Nanopore Sequencing Enables Comprehensive Transposable Element Epigenomic Profiling

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. [Display omitted] •Transposons from long DNA reads (TLDR) detects transposable element (TE) insertions•TLDR resolves entire TE insertions, including SVA internal tandem repeat expansions•Nanopore analysis finds aberrant and allele-specific TE methylation in normal tissues•Young LINE-1s show highly dynamic locus- and element-specific methylation in cancer Ewing et al. report TLDR, a tool to fully resolve transposable element (TE) insertions with long-read sequencing. TLDR detects polymorphic and tumor-specific TE insertions in whole-genome nanopore sequencing data from normal and cancerous human tissues. Nanopore analysis reveals CpG methylation landscapes of young LINE-1, Alu, and SVA retrotransposon families.