Dynamic CpG island methylation landscape in oocytes and preimplantation embryos

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.