Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer
Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer
复制标题
5-羟甲基胞嘧啶的缺失与肾癌基因体高甲基化有关
DOI：
10.1038/cr.2015.150
复制
发表时间：
2016-01-01
期刊：
影响因子：
44.1
通讯作者：
Ci, Weimin
中科院分区：
文献类型：
--
作者：
Chen, Ke;Zhang, Jing;Ci, Weimin
5-甲基胞嘧啶（5 mC）及其氧化形式5-羟甲基胞嘧啶（5 hmC）均被认为与肿瘤发生有关。由于广泛使用的5 mC作图方法，亚硫酸氢盐测序（BS-seq）的读数是5 mC和5 hmC水平的总和，因此5 mC/5 hmC模式和这两种修饰的关系仍然知之甚少。通过以单核苷酸分辨率同时分析真实的5 mC（经Tet-assisted BS-seq校正的BS-seq，TAB-seq）和5 hmC（TAB-seq）水平，我们在此证明与匹配的正常组织相比，肾肿瘤中没有5 mC的整体丢失。相反，5 hmC在几乎所有肾肿瘤组织中整体丢失。肿瘤组织中的5 hmC水平是肾癌的独立预后标志物，较低的5 hmC水平与较短的总生存期相关。此外，我们证明了与匹配的正常组织相比，5 hmC的丢失与肿瘤中的超甲基化有关，特别是在基因体区域。引人注目的是，基因体超甲基化与肿瘤相关基因的沉默显著相关。IDH 1的下调被确定为肾癌中5 hmC丢失的潜在机制。在异种移植模型中，恢复5 hmC水平减弱了肿瘤细胞的侵袭能力并抑制了肿瘤生长。总的来说，我们的研究结果表明，5 hmC的损失是一个预后标志物和致癌事件在肾癌通过重塑DNA甲基化模式。
Both 5-methylcytosine (5mC) and its oxidized form 5-hydroxymethylcytosine (5hmC) have been proposed to be involved in tumorigenesis. Because the readout of the broadly used 5mC mapping method, bisulfite sequencing (BS-seq), is the sum of 5mC and 5hmC levels, the 5mC/5hmC patterns and relationship of these two modifications remain poorly understood. By profiling real 5mC (BS-seq corrected by Tet-assisted BS-seq, TAB-seq) and 5hmC (TAB-seq) levels simultaneously at single-nucleotide resolution, we here demonstrate that there is no global loss of 5mC in kidney tumors compared with matched normal tissues. Conversely, 5hmC was globally lost in virtually all kidney tumor tissues. The 5hmC level in tumor tissues is an independent prognostic marker for kidney cancer, with lower levels of 5hmC associated with shorter overall survival. Furthermore, we demonstrated that loss of 5hmC is linked to hypermethylation in tumors compared with matched normal tissues, particularly in gene body regions. Strikingly, gene body hypermethylation was significantly associated with silencing of the tumor-related genes. Downregulation of IDH1 was identified as a mechanism underlying 5hmC loss in kidney cancer. Restoring 5hmC levels attenuated the invasion capacity of tumor cells and suppressed tumor growth in a xenograft model. Collectively, our results demonstrate that loss of 5hmC is both a prognostic marker and an oncogenic event in kidney cancer by remodeling the DNA methylation pattern.