Frigola Jordi, Song Jenny, Stirzaker Clare, Hinshelwood Rebecca A, Peinado Miguel A, Clark Susan J
Cancer Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney 2010, New South Wales, Australia.
Nat Genet. 2006 May;38(5):540-9. doi: 10.1038/ng1781. Epub 2006 Apr 23.
We report a new mechanism in carcinogenesis involving coordinate long-range epigenetic gene silencing. Epigenetic silencing in cancer has always been envisaged as a local event silencing discrete genes. However, in this study of silencing in colorectal cancer, we found common repression of the entire 4-Mb band of chromosome 2q.14.2, associated with global methylation of histone H3 Lys9. DNA hypermethylation within the repressed genomic neighborhood was localized to three separate enriched CpG island 'suburbs', with the largest hypermethylated suburb spanning 1 Mb. These data change our understanding of epigenetic gene silencing in cancer cells: namely, epigenetic silencing can span large regions of the chromosome, and both DNA-methylated and neighboring unmethylated genes can be coordinately suppressed by global changes in histone modification. We propose that loss of gene expression can occur through long-range epigenetic silencing, with similar implications as loss of heterozygosity in cancer.
我们报告了一种癌症发生的新机制，涉及协同的长程表观遗传基因沉默。癌症中的表观遗传沉默一直被认为是使离散基因沉默的局部事件。然而，在这项关于结直肠癌沉默的研究中，我们发现2号染色体q14.2区域整个4兆碱基（Mb）条带的共同抑制，这与组蛋白H3赖氨酸9的整体甲基化有关。受抑制基因组区域内的DNA高甲基化定位于三个独立的富集CpG岛“郊区”，最大的高甲基化郊区跨度为1 Mb。这些数据改变了我们对癌细胞中表观遗传基因沉默的理解：即表观遗传沉默可跨越染色体的大片区域，并且DNA甲基化基因和相邻的未甲基化基因都可通过组蛋白修饰的整体变化而被协同抑制。我们提出，基因表达的丧失可通过长程表观遗传沉默发生，这与癌症中杂合性丧失具有相似的意义。
