Following fertilisation, a genome-wide demethylation wave reprogrammes the genome. However, in mammals, certain loci can remain methylated specifically on the maternal or paternal chromosome, i.e. imprinted, in somatic cells. It was previously shown in transgenic mice carrying a fragment of the H19 imprinting control region (ICR) that the paternally inherited H19 ICR does not need to be methylated in the germline to be imprinted, pointing at the existence of an unknown epigenetic mark inducing post-fertilisation methylation of that locus. Now, using the same H19 ICR transgenic line, Keiji Tanimoto and co-workers (p. 3833) show that H19 ICR imprinting is achieved through maternally inherited DNMT3A- and DNMT3L-mediated de novo methylation. This process is also at play at the endogenous H19 locus. Further, the authors identify the sequences responsible for the post-fertilisation methylation of the transgenic H19 ICR and show that their removal from the endogenous locus leads to partial H19 ICR demethylation and delayed embryonic growth in the offspring that inherited the mutation. These results provide a mechanistic understanding of the contribution of de novo methylation to genomic imprinting in the absence of germline methylation, though the nature of the putative epigenetic mark that directs this methylation has yet to be discovered.
- © 2015. Published by The Company of Biologists Ltd