Comprehensive locus-specific L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites

Sophie Lanciano (1) , Claude Philippe (1) , Arpita Sarkar (1) , David Pratella (1) , Cécilia Domrane (2) , Aurélien Doucet (1) , Dominic Van Essen (1) , Simona Saccani (1) , Laure Ferry (2) , Pierre-Antoine Defossez (2) , Gael Cristofari (1)

1 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
2 EDC - Centre épigénétique et destin cellulaire

Long interspersed element-1 (L1) retrotransposons play important roles in human disease and evolution. Their global activity is repressed by DNA methylation, but studying the regulation of individual copies has been difficult. Here, we combine short- and long-read sequencing to resolve the DNA methylation profiles of these repeated sequences in a panel of normal and cancer cells genome-wide at single-locus resolution. We unveil key principles underpinning L1 methylation heterogeneity among cell-types, families and integration sites. First, intronic L1 methylation is intimately associated with gene transcription. Conversely, L1s can influence the methylation status of the upstream region over short distances (300 bp). This phenomenon is accompanied by the binding of specific transcription factors, which drive the expression of L1 and chimeric transcripts. Finally, L1 hypomethylation alone is generally insufficient to trigger L1 expression due to redundant silencing pathways. Our results illuminate the epigenetic and transcriptional interplay between retrotransposons and their host genome.

Mots clés: LINE-1; L1; transposable elements; mobile genetic element; transposon; transposition; retrotransposon; retrotransposition; mobile element insertion; DNA methylation; methyl-cytosine; nanopore sequencing; chromatin states; transcription; L1 chimeric transcripts; LCTs; YY1; ESR1; transcription factor; nuclear receptor; genomic profiling

Domaines: Sciences du Vivant [q-bio]; Biologie moléculaire; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Bio-Informatique, Biologie Systémique [q-bio.QM]; Cancer; Génétique humaine

Sophie Lanciano, Claude Philippe, Arpita Sarkar, David Pratella, Cécilia Domrane, et al.. Comprehensive locus-specific L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites. 2024. ⟨hal-04245960⟩