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DNMT3C, a DNA methylation enzyme at the front in the battle against transposons

Dnmt3C_paper_IFs

DNA methylation is prevalent in mammalian genomes and plays a central role in the epigenetic control of development. Our team has uncovered a new DNA methylation enzyme, which is highly specialized in protecting male fertility against the activity of transposons.

Since the cloning of the first DNA methyltransferase in 1982, the last three decades of research had produced a list of four mammalian representatives of this family, along with their biochemical and developmental specificities: a maintenance enzyme, DNMT1 in 1982, two de novo enzymes, DNMT3A and DNMT3B in 1999, and an accessory co-factor, DNMT3L in 2001. Each of these DNMT is essential on its own: individual mutations in these genes  lead to obligate DNA methylation defects and to pathological phenotypes -early embryonic lethality, sterility, developmental syndrome and cancer- both in mouse models and in humans. Thorough inspection of available genome sequences had led to the conclusion that all members of this family were now known and that all DNA methylation-based biological processes should be explained by this available set of protagonists.

However, we unexpectedly uncovered a new DNA methyltransferase-encoding gene. As part of an unbiased forward genetic screen program (collaboration with Florian Guillou (INRA) and Yann Hérault-IGBMC, CNRS/Inserm), we identified a spontaneous mutation in a locus annotated as a pseudogene, Gm14490, which segregated with a severe testis size reduction phenotype in our mouse colony. Through mouse developmental biology, genetic engineering, genome-wide DNA methylation and transcriptomic maps and in vivo DNA methylation assays, we definitively demonstrated that Gm14490 was not a pseudogene but a genuine functional gene that encodes DNMT3C, a novel de novo DNA methyltransferase enzyme. The most striking characteristics of DNMT3C is its high level of specialization:  it selectively methylates the promoters of evolutionary young retrotransposons and only in the context of fetal spermatogenesis. Its absence cannot be compensated by DNMT3A and DNMT3B; retrotransposons get massively reactivated in germ cells of male Dnmt3C mutant mice, in association with an obligate sterility phenotype. The evidence strongly indicates that DNMT3C is the long-sought methylation enzyme that induces life-long epigenetic silencing of the most recent and dangerous transposons during early spermatogenesis.

The Dnmt3C gene appears to have risen from an ancient Dnmt3B duplication event, and has since evolved a highly specialized and essential function, which has diverged from the ancestral DNMT3B protein. Despite the strict requirement of DNMT3C for male fertility in the mouse, we unexpectedly found that this addition is not universal among mammals but specifically occurred 46MYA in the Muroidea lineage, which represents the largest mammalian superfamily. Notably, this group includes the two primary models in biomedical research, and in particular in reproductive and endocrinology studies, the mouse and the rat. If the fertility of the most successive mammalian group is correlated with the presence of DNMT3C, this naturally raises the question as to how DNMT3C-less male mammals, including humans, safeguard their germline against transposon activity.

Our discovery of DNMT3C raises a new set of challenges to the current views of the remarkable evolution of DNA methyltransferases, the regulation of the de novo methylation process and its tight links with the selective pressure to epigenetically control transposons in the germ line and to protect reproductive functions. As an immediate perspective, we are now investigating the mechanisms by which DNMT3C targeting to young retrotransposons may be achieved.

 

The DNA methyltransferase DNMT3C protects male germ cells from transposon activity
Joan Barau, Aurélie Teissandier, Natasha Zamudio, Stéphanie Roy, Valérie Nalesso, Yann Hérault, Florian Guillou, Déborah Bourc’his