Patricia Gerdes1, Dorothy Chan1, Mischa Lundberg1,2,3, Francisco J. Sanchez-Luque1,4,5, Gabriela O. Bodea1,6, Adam D. Ewing1, Geoffrey J. Faulkner1,6 and Sandra R. Richardson1 1Mater Research Institute - University of Queensland, TRI Building, Woolloongabba, Queensland 4102, Australia; 2The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia; 3Translational Bioinformatics, Commonwealth Scientific and Industrial Research Organisation, Sydney, New South Wales 2113, Australia; 4GENYO. Centre for Genomics and Oncological Research (Pfizer-University of Granada-Andalusian Regional Government), PTS Granada, 18016, Spain; 5MRC Human Genetics Unit, Institute of Genetics and Cancer (IGC), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; 6Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia Corresponding authors: faulknergjgmail.com, sandra.richardsonmater.uq.edu.au Abstract

Mice harbor ∼2800 intact copies of the retrotransposon Long Interspersed Element 1 (L1). The in vivo retrotransposition capacity of an L1 copy is defined by both its sequence integrity and epigenetic status, including DNA methylation of the monomeric units constituting young mouse L1 promoters. Locus-specific L1 methylation dynamics during development may therefore elucidate and explain spatiotemporal niches of endogenous retrotransposition but remain unresolved. Here, we interrogate the retrotransposition efficiency and epigenetic fate of source (donor) L1s, identified as mobile in vivo. We show that promoter monomer loss consistently attenuates the relative retrotransposition potential of their offspring (daughter) L1 insertions. We also observe that most donor/daughter L1 pairs are efficiently methylated upon differentiation in vivo and in vitro. We use Oxford Nanopore Technologies (ONT) long-read sequencing to resolve L1 methylation genome-wide and at individual L1 loci, revealing a distinctive “smile” pattern in methylation levels across the L1 promoter region. Using Pacific Biosciences (PacBio) SMRT sequencing of L1 5′ RACE products, we then examine DNA methylation dynamics at the mouse L1 promoter in parallel with transcription start site (TSS) distribution at locus-specific resolution. Together, our results offer a novel perspective on the interplay between epigenetic repression, L1 evolution, and genome stability.

Footnotes

[Supplemental material is available for this article.]

Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.278003.123.

Freely available online through the Genome Research Open Access option.

Received April 25, 2023. Accepted August 21, 2023.