You’ve heard before that timing is everything, and this is doubly true in developmental biology. New research out of Fuchou Tang’s lab (Peking University, Beijing) singles in on the timing of methylation changes during embryonic development, and exposes the delicate epigenetic dance of global demethylation and targeted remethylation.
Tang’s lab is no stranger to embryonic epigenetics, previously reporting on the DNA methylation landscape in early embryos. Now this talented lab team made use of post-bisulfite adaptor tagging (PBAT) to perform whole-genome bisulfite sequencing of individual cells in human preimplantation embryos. Using this technique in euploid embryos, they interrogated changes in the genome-wide methylation status throughout pre-implantation development and early post-implantation. Additionally, they compared methylation patterns of the maternal and paternal genomes from the sperm and oocyte stages onward.
These ambitious authors analyzed over 6.5 Tb of sequencing data covering 10.8 million CpG sites to reveal the following:
- In the preimplantation embryo, there are three major demethylation waves interspersed with two periods of de novo methylation
- Extensive global demethylation occurs at 10-12 hours post-fertilization, the late zygote to two-cell stage, and the eight-cell to morula stage. While the first wave of demethylation occurs mostly at enhancer and gene body regions, the second two waves are primarily at introns and SINEs
- Widespread de novo methylation occurs at the male pro-nuclear stage and the four-cell to eight-cell stage; these sites are enriched for families of repetitive elements (SINEs, LINEs, LTRs)
- Sites of de novo methylation sites are often demethylated in subsequent developmental stages
- Throughout the global methylation changes, the paternal genome is demethylated faster and more completely than the maternal genome
- This does not appear to be related to genomic imprinting
- Differentially methylated regions (DMRs) in oocytes are enriched at CpG islands, gene promoters, and SINEs, whereas the sperm DMRs are enriched in somatic-cell-specific enhancers and SINEs
- DNA methylation is asymmetrically inherited during cell division, allowing blastomeres at the four-cell stage to be traced back to the parental cell
Overall, this work highlights the epigenetic intricacies in a developing embryo: the balance between demethylation of inherited parental sites and de novo methylation, as well as a unique timing component.
To see how the story develops further, check out Nature Genetics, January 2018