Abstract
Preimplantation embryos experience profound resetting of epigenetic information inherited from the gametes. Genome-wide analysis at single-base resolution has shown similarities but also species differences between human and mouse preimplantation embryos in DNA methylation patterns and reprogramming. Here, we have extended such analysis to two key livestock species, the pig and the cow. We generated genome-wide DNA methylation and whole-transcriptome datasets from gametes to blastocysts in both species. In oocytes from both species, a distinctive bimodal methylation landscape is present, with hypermethylated domains prevalent over hypomethylated domains, similar to human, while in the mouse the proportions are reversed.An oocyte-like pattern of methylation persists in the cleavage stages, albeit with some reduction in methylation level, persisting to blastocysts in cow, while pig blastocysts have a highly hypomethylated landscape. In the pig, there was evidence of transient de novo methylation at the 8–16 cell stages of domains unmethylated in oocytes, revealing a complex dynamic of methylation reprogramming. The methylation datasets were used to identify germline differentially methylated regions (gDMRs) of known imprinted genes and for the basis of detection of novel imprinted loci. Strikingly in the pig, we detected a consistent reduction in gDMR methylation at the 8–16 cell stages, followed by recovery to the blastocyst stage, suggesting an active period of imprint stabilization in preimplantation embryos. Transcriptome analysis revealed absence of expression in oocytes of both species of ZFP57, a key factor in the mouse for gDMR methylation maintenance, but presence of the alternative imprint regulator ZNF445. In conclusion, our study reveals species differences in DNA methylation reprogramming and suggests that porcine or bovine models may be closer to human in key aspects than in the mouse model.
Highlights
Genes are inherited from parents and, once their specific sequence after recombination during meiosis is established, they remain almost unaltered through cell divisions during an individual’s life, unless external agents or replication mistakes act on them producing mutations
Global methylation levels exhibited similar trajectories from the gametes to the blastocyst in the two species, and these patterns were grossly similar to what has been described in mouse and human preimplantation embryos
We evaluated expression and methylation of genes for key factors known to be involved in the mouse and/or human in maintaining DNA methylation at germline differentially methylated regions: the zinc-finger proteins ZFP57 and ZNF445 that have sequence-specific binding for methylated Germline differentially methylated regions (gDMR) and recruit TRIM28 (KAP1), part of the complex that mediates DNA methylation and repressive chromatin [36, 39, 41, 51, 67]
Summary
Genes are inherited from parents and, once their specific sequence after recombination during meiosis is established, they remain almost unaltered through cell divisions during an individual’s life, unless external agents or replication mistakes act on them producing mutations. Changes in epigenetic information, associated with states of gene activity, are at least one order of magnitude more frequent than genetic changes [3] and more susceptible to environmental conditions. Epigenetic states are dynamic during gametogenesis and early embryonic development when extensive reprogramming takes place [7]. Their correct establishment during preimplantation development may be crucial to avoid immediate or future alterations in the offspring’s health. According to the DOHAD hypothesis [1], the knowledge of the epigenetic marks that are rewritten during early embryonic development of an individual may serve to predict predisposition to certain diseases in adult life. It is important to establish the normal patterns, as well as the expected changes during the lifecourse, of these marks in each species, and find out the similarities and differences between them
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