DNA methylation – the transfer of a methyl group to DNA - is a well-studied epigenetic modification. Although the roles of different DNA methyltransferases have been examined in detail, less is known about the effects of altering methyl group availability. Now, Jacquetta Trasler and co-workers show that paternal deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in methyl group production, leads to loss of sperm DNA methylation in mice and to reproductive decline across generations. The researchers first show that paternal MTHFR deficiency leads to testicular abnormalities, with the testes of the F2 generation being more severely affected than those of the F1 generation. They further report that MTHFR deficiency causes profound genome-wide loss of sperm DNA methylation in both the F1 and F2 generations. Detailed analysis of the hypomethylated regions reveals that they are enriched for evolutionarily young retrotransposons. Moreover, these regions are marked by H3K4me3 and correspond to sites that are subject to late de novo methylation during germline epigenetic reprogramming. These findings lead the authors to propose that the preferential loss of DNA methylation at young retrotransposons, which are normally kept highly methylated during reprogramming, could contribute to the worsened reproductive defect seen in the F2 generation, potentially via increased expression of these retrotransposons. Importantly, these results highlight that epimutations can be passed on to subsequent generations rather than being removed during epigenetic reprogramming.
