The mammalian zygote is a platform for a multi-act show of dramatic rises and falls in DNA methylation. However, new research suggests that backstage, in the developing oocyte, resides the real star of the show: Stella. Stella oversees the complex choreography of DNA methyltransferases and the supporting cast to make sure the right cues are met during oogenesis.
Normal gamete development involves a widespread loss of DNA methylation followed by a gradual increase in methylation levels as cells mature. However, unlike in the developing sperm, oocytes retain low levels of methylation at transcriptionally silent regions throughout their life cycle. Recently, the Zhu lab (Chinese Academy of Sciences, Beijing) set out to explore this phenomenon, and investigate how it might impact the development of a mouse embryo.
They focused on Stella, a protein that is expressed throughout oogenesis and is related to female fertility, and found that:
- Genetic knockout of the Stella gene in female mice prevents UHRF1 (a recruiter of DNMT1) from exiting the nucleus; whereas ectopic expression of Stella mRNA in wildtype cells keeps UHRF1 completely cytoplasmic
- Stella-/- oocytes have much higher levels of DNA methylation, as revealed by reduced representation bisulfite sequencing (RRBS), and acquire methylation at approximately 28 000 more loci during development than wildtype oocytes
- Aberrant methylation is enriched at promoters of select genes which, while already inactive in oocytes, are expressed during zygote genome activation (ZGA)
- Embryos from Stella-/- oocytes typically fail to develop beyond the four-cell stage, and contain high levels of 5mc and 5hmC, as determined by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS)
- In Stella-/- oocytes, UHRF1 co-localizes to pericentric heterochromatin, along with DNMT1, but not DNMT3A
- Conditional knockout of DNMT1 in Stella-/- oocytes reverses 81% of aberrant methylation compared to Stella-/- oocytes with wildtype DNMT1
Taken together, these results suggest that Stella plays a surveillance role in the oocyte and prevents aberrant de novo DNA methylation by DNMT1 that could impair embryonic development.
You can get a front row seat to see these findings shine in Nature, November 2018