Highlight Publication September 2008

Ray Kit Ng, Wendy Dean, Claire Dawson, Diana Lucifero, Zofia Madeja, Wolf Reik & Myriam Hemberger (2008)
Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5
Nature Cell Biology Published online: 5 October 2008
http://dx.doi.org/10.1038/ncb1786

For further information, please click here to refer to the press release relating to these findings
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Lay description

Cell differentiation is usually a one way process, starting from a precursor cell that initially has the potential to follow various differentiation pathways, getting increasingly specialised in function until its ‘cell fate’ is realised and it becomes ‘terminally differentiated’ into a particular cell type, such as a nerve or muscle cell. The fertilised embryo possesses the greatest plasticity: it has the potential to make all the cell types of the adult as well as the nutrient supplying organ, the placenta. The first definitive divergence in differentiation pathways occurs early on in development at the point where cells that will form the placenta are set aside from those that will form the foetus. Ordinarily, once this decision has been made, there is no turning back or crossover between future placental and embryonic cells.

How this strict lineage separation is achieved, however, has remained elusive. Since all cells contain the same genetic material, it must be regulated by marks that are imposed onto the genomic sequence – so-called ‘epigenetic marks’ –that are able to impose, and lock in, future cell fate in both populations.

This article, to be published in the November issue of Nature Cell Biology, reports the identification of such an epigenetic restriction of cell lineage fate and of a particular gene important to keep placental and embryonic cells apart. This gene, Elf5, is modified by DNA methylation marks in cells destined to give rise to the embryo, and it is this modification that keeps the gene in a stable ‘off’ state. In future placental cells, by contrast, the sequence is not modified, the gene is kept ‘on’ and this is turn reinforces placental cell fate. By removing the DNA methylation mark in embryonic cells, we could convert them into cells with placental cell characteristics.

This work furthers our understanding of how cell fate is normally locked in to achieve stable differentiation. This is of particular importance for strategies in regenerative medicine that aim to generate a specific cell type from multi- or pluripotent stem cells and to prevent its de-differentiation, a process often associated to tumour formation. Ultimately, these results may supply critical understanding of the potential for differentiated cells to be specifically instructed to generate other essential cell types. This knowledge will open up new possibilities into research of pregnancy complications that have a specific placental origin.

The work was supported by an MRC Career Development Award to Dr Myriam Hemberger, a career-track Group Leader at the Institute, and by the recently established Centre for Trophoblast Research in Cambridge. http://www.trophoblast.cam.ac.uk/

About the lead author

Ray Ng did his undergraduate and masters degree in Biochemistry at the Chinese University of Hong Kong from 1997 to 2002. He was then offered a scholarship by the University of Cambridge and pursued his PhD degree under the supervision of Prof. John Gurdon, at the Wellcome Trust/Cancer Research UK Gurdon Institute. His PhD work was focused on epigenetic memory of nuclear transplanted Xenopus embryos. He stayed in Prof. Gurdon’s lab for one additional year and then joined Wolf Reik’s group in the Babraham Institute as a post-doc working jointly with Myriam Hemberger and colleagues on the epigenetic regulation of the first cell lineage differentiation event in early mouse embryo. Ray has recently moved to start his own research group in the Department of Pathology, University of Hong Kong, where he will continue to work on the epigenetic regulation of early cell lineage decisions and on the epigenetics of haematopoiesis and leukaemogenesis.