Integrative Single-cell Analysis of Transcriptome, DNA Methylome and Chromatin Accessibility in Mouse Oocytes

Oocyte growth is a key step in forming mature eggs that are ready to be fertilized. The states and modifications of chromatin represent critical sources of information for this process, yet the dynamic features and interrelations of these chromatin characteristics remain elusive. In this study, we applied an improved scCOOL-seq technique (iscCOOL-seq), which is a multi-omic, single-cell, single-base-resolution method with high mapping rates, to explore the chromatin accessibility landscape and its relationship to DNA methylation in growing mouse oocytes. The most dramatic change in chromatin accessibility happened during the transition from a non-growing to a growing oocyte, with transcriptome alterations and an elevated variation in DNA methylation among individual oocytes. Unlike CpG islands (CGIs), partially methylated domains (PMDs) were associated with a low density of nucleosome-depleted regions (NDRs) during the whole maturation period. Surprisingly, highly expressed genes were usually associated with NDRs at their transcriptional end sites (TESs). In addition, de novo methylated gene bodies were always enriched in open chromatins at corresponding genes promoters. Furthermore, epigenetic and transcription factors that might be involved in oocyte maturation were identified. Our work paves the way for dissecting the complex, yet highly coordinated, epigenetic alterations during mouse oocyte maturation and the establishment of totipotency.