A dog walk in the countryside led to Velcro, the search for chest pain therapies gave us (who me?) Viagra, and a messy microbiology lab bench provided penicillin. Some big research discoveries appear to have arrived in an “accidental” form and maybe, just maybe, new research from the laboratory of Déborah Bourc’his can be spoken of in the same manner! Their new study started off as a hunt for factors that can modulate the silencing of pesky transposable elements in the mouse male germ line and ended in the discovery of a new piece of DNA methylation machinery – DNMT3C!
Silencing of transposable elements via DNA methylation is required for fertility and overall genome stability. The DNA methylation machinery was thought to be entirely composed of three DNA methyltransferase (DNMT) enzymes (DNMT1, DNMT3A, and DNMT3B) and one catalytically inactive cofactor (DNMT3L). However, a mutagenesis-based mouse screen for modulators of retrotransposon activity kept leading Barau et al. to Gm14490, a gene previously described as an inactive duplicate of Dnmt3B.
Further probing demonstrated exclusive expression of Gm14490 in male germ cells with peak levels coinciding with known periods of de novo DNA methylation. Combine this with in vivo assays demonstrating that Gm14490 codes for an enzymatically active de novo DNA methyltransferase and Gm14490 becomes Dnmt3C! Dnmt3C shares many features of Dnmt3B (70% identity) and Dnmt3A (46% identity) with the long isoform containing an N-terminal ATRX-DNMT3L-DNMT3A (ADD) domain, which binds unmethylated lysine 4 histone H3 (H3K4), but lacking the Pro-Trp-Trp-Pro (PWWP) domain which targets gene bodies through recognition of H3K36 trimethylation (H3K36me3).
Interestingly, Dnmt3C loss led to sterility in male mice and correlated with a reduction in DNA methylation at the promoters of some transposable elements (e.g. young L1s and specific ERVKs) and an upregulation of their expression in the testes.
Overall, this new piece of DNA methylation machinery appears to have evolved in both function and target specificity to play a specific and specialized role in methylating and silencing “young” retrotransposon promoters in the male germ line. The authors note that the Dnmt3C is not universal among mammals but does appear in two important laboratory model animals, mouse and rat, and its presence may be due to the high levels of recent transposon integration (within the last 25 million years!) and the high level of still active copies.
What “accidental” discoveries will YOU make today? Before you head off on the path to glory, read all about the new part of the DNA Methylation machinery in Science, November 2016.