Madakashira Bhavani P, Sadler Kirsten C
Program in Biology, New York University Abu Dhabi,Abu Dhabi, United Arab Emirates.
Front Genet. 2017 Jun 7;8:76. doi: 10.3389/fgene.2017.00076. eCollection 2017.
The dramatic re-organization of the cancer cell nucleus creates telltale morphological features critical for pathological staging of tumors. In addition, the changes to the mutational and epigenetic landscape in cancer cells alter the structure and stability of the genome and directly contribute to malignancy. DNA methylation is one of the best studied epigenetic changes in cancer, as nearly every type of cancer studied shows a loss of DNA methylation spread across most of the genome. This global hypomethylation is accompanied by hypermethylation at distinct loci, and much of the work on DNA methylation in cancer has focused on how local changes contribute to gene expression. However, the emerging picture is that the changes to DNA methylation in cancer cells has little direct effect on gene expression but instead impacts the organization of the genome in the nucleus. Several recent studies that take a broad view of the cancer epigenome find that the most profound changes to the cancer methylome are spread across large segments of the genome, and that the focal changes are reflective of a whole reorganization of epigenome. Hallmarks of nuclear reorganization in cancer are found in the long regions of chromatin marked by histone methylation (LOCKs) and nuclear lamina interactions (LADs). In this review, we focus on a novel perspective that DNA methylation changes in cancer impact the global structure of heterochromatin, LADs and LOCKs, and how these global changes, in turn, contribute to gene expression changes and genomic stability.
癌细胞核的显著重组产生了对肿瘤病理分期至关重要的特征性形态学特征。此外，癌细胞中突变和表观遗传格局的变化改变了基因组的结构和稳定性，并直接促成了恶性肿瘤的发生。DNA甲基化是癌症中研究得最为深入的表观遗传变化之一，因为几乎每种被研究的癌症类型都显示出全基因组范围内DNA甲基化的缺失。这种全基因组低甲基化伴随着特定基因座的高甲基化，而且癌症中关于DNA甲基化的许多研究都集中在局部变化如何影响基因表达上。然而，新出现的情况是，癌细胞中DNA甲基化的变化对基因表达几乎没有直接影响，而是影响细胞核中基因组的组织。最近几项对癌症表观基因组进行全面观察的研究发现，癌症甲基化组最深刻的变化分布在基因组的大片段上，而局部变化反映了表观基因组的整体重组。癌症中核重组的特征见于以组蛋白甲基化标记的染色质长区域（LOCKs）和核纤层相互作用区域（LADs）。在这篇综述中，我们关注一个新的观点，即癌症中的DNA甲基化变化会影响异染色质、LADs和LOCKs的整体结构，以及这些整体变化如何反过来影响基因表达变化和基因组稳定性。
