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Single-Cell Methylome Sequencing Uncovers Dynamics of DNA Methylation in Human Embryos

NEW YORK (GenomeWeb) – DNA methylation reprogramming within embryos is a balance between widespread demethylation and targeted remethylation, a new single-cell study has found.

During early development, embryos undergo global DNA methylation changes. Researchers from Peking University performed single-cell methylome sequencing on preimplantation cells to examine reprogramming dynamics. As they reported in Nature Genetics today, the researchers also found asymmetric methylation of the maternal- and paternal-origin genomes.

"Our work paves the way for deciphering the secrets of DNA methylation reprogramming in early human embryos," Peking's Fuchou Tang and his colleagues wrote in their paper.

The researchers performed single-cell post-bisulfite adaptor tagging methylome sequencing of 480 single cells obtained from 50 human oocytes, 23 sperm cells, and 62 preimplantation embryos. For each cell, they sequenced an average of 8.4 gigabases and covered 10.8 million CpG sites. Overall, they uncovered tens of thousands of loci with de novo DNA methylation.

Demethylation occurs in preimplantation embryos in three waves, the researchers reported. In the first wave, taking place about 10 hours to 12 hours after fertilization, the median DNA methylation level drops from 82 percent in the sperm to 52.9 percent in the early male pronucleus for the paternal genome and from 54.5 percent in the mature oocyte to 50.7 percent in the early female pronucleus for the maternal genome.

During the second wave, which occurs from the late zygote to two-cell stage, the median DNA methylation drops further to 40.4 percent, and during the third wave, from the eight-cell to morula stages, it drops again to 35.1 percent. The demethylated regions were enriched for introns and short interspersed nuclear elements, the researchers noted.

Interspersed with those waves of demethylation, two waves of methylation occur, the researchers found. One wave happens during the shift from the early male pronuclear to the mid-pronuclear stage and the other during the four-cell to eight-cell stages. The methylated regions were strongly enriched for major repeat element families like SINEs, long interspersed nuclear elements, and long terminal repeats.

"This finding indicates that drastic de novo methylation occurs during preimplantation development in embryos, and the global DNA methylation reprogramming is in fact a dynamic balance between strong genome-wide demethylation and focused remethylation," Tang and his colleagues wrote.

However, the demethylation dynamics differed between the paternal and maternal genomes, the researchers found. The rate of demethylation is faster for the paternal genome than it is for the maternal. In addition, after the two-cell stage, the level of methylation of the paternal genome was consistently lower than that of the maternal genome. That, the researchers noted, is despite the paternal genome starting within sperm with a higher level of methylation.

The maternal genome methylation level is consistently, though weakly, higher than the paternal genome in the postimplantation embryo, the researchers added. To them, this suggested the maternal genome is preferentially hypermethylated during pre- and postimplantation development.

While single-cell RNA sequencing and DNA methylome sequencing of the inner cell mass and trophectoderm cells from blastocysts uncovered higher DNA methylation of the maternal genome, the researchers noted that this did not appear to contribute to allele-specific gene expression.

Tang and his colleagues further reported that DNA methylation analysis could be used to trace the genetic lineage of early blastomeres. "Altogether, these findings offer a roadmap for elucidating the contribution of these features to cell fate determination and genome integrity during early development," they wrote.

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