Stability and Lability of Parental Methylation Imprints in Development and Disease

Abstract

DNA methylation plays essential roles in mammals. Of particular interest are parental methylation marks that originate from the oocyte or the sperm, and bring about mono-allelic gene expression at defined chromosomal regions. The remarkable somatic stability of these parental imprints in the pre-implantation embryo—where they resist global waves of DNA demethylation—is not fully understood despite the importance of this phenomenon. After implantation, some methylation imprints persist in the placenta only, a tissue in which many genes are imprinted. Again here, the underlying epigenetic mechanisms are not clear. Mouse studies have pinpointed the involvement of transcription factors, covalent histone modifications, and histone variants. These and other features linked to the stability of methylation imprints are instructive as concerns their conservation in humans, in which different congenital disorders are caused by perturbed parental imprints. Here, we discuss DNA and histone methylation imprints, and why unravelling maintenance mechanisms is important for understanding imprinting disorders in humans.

Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3

“…The nature of the interaction is unknown. Mechanisms exist to prevent the loss of 5mC from methylated DMRs 53 and functionally analogous pathways might protect H3K27me3 imprints in blastocysts, but which are subsequently de-activated during implantation. We speculate that low global DNA-methylation levels observed at the blastocyst stage 54 could produce less stable imprint regulation by DMRs and that transcriptional repression could be ensured by Polycomb-mediated silencing activity.…”

Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility

“…Moreover, the paternal genome is subjected to global demethylation within the first 24 h of embryo development, much faster than the maternal genome [22]. However, the evidence has shown that parental imprinted regions escape from demethylation, although the reason for this is not fully understood [23]. Some researchers hypothesized that paternally-expressed imprinted genes (e.g., IGF2, a sperm-carried transcript [24]) may be of particular importance in preimplantation embryo development [25].…”

ASMdb: a comprehensive database for allele-specific DNA methylation in diverse organisms

“…Owing to this feature of haplotypes, imprinted genes are susceptible targets for many animal and plant diseases, and the destruction of imprinting can lead to cell dysfunction ( 13 ). Imprinting is mainly related to allele-specific DNA methylation (ASM), and different methylation patterns in alleles can lead to different phenotypes, such as diseases and even different therapeutic and drug responses to diseases ( 7 , 14–16 ).…”