Fetal or placental cells?

Genetic 'signatures' of early-stage embryos confirm development begins as early as the second day after conception, when we are a mere four cells. According to new research, even though appearing to be identical, two day-old embryo cells have subtle — but important differences.

Once an egg is fertilized, it divides several times, becoming a large free-floating ball of stem cells.

At first, these stem cells are 'totipotent', which means they can divide and grow into everything — every single cell of the whole body and placenta to attach the embryo to the mother's womb. The stem cells then change into a 'pluripotent' state, where their development is restricted to becomming the cells of the whole body, but not the placenta.

However, the point when cells begin to become a specific cell type is unclear.

Now, in a study published in the journal Cell, scientists at the University of Cambridge and the European Bioinformatics Institute (EMBL-EBI) suggests that as early as the four-cell embryo stage, cells are indeed different from each other.

Researchers used the latest sequencing technologies on mice to model embryo development. They looked at individual genes at a single cell level — and found some genes in each of the first four cell divisions began to behave differently.

The activity of one gene in particular, Sox21, differed the most between cells. Sox21 gene forms part of the 'pluripotency network'. When this gene's activity is decreased, a master regulator gene that directs cells to develop into the placenta increases.

"We know life starts when a sperm fertilises an egg, but we're interested in when important decisions determining our future development occur," adds Magdalena Zernicka-Goetz PhD, professor in the department of Physiology, Development and Neuroscience at the University of Cambridge.

"We now know that even as early as the four-stage embryo - just two days after fertilisation - the embryo is being guided in a particular direction and its cells are no longer identical. Because of high-resolution techniques, we are now able to see the genetic and epigenetic signatures indicating the direction which early embryo cells will travel."

Dr John Marioni of EMBL-EBI, the Wellcome Trust Sanger Institute and the Cancer Research UK Cambridge Institute.

Abstract Highlights
•Transcription factors display temporally distinct DNA binding in live mouse embryos
•Sox2-DNA binding is heterogeneous between four-cell blastomeres within the embryo
•Histone 3 arginine 26 methylation regulates Sox2-DNA binding
•More Sox2 engaged in long-lived DNA binding predicts inner cell allocation

Summary
Transcription factor (TF) binding to DNA is fundamental for gene regulation. However, it remains unknown how the dynamics of TF-DNA interactions change during cell-fate determination in vivo. Here, we use photo-activatable FCS to quantify TF-DNA binding in single cells of developing mouse embryos. In blastocysts, the TFs Oct4 and Sox2, which control pluripotency, bind DNA more stably in pluripotent than in extraembryonic cells. By contrast, in the four-cell embryo, Sox2 engages in more long-lived interactions than does Oct4. Sox2 long-lived binding varies between blastomeres and is regulated by H3R26 methylation. Live-cell tracking demonstrates that those blastomeres with more long-lived binding contribute more pluripotent progeny, and reducing H3R26 methylation decreases long-lived binding, Sox2 target expression, and pluripotent cell numbers. Therefore, Sox2-DNA binding predicts mammalian cell fate as early as the four-cell stage. More generally, we reveal the dynamic repartitioning of TFs between DNA sites driven by physiological epigenetic changes.

Reference
Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in Four-Cell Mouse Embryos. Cell; 24 March 2016. DOI: 10.1016/j.cell.2016.01.047

The research was funded by the Wellcome Trust, the European Molecular Biology Laboratory and Cancer Research UK.

About the University of Cambridge
The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 90 affiliates of the University have won the Nobel Prize.

Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions.

Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

The University sits at the heart of one of the world's largest technology clusters. The 'Cambridge Phenomenon' has created 1,500 hi-tech companies, 14 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation. www.cam.ac.uk

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Image Credit: Melanie White, Nicolas Plachta,
Institute of Molecular and Cell Biology, Singapore.