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Epigenetic regulation of a genetic gatekeeper, Elf5, provides new insights into cell fate at a developmental crossroad

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 is really the first molecular example of an epigenetic restriction of lineage fate. Elf5 really sits at the junction of lineage divergence between the embryonic and trophoblast lineages in early development."

This work 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.

This work was supported by an MRC Career Development fellowship to Dr Hemberger, a Croucher Foundation Fellowship to Dr Ng, by BBSRC, MRC, EU NoE The Epigenome, CellCentric, and DIUS.

Claire Cockcroft | alfa
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