应。我们表明基因抑制与染色质紧缩状态密切相关，而与 H3K27me3 的水平无关——通过敲低 EZH2 去除 H3K27me3 不会诱导显著的基因表达或染色质去紧缩。此外，转录可以在完整的高 H3K27me3 水平下发生；组蛋白去乙酰化酶抑制剂的处理可以缓解染色质紧缩和基因抑制，而不改变 H3K27me3 水平。我们的发现意味着在癌细胞中 PRC2 失调不是导致大染色质区域紧缩和随后抑制的直接原因。通过挑战 EZH2 在癌症中异常基因沉默中的作用，这些发现具有治疗意义，特别是对于具有多个区域表观遗传改变的肿瘤选择表观遗传药物。
