Taberlay Phillippa C, Statham Aaron L, Kelly Theresa K, Clark Susan J, Jones Peter A
Epigenetics Research, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; Departments of Biochemistry and Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, USA; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia;
Epigenetics Research, Cancer Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia;
Genome Res. 2014 Sep;24(9):1421-32. doi: 10.1101/gr.163485.113. Epub 2014 Jun 10.
It is well established that cancer-associated epigenetic repression occurs concomitant with CpG island hypermethylation and loss of nucleosomes at promoters, but the role of nucleosome occupancy and epigenetic reprogramming at distal regulatory elements in cancer is still poorly understood. Here, we evaluate the scope of global epigenetic alterations at enhancers and insulator elements in prostate and breast cancer cells using simultaneous genome-wide mapping of DNA methylation and nucleosome occupancy (NOMe-seq). We find that the genomic location of nucleosome-depleted regions (NDRs) is mostly cell type specific and preferentially found at enhancers in normal cells. In cancer cells, however, we observe a global reconfiguration of NDRs at distal regulatory elements coupled with a substantial reorganization of the cancer methylome. Aberrant acquisition of nucleosomes at enhancer-associated NDRs is associated with hypermethylation and epigenetic silencing marks, and conversely, loss of nucleosomes with demethylation and epigenetic activation. Remarkably, we show that nucleosomes remain strongly organized and phased at many facultative distal regulatory elements, even in the absence of a NDR as an anchor. Finally, we find that key transcription factor (TF) binding sites also show extensive peripheral nucleosome phasing, suggesting the potential for TFs to organize NDRs genome-wide and contribute to deregulation of cancer epigenomes. Together, our findings suggest that "decommissioning" of NDRs and TFs at distal regulatory elements in cancer cells is accompanied by DNA hypermethylation susceptibility of enhancers and insulator elements, which in turn may contribute to an altered genome-wide architecture and epigenetic deregulation in malignancy.
癌症相关的表观遗传抑制与启动子处的CpG岛高甲基化和核小体丢失同时发生，这一点已得到充分证实，但核小体占据和表观遗传重编程在癌症远端调控元件中的作用仍知之甚少。在这里，我们使用DNA甲基化和核小体占据的全基因组同步映射（NOMe-seq）来评估前列腺癌细胞和乳腺癌细胞中增强子和绝缘子元件处的全局表观遗传改变范围。我们发现，核小体缺失区域（NDRs）的基因组位置大多具有细胞类型特异性，并且优先存在于正常细胞的增强子中。然而，在癌细胞中，我们观察到远端调控元件处NDRs的全局重新配置，同时癌症甲基化组也发生了大量重组。增强子相关NDRs处核小体的异常获得与高甲基化和表观遗传沉默标记相关，相反，核小体的丢失与去甲基化和表观遗传激活相关。值得注意的是，我们表明，即使没有NDR作为锚定，核小体在许多兼性远端调控元件处仍保持强烈的组织化和相位化。最后，我们发现关键转录因子（TF）结合位点也显示出广泛的周边核小体相位化，这表明TFs有可能在全基因组范围内组织NDRs，并导致癌症表观基因组的失调。总之，我们的研究结果表明，癌细胞远端调控元件处NDRs和TFs的“退役”伴随着增强子和绝缘子元件的DNA高甲基化易感性，这反过来可能导致恶性肿瘤中全基因组结构改变和表观遗传失调。
