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Elucidating how and to what extent CpG islands (CGIs) are methylated in germ cells is essential to understand genomic imprinting and epigenetic reprogramming1-3. Here, we present the first integrated epigenomic analysis of mammalian oocytes, identifying over a thousand CGIs methylated in mature oocytes. We show that these CGIs depend on DNMT3A and DNMT3L4-5, but are not distinct at the sequence level, including in CpG periodicity6. They are preferentially located within active transcription units and are relatively depleted in H3K4me3, supporting a general transcription-dependent mechanism of methylation. Very few methylated CGIs are fully protected from post-fertilisation reprogramming but, surprisingly, the majority exhibits incomplete demethylation in E3.5 blastocysts. Our study shows that CGI methylation in gametes is not entirely related to genomic imprinting, but is a strong factor in determining methylation status in preimplantation embryos, suggesting a need to reassess mechanisms of post-fertilization demethylation. |