Genome-wide, Single-Cell DNA Methylomics Reveals Increased Non-CpG Methylation during Human Oocyte Maturation

Abstract

SummaryThe establishment of DNA methylation patterns in oocytes is a highly dynamic process marking gene-regulatory events during fertilization, embryonic development, and adulthood. However, after epigenetic reprogramming in primordial germ cells, how and when DNA methylation is re-established in developing human oocytes remains to be characterized. Here, using single-cell whole-genome bisulfite sequencing, we describe DNA methylation patterns in three different maturation stages of human oocytes. We found that while broad-scale patterns of CpG methylation have been largely established by the immature germinal vesicle stage, localized changes continue into later development. Non-CpG methylation, on the other hand, undergoes a large-scale, generalized remodeling through the final stage of maturation, with the net overall result being the accumulation of methylation as oocytes mature. The role of the genome-wide, non-CpG methylation remodeling in the final stage of oocyte maturation deserves further investigation.

Non‐canonical Bases in the Genome: The Regulatory Information Layer in DNA

“…[95] mdC is by far the most abundant of these bases.I to ccurs predominantly symmetric in CpG dinucleotide sequences, which are methylated to about 70-80 %. [168,169] mdC is also found in non-CpG context in plants [170] and animals,w ith highest levels in mature oocytes, [171,172] followed by neurons, [173] ESCs [174][175][176][177] and other somatic tissues. [178,179] The presence of mdC has aprofound effect on the transcriptional activity of genes.…”

Advances in the Profiling of Single‐Cell DNA Modifications

“…Many novel findings have been reported by applying single‐cell methylome sequencing on gametogenesis and early mammalian embryonic development. These findings include maturation of mammalian oocytes, paternal and maternal pronuclei demethylation in mammalian zygotes, and epigenetic reprogramming in preimplantation embryonic development . These results indicate that the regulatory links between DNA methylome and transcription can be complex in niche cell populations and dependent on different development stages.…”

Maternal effects and parent–offspring conflict

“…; Yu et al. ), showing that individual‐level signaling to young is certainly possible. Also, studies on avian hormones show that mothers are able to adjust hormone levels on a per‐egg basis (e.g., Eising and Groothuis ) although between‐clutch variation in hormone levels is typically larger than within‐clutch variation (Groothuis et al.…”

“…In addition, when a mother is unable to signal to each of her young independently, the scope for maternal manipulation is also likely to be reduced. However, the generality of this constraint remains to be evaluated: for example, some studies find that there is substantial variation in DNA methylation among gametes from the same human parent (e.g., Jenkins et al 2015;Yu et al 2017), showing that individual-level signaling to young is certainly possible. Also, studies on avian hormones show that mothers are able to adjust hormone levels on a per-egg basis (e.g., Eising and Groothuis 2003) although between-clutch variation in hormone levels is typically larger than within-clutch variation (Groothuis et al 2005;Postma et al 2014).…”