Resolving the heterogeneity of L1 DNA methylation reveals the epigenetic and transcriptional interplay between L1s and their integration sites

Primate-specific long interspersed elements-1 (LINE-1 or L1) play important roles in human disease and evolution, but are difficult to study given their repetitive nature. Here, we combine short- and long-read sequencing to resolve the DNA methylation profiles of L1 elements genome-wide and at single-locus resolution. With this approach, we uncover cell-type-, family- and locus-specific patterns. We show that the methylation of intragenic L1 elements is associated with gene body methylation of transcriptionally active genes and conversely, that L1s frequently propagate their methylation state to the surrounding genomic region. We identify sets of transcription factors bound to unmethylated L1s and their flank, some of which control the expression of chimeric gene-retrotransposon transcripts. Finally, we demonstrate that hypomethylation alone is insufficient to unleash L1 expression. Together, our results highlight the interplay between L1 retrotransposons and their integration sites, and reveal unanticipated layers of cell-type-specific epigenetic regulation. ### Competing Interest Statement GC is an unpaid associate editor of the journal Mobile DNA (Springer-Nature).