DNA methylation links lagging strand replication to transposable element control

Fajri, N.; Coulée, M.; Pigeon, A.; Badugu, S.; Güller, A.; Bandau, S.; Jiang, H.; Lamond, A.; Ferry, L.; Greenberg, M.; Defossez, P.; Alabert, C.; Somyajit, K.; Petryk, N.

doi:10.64898/2026.06.23.733924

bioRxiv · 10.64898/2026.06.23.733924

DNA methylation links lagging strand replication to transposable element control

Fajri, N.·Coulée, M.·Pigeon, A.·Badugu, S.·Güller, A.·Bandau, S.·Jiang, H.·Lamond, A.·Ferry, L.·Greenberg, M.·Defossez, P.·Alabert, C.·Somyajit, K.·Petryk, N.

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Abstract

DNA methylation is an essential epigenetic mark that silences transposable elements (TEs) in mammalian genomes1,2. Following DNA replication, methylation patterns must be faithfully restored3,4, yet how the two processes are coordinated remains unclear. Here, using strand-specific, genome-wide analyses5-7 in mouse embryonic stem cells, we show that DNA methylation maintenance is coupled to the lagging-strand synthesis in TE-rich regions. Paradoxically, despite this targeting, the lagging strand is more permissive for TE integration than the leading strand. Notably, insertions of full-length LINE-1s, SINEs, and satellite repeats are all enriched on the lagging strand over evolutionary time. Consequently, most TEs, particularly young elements, are oriented head-on relative to replication forks in the mouse genome, creating an unfavorable genomic configuration8 that is preferentially targeted by DNA methylation maintenance. Mechanistically, DNA methylation maintenance is coupled to the lagging-strand replication via UHRF1-LIG19 and PCNA-PAF1510 interactions, and the interference in this mechanism slows Okazaki fragment maturation, and thereby potentially may facilitate TE retention. Together, we show a mechanism of TE control during DNA replication with an unexpected evolutionary interplay in which DNA methylation may facilitate, rather than solely prevent, TE expansion.

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Fajri, N., Coulée, M., Pigeon, A., Badugu, S., Güller, A., Bandau, S., Jiang, H., Lamond, A., Ferry, L., Greenberg, M., Defossez, P., Alabert, C., Somyajit, K., Petryk, N.. 2026-06-23. DNA methylation links lagging strand replication to transposable element control. https://doi.org/10.64898/2026.06.23.733924

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