Abstract
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. However, the dynamics and interrelations of these chromatin characteristics remain elusive. In this study, we developed an improved scCOOL-seq technique (iscCOOL-seq), which is a multi-omics, single-cell and single-base resolution method with high mapping rates, and explored the chromatin accessibility landscape and its relationship to DNA methylation in growing mouse oocytes. The most dramatic change in chromatin accessibility occurs during oocyte growth initiation, accompanied with prominent transcriptome alterations and an elevated variation in DNA methylation levels among individual oocytes. Unlike CpG islands (CGIs), partially methylated domains (PMDs) are associated with a low density of nucleosome-depleted regions (NDRs) during the whole maturation period. Surprisingly, highly expressed genes are usually associated with NDRs at their transcriptional end sites (TESs). In addition, genes with de novo methylated gene bodies during oocyte maturation are already open at their promoters before oocyte growth initiation. Furthermore, epigenetic and transcription factors that might be involved in oocyte maturation are identified. Our work paves the way for dissecting the complex, yet highly coordinated, epigenetic alterations during mouse oocyte growth and the establishment of totipotency.
Highlights
The development of the female germline undergoes several key steps to generate mature oocytes that are ready for fertilization; these steps include the formation of primordial germ cells (PGCs) from a limited number of epiblast founders, the transition from mitosis to meiosis after the completion of epigenetic reprogramming in the PGCs, and oogenesis during postnatal growth[1,2]
We found that individual MII oocytes, either from iscCOOL-seq, scCOOL-seq or scBS-seq dataset, were clustered together or separated from mouse ES cells (Supplementary information, Fig. S1d), whereas individual ES cells, which were separated from MII oocytes, were clustered together and divided into two subgroups (Supplementary information, Fig. S1d)
Because partially methylated domains (PMDs) and CpG islands (CGIs) have been reported to be associated with H3K4me[3] modifications in mouse oocytes, which is considered to be an active histone marker[41,42,43], we investigated the chromatin accessibility of these regions during oocyte growth
Summary
The development of the female germline undergoes several key steps to generate mature oocytes that are ready for fertilization; these steps include the formation of primordial germ cells (PGCs) from a limited number of epiblast founders, the transition from mitosis to meiosis after the completion of epigenetic reprogramming in the PGCs, and oogenesis during postnatal growth[1,2]. The epigenetic features of oocyte growth (oogenesis), especially the chromatin configuration and its relationship with essential chromatin modifications, such as DNA methylation, remain elusive. De novo DNA methylation takes place in growing oocytes during postnatal growth[19]. Targeted sequences will be methylated during this de novo DNA methylation process, including the germline differentially methylated regions of imprinted genes, forming oocyte-specific DNA methylation profiles[19]. Due to an extremely limited cell source, it is difficult to explore the chromatin accessibility landscape during oogenesis
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