DNA represents a dynamic form of information, balancing efficient storage and access requirements. Packaging approximately 1.8m of DNA into something as small as a cell nucleus is no mean feat, but unpacking it again to access the required sections and genes? That requires organisation.
In a nutshell, this is achieved through DNA condensed and packaged as chromatin, a complex of DNA and proteins called histones, which is constantly modified as the DNA is accessed. The histone proteins need constant replacement to maintain the correct chromatin structure required for all DNA related processes in the cell.
To understand more about the importance of histone replacement, researchers at the Babraham Institute and MRC Clinical Sciences Centre used developing mouse egg cells, oocytes. Developing oocytes provide a system where the mechanics of how DNA is packaged into cells can be explored in the absence of DNA replication, as egg cells do not divide. However, their genomes are highly active as the development of the egg involves widespread turning on and off of genes and DNA modification before the mature egg cell is ready for fertilisation. The work, published in the latest issue of Molecular Cell, relied on the Institute's expertise in single cell analysis, allowing accurate mapping of the epigenetic landscape in precious cells.
The researchers deleted a histone chaperone protein - one of a group of proteins that are responsible for replacing histones in the chromatin structure - and analysed the effects on egg cell development, DNA integrity and accumulation of DNA methylation.
"Oocytes lacking the Hira histone chaperone showed severe developmental defects which often led to cell death." said Dr Gavin Kelsey, research group leader in the Institute's Epigenetics programme and author on the paper. "The whole system is disrupted, eggs accumulate DNA damage and the altered chromatin means that genes cannot be efficiently silenced or activated. But we also uncovered an intricate relationship between the different epigenetic systems operating in the oocyte, where failure to ensure normal histone levels severely compromised deposition of methylation on the underlying DNA."
The research addresses the importance of histone turnover in maintaining genomic fidelity and adds to our understanding about the mechanisms in place to protect the integrity of the genome as it is remodelled and reshaped. Studying this in the context of the developing oocytes provides new insights into our dynamic genome, unclouded by the complications of DNA replication, and also reveals how important maintaining chromatin dynamics is to the integrity of our gametes.
This work was supported by funding from the Biotechnology and Biological Research Council and Medical Research Council (MRC) to Gavin Kelsey at the Babraham Institute and the MRC and FP7 EpiGeneSys network to Petra Hajkova at the MRC Clinical Sciences Centre.
A schematic illustration of developmental stages during oogenesis. Nashun et al. Molecular Cell 2015. Figure adapted from (De La Fuente, 2006; Lan et al., 2004; Li and Albertini, 2013; Tomizawa et al., 2012).
Sebastien Smallwood, postdoc researcher (Kelsey lab)
Stephen Clark, postdoc researcher (Reik lab)
Gavin Kelsey, Research group leader, Epigenetics Programme
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The collaborative research presented here involved the use of mice. All animal experiments were carried out under a UK Home Office Project licence in a Home-Office designated facility. Detailed information is available in the publication’s Supplementary Experimental Procedures.
This work is a particular example of how the Institute works towards the 3R principles of Replacement, Reduction and Refinement. Using single cell profiling allowed the collection of data from a cell type (egg cells) that couldn’t be analysed by other means due to the number of cells, and hence animals, that would be required.
Please follow the link for further details of our animal research, how we use alternatives whenever possible and our animal welfare practices.
Nashun et al. (2015) Continuous histone replacement by Hira is essential for normal transcriptional regulation and efficient de novo DNA methylation during mouse oogenesis. Molecular Cell
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