DNA methylation dynamics of the human preimplantation embryo

Abstract

In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell type-specific regulation directed by DNA binding factors1-3. This comparatively static landscape dramatically contrasts the events of fertilization, where the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, though methylation is maintained at several notable features4-7. While these dynamics have been extensively characterized in the mouse, only limited observations are available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved8-10. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell (ESC) derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of persistent maintenance are primarily restricted to gene bodies. While most features share similar dynamics to mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island (CGI) promoters that extend beyond known Imprint Control Regions (ICRs). Retrotransposon regulation is also highly diverse and transitions from maternally to embryonically expressed, species-specific elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation.

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

“…High levels of CG methylation (70-85%) are found throughout the somatic tissues of humans and mice [16,17]. However, earlier in development, naive 'pluripotent' cells within the blastocyst (which go on to form all cells and tissues of the body) display only 20-30% CG methylation [18]. Equally low levels of methylation are also seen in cultured cells recently found to recapitulate the naive pluripotent characteristics of the early embryo [19][20][21][22][23][24].…”

Hypermethylated LTR retrotransposon exhibits enhancer activity

“…27,31,71,72 These findings indicate that the transcriptional activities of the LTRs are correlated with and can be fine-tuned by the extents of LTR methylation. Thus, ERV-9 LTR retrotransposons, through differential methylation of CpGs may be able to differentially regulate transcription of the cis-linked genes to coordinate the transcription networks of human development and differentiation.…”

Épigénétique et réponses transgénérationnelles aux impacts de l’environnement

“…Au moment de la fécondation, chez l'humain comme chez la souris, le nombre de sites méthylés sur l'ADN est beaucoup plus important dans le spermatozoïde que dans l'ovocyte [46]. Une déméthylation étendue, mais spécifique de site, se produit dans le pronoyau mâle et dans le pronoyau femelle après la fécondation, selon des mécanismes actifs et passifs différents, en fonction de l'origine parentale du chromosome [46].…”