Using the power of single-cell analysis, researchers at the Babraham Institute have assessed the effects of age on egg cells (oocytes) in mice, particularly looking to identify genomic and epigenetic factors that relate to reduced developmental competence. The knowledge uncovered by this research provides new insights into the mechanisms underlying egg quality and is relevant to the development of techniques to assess the quality of human egg cells, an area of growing importance as the use of fertility treatments increases. The research is published today in the journal Aging Cell.
The most recent results by the UK’s Office of National Statistics report that for the 10th consecutive year, the average age of mothers in England and Wales increased to 30.6 years*. Trends indicate that women are choosing to delay the decision to have children with the number of children born to women aged 40 or above steadily increasing since 1978**.
Societal factors aside, advancing maternal age causes a gradual reduction in fertility. “Why egg cells lose their development competence is something we don’t fully understand but it’s like to be due to a combination of factors.” says Dr Gavin Kelsey, Head of the Epigenetics research programme at the Babraham Institute, who led this work.
The research used a cutting-edge single-cell technique developed at the Institute to obtain parallel read-outs on all gene expression and DNA methylation (the addition of epigenetic marks that modify DNA without altering its sequence) occurring in the same egg. The approach allowed a genome-wide analysis of each egg and in addition to comparing eggs from younger and older mice it also allowed the researchers to explore variation between eggs from similarly aged mice.
Using this technique the researchers were able to identify the characteristics of eggs with reduced developmental competence and distinguish eggs from older females that retained a young-like profile. In particular, eggs from older females had less active gene expression and showed greater variability in this level egg-to-egg. Epigenetic marks in general correlated between eggs taken from younger and older mice, providing reassurance that age does not affect key sites of DNA methylation in the genome. The researchers did find some genes showing coupled change between gene activity and epigenetic marks, suggesting that epigenetics could be used as a readout for the gene activity quality of the egg.
“As far as we know, this is the first genome-wide assessment of DNA methylation at single-nucleotide resolution in eggs from aged female mice. Our development of methods that capture epigenetic information in single cells has enabled us to examine both the quality of epigenetic marks across the whole genome in single eggs and how individual eggs differ as a function of maternal age.” explains Juan Castillo-Fernandez, a postdoctoral researcher in the Kelsey lab and joint first author on the paper. “We are particularly interested in epigenetic changes as they can be inherited into the embryo and predispose to later-onset problems in otherwise healthy-looking offspring.”
“Our combined method for parallel read-outs from one cell gives a powerful tool, not only for opening up areas of biology to discover new knowledge but also for the application of both knowledge and techniques in the clinic. As demonstrated by this research, single-cell techniques and epigenetic analysis could be used to indicate the quality of an egg in terms of forming a healthy embryo after fertilisation,” concludes Dr Kelsey.
* Birth characteristics in England and Wales: 2018. Office of National Statistics, released 6 December 2019.
** Births in England and Wales: 2019. Office of National Statistics, released 22 July 2020.
Castillo-Fernandez, J. & Herrera-Puerta, E. et al. Increased transcriptome variation and localised DNA methylation changes in oocytes from aged mice revealed by parallel single-cell analysis. Aging Cell
Dr Louisa Wood, Communications Manager, email@example.com
Stylised images of the same mouse oocyte, representing the use of single-cell techniques and parallel methods to deliver related but distinct insights.
Affiliated authors (in author order):
Juan Castillo-Fernande, postdoctoral researcher, Kelsey lab
Erika Herrera-Puerta, visiting PhD student, Kelsey lab
Hannah Demond, postdoctoral researcher, Kelsey lab
Stephen Clark, postdoctoral researcher, Reik lab
Courtney Hanna, research fellow, Kelsey lab
Myriam Hemberger, Cumming Schools of Medicine, University of Calgary, CanadaGavin Kelsey, Head of the Epigenetics research programme
Work in the Kelsey lab is supported by grants from the UK Biotechnology and Biological Sciences Research Council, including strategic funding to the Epigenetics research programme, and Medical Research Council. Erika Herrera-Puerta was supported by the National Researcher Training Program of Colciencias.
News, 7th September 2020 Institute announces new Epigenetics and Signalling research programme leaders
News, 28th January 2019 Kick-starting the genome in early development
News, 1st January 2018 Keeping egg cells fresh with epigenetics
Animal research statement
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here use eggs removed post-mortem from spontaneously ovulating young adult female mice (12 weeks old) and from females nearing their normal reproductive lifespan (44-54 weeks old). Ten mice were used in total. The ability to analyse single cells greatly reduced the number of mice that would otherwise have been needed to obtain these results.
All experimental procedures were performed under licences issued by the Home Office (UK) in accordance with the Animals (Scientific Procedures) Act 1986 and were approved by the Animal Welfare and Ethical Review Board at the Babraham Institute.
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About the Babraham Institute
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular 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. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
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18 November 2020