Epigenetic regulation of a genetic gatekeeper, Elf5, provides new insights into cell fate decisions during early development

6th October 2008

Scientists at the Babraham Institute and the Centre for Trophoblast Research in Cambridge have established that a gene, known as Elf5, plays a critical role in early development using elegant epigenetic mechanisms to keep placental and embryonic cells apart. The findings, reported in November’s Nature Cell Biology, provide new insights into the developmental decisions that are made after fertilisation, to ensure that cells either become committed to forming the placenta or the embryo. Epigenetic control mechanisms are at the heart of this, orchestrating the formation of many different tissues and organs from a fertilised egg, and ensuring that once certain developmental decisions are made, cell fate is normally irreversible. The discovery of the ability to reverse cell fate through epigenetic regulation of Elf5 offers new insights into regenerative medicine and stem cell therapy.

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 a particular cell type, such as a nerve or muscle cell, a process called terminal differentiation.

The fertilised embryo possesses the greatest plasticity; it is totipotent and can differentiate into all cell types of the foetus as well as the placenta. One of the first definitive divergences in cell differentiation pathways is the point where cells that will form the placenta are set aside from those that will form the foetus. Once this decision has been made, it was thought that 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 in an individual contain the same genetic material, but behave differently depending on which organs eventually comprise, an elaborate mechanism has evolved to fine tune our genes and their expression in different places at different times, leading to the amazing complexity we see in humans despite the relatively small number of unique genes. This process involves specific chemical modifications to the DNA, such as methylation, which modify the structure of the DNA but not its sequence, and regulate gene function. A failure of these epigenetic control mechanisms is linked to a number of human genetic diseases, psychiatric disorders and ageing as well as contributing to some pregnancy complications such as pre-eclampsia. Babraham scientists recently reported that these epigenetic mechanisms can be traced to the divergence of placental mammals and marsupials from the curious egg-laying monotremes, notably the platypus, 150 million years ago.  

These ‘epigenetic marks’ are able to impose, and lock in, future cell fate in either placental cell populations or those that embark upon embryonic development. This paper reports on the identification of such an epigenetic restriction of cell lineage fate, directed on a particular gene to keep placental and embryonic cells apart. Elf5 has been identified as the key gene determining cell fate at the gateway of placental versus embryo development.

“The DNA sequence of the gene Elf5 is modified by a methylation mark in future populations of embryonic cells ensuring that the gene is kept in a stable ‘off’ state. In contrast the sequence is not modified in placental cells; the gene is ‘on’ and reinforces placental cell fate. We demonstrated that by removing the methylation mark in embryonic cells, we could convert these normally committed embryonic cells into cells with placental characteristics”, said Dr Myriam Hemberger.

This work, supported by an MRC Career Development fellowship to Dr Hemberger, has provided new insights into the apparent irreversibility of cell fate and 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 that bears the risk of tumour formation. Ultimately, these results may pave the way for differentiated cells to be specifically instructed to generate other essential cell types for therapeutic use. This knowledge will open up new possibilities into research of pregnancy complications that have a specific placental origin.

Contact details:

Dr Claire Cockcroft   
Head, External Relations
The Babraham Institute
Babraham Research Campus
Cambridge, CB22 3AT
United Kingdom

Email:   Contact by email
Tel:       +44 (0)1223 496260
Fax:      +44 (0)1223 496002
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http://www.babraham.ac.uk

Dr Myriam Hemberger
Tel:       +44 (0)1223 496000
Email:   Contact by email
www.babraham.ac.uk/devgen/hemberger.html

Publication details

Advanced Online Publication in Nature Cell Biology, Sunday 5th October 13:00 (EST) 18:00 (UK time)
The DOI is 10.1038/ncb1786. Once the paper is published electronically, the DOI can be used to retrieve the abstract and full text (abstracts are available to everyone, full text only to subscribers) by using the following URL: http://dx.doi.org10.1038/ncb1786/  

The Babraham Institute is a charitable organisation devoted to biomedical research and is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC). The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and on how their failure or abnormality may lead to disease. As such, Institute scientists are striving to find cures for conditions where there is currently no treatment or where the existing treatment is not fully effective or causes serious side effects. The latest technologies are being used to study the basis of conditions such as neurodegenerative disorders, birth defects, cancer and diseases of the immune and cardiovascular systems. With a strategic focus on ‘healthy ageing’, novel approaches for tackling chronic diseases and public health concerns like obesity are being discovered. The Institute’s innovative research is commercialised through Babraham Bioscience Technologies (BBT) Ltd, which also manages Babraham’s vibrant Bioincubator on the Babraham Research Campus, six miles south-east of Cambridge.  Website: www.babraham.ac.uk

The Centre for Trophoblast Research is an exciting new inter-departmental initiative that aims to promote the study of placental biology, with special reference to the trophoblast, both within and outside Cambridge. The centre, which draws together researchers from Babraham, The Department of Physiology, Development and Neuroscience, The Gurdon Institute and Addenbrookes Hospital, was officially launched in July 2008 and aims to facilitate interactions and collaborations between established researchers, both nationally and internationally. The Centre aims to promote research and teaching in placental biology and the developmental origins of the trophoblast within the University of Cambridge and affiliated institutes through Next Generation Research Fellowships, Graduate Studentships, seminars, workshops, and infrastructural support. One of the Centre’s principal aims, however, is to encourage young investigators into the field and foster their careers.  www.trophoblast.cam.ac.uk/

Epigenetics notes:

We all get two copies of every gene, one from our mother and one from our father. In many cases both copies are used or ‘expressed’, however it is becoming clear that for some genes either the mother’s or the father’s version is used preferentially, a phenomenon known as genomic imprinting. Specific chemical modifications to the DNA, such as methylation, appear to give the chromosomes a "memory" as to their parental origin. These ‘epigenetic’ imprints, from the Greek meaning ‘on top of’, modify the structure of the DNA but not its sequence. In addition to parental modifications, it is thought that epigenetic changes may also arise in response to environmental factors, enabling an organism's genes to adapt and respond differently, even though the gene sequence does not change.