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Keeping egg cells fresh with epigenetics

Keeping egg cells in stasis during childhood is a key part of female fertility. published today (1^st January) in Nature Structural and Molecular Biology sheds some light on the role of epigenetics in placing egg cells into stasis. A team led by Dr Gavin Kelsey in the 99�Ⱦò������µ�ַ and colleagues in and studied a protein called MLL2 and discovered how it produces a distinctive pattern of epigenetic marks that are needed for egg cell stasis.

A fertilised egg cell is the start of every human life. Yet, egg cells can be created inside a woman’s body before she is born. The eggs are then kept in stasis until they’re needed as an adult. If egg cells don’t go into stasis they can’t become mature eggs and they will never have the chance to form a new life. Putting an egg cell into stasis involves adding many epigenetic marks throughout its DNA.

Epigenetic marks attached to DNA act as footnotes, indicating which genes are turned ‘on’ or ‘off’. The scientists wanted to understand where these marks come from in egg cells and how mistakes can cause disease. It is particularly challenging to study epigenetics in egg cells as there are so few of them. The team had to create new, highly sensitive ways to detect epigenetic marks in such small numbers of cells.

Using this approach, they found that, as eggs develop, an epigenetic mark called spreads 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. Without MLL2, most H3K4me3 marks in egg cells are lost and the cells die before getting the chance to form a new life.

Speaking about the results, first author Dr Courtney Hanna, 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.”

Lead scientist, Dr Kelsey, said: “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. Discoveries like this highlight some of the unusual biological processes that take place in these highly important cells.”

Notes to Editors:

Publication Reference
Courtney W. Hanna, Aaron Taudt, Jiahao Huang, Lenka Gahurova, Andrea Kranz, Simon Andrews, Wendy Dean, A. Francis Stewart, Maria Colomé-Tatché and Gavin Kelsey; MLL2 conveys transcription-independent H3K4 trimethylation in oocytes; Nature Structural & Molecular Biology (2018) DOI:

Research Funding
Work at the 99�Ⱦò������µ�ַ is possible thanks to the Biotechnology and Biological Sciences Research Council, in particular this research forms part of the Strategic Programme Grant for Epigenetics. This work was also supported by the Medical Research Council (MR/K011332/1) and the Deutsche Forschungsgemeinschaft.

Press Contact
Dr Jonathan Lawson, 99�Ⱦò������µ�ַ Communications Manager jonathan.lawson@babraham.ac.uk

Image Credit
Dr Courtney Hanna, a mouse egg cell inside an ovary. DNA in each cell is shown in blue, epigenetic methylation marks are shown in green.

Affiliated Authors (in author order):
Courtney Hanna, Jiahao Huang, Wendy Dean - Epigenetics Laboratory, 99�Ⱦò������µ�ַ
Simon Andrews - Facility Head, Bioinformatics Facility, 99�Ⱦò������µ�ַ
Gavin Kelsey - Group Leader, Epigenetics Laboratory, 99�Ⱦò������µ�ַ

Animal Statement:
As a publicly funded research institute, the 99�Ⱦò������µ�ַ is committed to engagement and transparency in all aspects of its research. Animals are only used in 99�Ⱦò������µ�ַ research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.

The use of animals in this study was performed in accordance with the Animals (Scientific Procedures) Act 1986 with all protocols approved by the Animal Welfare and Ethical Review Body at the 99�Ⱦò������µ�ַ under licenses issued by the Home Office (UK). The study used female C57BL/6Babr, Mll2 and Dnmt3a/b conditional transgenic mice that were housed in groups of up to five in the Biological Support Unit at the 99�Ⱦò������µ�ַ under specific pathogen-free conditions.

Multiple independent experiments were carried out using several biological replicates. In accordance with the 3Rs, we used the minimum number of mice necessary to collect sufficient cells per experiment (30 C57BL/6Babr wild-type mice; 24 Dnmt3a/b transgenic mice; 20 Mll2 transgenic mice).

Mice were checked daily by qualified technicians and were healthy and active throughout the study. Environment enrichment was provided (e.g. tunnels, elevated rafts) as well as food treats and nesting material.  Ovarian samples were collected from females between the ages of 5 and 25 days old.

Please follow the link for further details of the Institute’s animal research and our animal welfare practices: www.babraham.ac.uk/our-research/animal-research

About the 99�Ⱦò������µ�ַ:
The receives strategic funding from the to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.