Abstract
The mammalian genome experiences profound setting and resetting of epigenetic patterns during the life-course. This is understood best for DNA methylation: the specification of germ cells, gametogenesis, and early embryo development are characterised by phases of widespread erasure and rewriting of methylation. While mitigating against intergenerational transmission of epigenetic information, these processes must also ensure correct genomic imprinting that depends on faithful and long-term memory of gamete-derived methylation states in the next generation. This underscores the importance of understanding the mechanisms of methylation programming in the germline. De novo methylation in the oocyte is of particular interest because of its intimate association with transcription, which results in a bimodal methylome unique amongst mammalian cells. Moreover, this methylation landscape is entirely set up in a non-dividing cell, making the oocyte a fascinating model system in which to explore mechanistic determinants of methylation. Here, we summarise current knowledge on the oocyte DNA methylome and how it is established, focussing on recent insights from knockout models in the mouse that explore the interplay between methylation and chromatin states. We also highlight some remaining paradoxes and enigmas, in particular the involvement of non-nuclear factors for correct de novo methylation.
Highlights
The mammalian genome experiences profound setting and resetting of epigenetic patterns during the life-course
Methylation probably has little influence in controlling gene activity in the oocyte itself because primary oocytes appear to initiate a faithful transcription programme before DNA methylation is put in place[11], and RNA-seq analysis of Dnmt3L-knockout oocytes that are effectively devoid of methylation indicate that there are no transcriptional differences compared with control oocytes[2]
Mechanistic predictions of DNA methyltransferase (DNMT) targeting There appears to be a simple logic to the methylation pattern that arises in oocytes, which is informed by the biochemical properties of the de novo methyltransferases involved: in mouse oocytes, this is DNMT3A as the active enzyme and the related DNMT3L as an essential auxiliary factor
Summary
The mammalian genome experiences profound setting and resetting of epigenetic patterns during the life-course. Mechanistic predictions of DNMT targeting There appears to be a simple logic to the methylation pattern that arises in oocytes, which is informed by the biochemical properties of the de novo methyltransferases involved: in mouse oocytes, this is DNMT3A as the active enzyme and the related DNMT3L as an essential auxiliary factor. Of the H3K4me[3] demethylases, lysine demethylase 5C (KDM5C) (JARID1C) is the most abundantly expressed at the transcriptional level in mouse oocytes, but oocyte-specific ablation of KDM5C does not impair de novo DNA methylation (Huang and Kelsey, unpublished data).
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