Hypomethylation of a LINE-1 Promoter Activates an Alternate Transcript of the MET Oncogene in Bladders with Cancer

It was recently shown that a large portion of the human transcriptome can originate from within repetitive elements, leading to ectopic expression of protein-coding genes. However the mechanism of transcriptional activation of repetitive elements has not been definitively elucidated. For the first time, we directly demonstrate that hypomethylation of retrotransposons can cause altered gene expression in humans. We also reveal that active LINE-1s switch from a tetranucleosome to dinucleosome structure, acquiring H2A.Z- and nucleosome-free regions upstream of TSSs, previously shown only at active single-copy genes. Hypomethylation of a specific LINE-1 promoter was also found to induce an alternate transcript of the MET oncogene in bladder tumors and across the entire urothelium of tumor-bearing bladders. These data show that, in addition to contributing to chromosomal instability, hypomethylation of LINE-1s can alter the functional transcriptome and plays a role not only in human disease but also in disease predisposition.

近期研究证实，人类转录组（transcriptome）的大部分序列可源自重复元件（repetitive elements），进而引发编码蛋白基因的异位表达（ectopic expression）。然而，重复元件的转录激活机制尚未得到明确阐释。本研究首次直接证明，反转录转座子（retrotransposons）的低甲基化（hypomethylation）可导致人类基因表达异常。研究同时揭示，活化的LINE-1会从四核小体（tetranucleosome）结构转换为双核小体（dinucleosome）结构，并在转录起始位点（TSS, Transcription Start Site）上游获得H2A.Z组蛋白修饰区域与无核小体区域——这类结构此前仅在活化的单拷贝基因中被观测到。此外，研究发现特定LINE-1启动子的低甲基化，可在膀胱肿瘤以及荷瘤膀胱的整个尿路上皮中，诱导MET癌基因（MET oncogene）产生可变转录本。上述数据表明，LINE-1的低甲基化除了会引发染色体不稳定性（chromosomal instability）外，还可改变功能性转录组，且其不仅与人类疾病的发生相关，还在疾病易感性的形成中发挥重要作用。