Nanopore sequencing enables comprehensive transposable element epigenomic profiling

In cancers, but not healthy tissues, LINE-1 “jumping genes” insert throughout the genome, sometimes activating oncogenes and disrupting tumour suppressor genes. While CpG methylation regulates LINE-1 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 LINE-1s in paired tumour and non-tumour liver as well as healthy tissues. We find pronounced demethylation of LINE-1s in cancer, allele-specific LINE-1 methylation, and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumour-specific LINE-1 insertions.