Transposable elements (TEs) drive genome evolution and are a notable source of pathogenesis, including cancer. While CpG methylation regulates TE activity, the locus-specific methylation landscape of mobile human TEs has to date proven largely inaccessible. Here, we apply new computational tools and long-read nanopore sequencing to directly infer CpG methylation of novel and extant TE insertions in hippocampus, heart, and liver, as well as paired tumor and non-tumor liver. As opposed to an indiscriminate stochastic process, we find pronounced demethylation of young long interspersed element 1 (LINE-1) retrotransposons in cancer, often distinct to the adjacent genome and other TEs. SINE-VNTR-Alu (SVA) retrotransposons, including their internal tandem repeat-associated CpG island, are near-universally methylated. We encounter allele-specific TE methylation and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumor-specific LINE-1 insertions and their retrotransposition hallmarks, demonstrating how long-read sequencing can simultaneously survey the epigenome and detect somatic TE mobilization.

转座因子（TEs）驱动基因组进化，是包括癌症在内的发病机理的重要来源。尽管CpG甲基化可调节TE的活性，但迄今为止，已证明流动人类TEs的特定于位点的甲基化态势基本上无法获得。在这里，我们应用新的计算工具和长时读取的纳米孔测序技术，直接推论海马，心脏和肝脏以及成对的肿瘤和非肿瘤肝中新的和现存的TE插入的CpG甲基化。与不加选择的随机过程相反，我们发现癌症中年轻的长散置元素1（LINE-1）逆转座子明显脱甲基，通常与相邻的基因组和其他TE截然不同。SINE-VNTR-铝（SVA）逆转座子，包括其内部串联重复相关的CpG岛，几乎全部被甲基化。我们在正常组织中遇到等位基因特异性TE甲基化和异常表达的年轻LINE-1s的去甲基化。最后，我们恢复了肿瘤特异性LINE-1插入的完整序列及其逆转标记，证明了长读测序可同时调查表观基因组和检测体细胞TE动员的方式。