DNA methylation couples lagging-strand synthesis with transposable element silencing
DNA methylation is a key epigenetic modification essential for genome stability and transposable element (TE) silencing in mammals. While DNA replication is asymmetric, with distinct leading and lagging strand synthesis, how DNA methylation maintenance integrates with this asymmetry to preserve epigenetic silencing remains unclear. Here, we employed strand-specific genome-wide assays in mouse embryonic stem cells to demonstrate that DNA methylation maintenance factors, including DNMT1, UHRF1 and PAF15 preferentially associate with the lagging strand during DNA replication. This targeting is enriched at head-on oriented LINE and SINE transposable elements, which show evolutionary bias for lagging-strand insertion and full-length retention. Loss of DNA methylation maintenance shifts silencing to H3K9me3-mediated mechanisms, highlighting complementary pathways. Furthermore, DNA methylation interferes with the lagging-strand replication stability via turnover of the lagging-strand PCNA-associated factors. These findings reveal a replication-coupled mechanism linking lagging-strand synthesis with epigenetic silencing of TEs, contributing to genome integrity and evolutionary dynamics.
DNA methylation is a key epigenetic modification essential for genome stability and transposable element (TE) silencing in mammals. While DNA replication is asymmetric, with distinct leading and lagging strand synthesis, how DNA methylation maintenance integrates with this asymmetry to preserve epigenetic silencing remains unclear. Here, we employed strand-specific genome-wide assays in mouse embryonic stem cells to demonstrate that DNA methylation maintenance factors, including DNMT1, UHRF1 and PAF15 preferentially associate with the lagging strand during DNA replication. This targeting is enriched at head-on oriented LINE and SINE transposable elements, which show evolutionary bias for lagging-strand insertion and full-length retention. Loss of DNA methylation maintenance shifts silencing to H3K9me3-mediated mechanisms, highlighting complementary pathways. Furthermore, DNA methylation interferes with the lagging-strand replication stability via turnover of the lagging-strand PCNA-associated factors. These findings reveal a replication-coupled mechanism linking lagging-strand synthesis with epigenetic silencing of TEs, contributing to genome integrity and evolutionary dynamics.
Institut Gustave Roussy