Extra Epigenetic Packaging Keeps Egg Cells Fresh

Keeping egg cells in stasis during childhood is a key part of female fertility. New research sheds light on the role of epigenetics in placing egg cells into stasis through childhood. A team has discovered a distinctive pattern of epigenetic marks that are needed for egg cell stasis. If egg cells don’t go into stasis they can’t become mature eggs and they will never have the chance to form new life.

A type of epigenetic mark that ordinarily causes gene activation may instead facilitate gene silencing in oocytes, cells that must be kept in stasis throughout childhood if they are to have the ability to contribute to new life in a woman’s adulthood. The mark, called histone 3 K4 trimethylation (H3K4me3), appears to exert its different effects – focused activation or widespread inactivation – depending on how it is distributed in the genome.

According to scientists based at the Babraham Institute, H3K4me3 marks accumulate in oocytes and develop a distinctive pattern, all through the action of a protein called MLL2, or histone-lysine N-methyltransferase 2D. Without MLL2, most H3K4me3 marks in egg cells are lost, and the cells die before getting the chance to form a new life.

Additional details appeared in the journal Nature Structural and Molecular Biology, in an article entitled, “MLL2 Conveys Transcription-Independent H3K4 Trimethylation in Oocytes.” The article describes how a scientific team led by Gavin Kelsey, Ph.D., at the Babraham Institute and colleagues in Dresden and Munich detailed the connection between epigenetics and egg development.

A key challenge was deriving adequate epigenetic information from egg cells, which are typically scarce. To overcome this challenge, the researchers developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac, and H3K27me3 marks throughout oogenesis.

“In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters,” wrote the article’s authors. “Ablation of the H3K4 methyltransferase gene Mll2 resulted in loss of transcription-independent H3K4 trimethylation but had limited effects on transcription-coupled H3K4 trimethylation or gene expression.”

Essentially, as eggs develop, H3K4me3 marks spread throughout the genome. Scientists have already seen the same mark close to the start of active genes in many cells, but the team discovered that its role in egg cells is different. They showed that the MLL2 protein is responsible for this unusual placement of H3K4me3 in egg cells.

“Deletion of Dnmt3a and Dnmt3b showed that DNA methylation protects regions from acquiring H3K4me3,” the article’s authors added. “Our findings reveal two independent mechanisms of targeting H3K4me3 to genomic elements, with MLL2 recruited to unmethylated CpG-rich regions independently of transcription.”

Speaking about the results, Babraham researcher and first author Courtney Hanna, Ph.D., said: “Our findings show that H3K4me3 is created in two ways. MLL2 can add the H3K4me3 mark without any nearby gene activity, while another process that doesn’t use MLL2 places the same mark around active genes. By studying this new mechanism, we hope to expand our knowledge of epigenetics in general as well as adding to our understanding of fertility.”

“We are only beginning to unravel the details of the connection between epigenetics and egg development, a fundamental aspect of biology that may play a part in transmitting information from mother to fetus,” added Dr. Kelsey. “Discoveries like this highlight some of the unusual biological processes that take place in these highly important cells.”