Ontogeny, conservation and functional significance of maternally inherited DNA methylation at two classes of non-imprinted genes

A functional role for DNA methylation has been well-established atimprinted loci, which inherit methylation uniparentally, most commonlyfrom the mother via the oocyte. Many CpG islands not associatedwith imprinting also inherit methylation from the oocyte, although thefunctional significance of this, and the common features of the genesaffected, are unclear. We identify two major subclasses of genesassociated with these gametic differentially methylated regions(gDMRs), namely those important for brain and for testis function.The gDMRs at these genes retain the methylation acquired in theoocyte through preimplantation development, but become fullymethylated postimplantation by de novo methylation of the paternalallele. Each gene class displays unique features, with the gDMRlocated at the promoter of the testis genes but intragenically for thebrain genes. Significantly, demethylation using knockout, knockdownor pharmacological approaches in mouse stem cells and fibroblastsresulted in transcriptional derepression of the testis genes, indicatingthat they may be affected by environmental exposures, in eithermother or offspring, that cause demethylation. Features of the braingene group suggest that they might represent a pool from whichmany imprinted genes have evolved. The locations of the gDMRs, aswell as methylation levels and repression effects, were alsoconserved in human cells.