Noise helps cells make decisions

Random differences between cells early in development could be the key to making different cells in the body, according to new research from a team co-led by Professor Wolf Reik. Different cell types – brain, blood, skin, gut etc. – all have unique and vital roles, yet they all start out the same. Cells become different as a result of a long sequence of biochemical choices made before we’re born. For us to be healthy, these choices need to ensure we get the right number of each cell type.

Scientists at the Babraham Institute, EMBL-EBI and the Wellcome Trust-Medical Research Council Stem Cell Institute examined the genetics of stem cells from embryos at the earliest stages of development. Typically, cells of the same type have matching patterns of gene activity – many of the same genes are turned off or on in all cells. This latest research, published in the journal Cell Reports reveals that when cells start specialising into different cell types their gene activity becomes more ‘noisy’ – each cell starts to turn different groups of genes on or off.

The results, which focus on two choices near the start of embryo formation, show that, when cells are making decisions about what to become, there is greater variation in the activity of the genes in different cells – the same genes may be turned on in some cells and off in others. By chance this noise will make some cells more likely to become one type of cell, whilst others will start to favour an alternative.

The paper’s co-first authors were Hisham Mohammed, Irene Hernando-Herraez and Aurora Savino. Dr Mohammed at the Babraham Institute, said: “Our analyses suggest that elevated transcriptional noise at two key points in early development coincides with cell fate decisions. By contrast, after these decisions cells become highly synchronised and grow rapidly. Our study systematically charts transcriptional noise and uncovers new processes associated with early lineage decisions.”

This process of making similar cells become different is called symmetry breaking. This study marks the first time that a technique called single-cell sequencing has been used to examine individual cells from mouse embryos in the early stages of development. Previous research has only examined groups of cells, so it has been impossible to investigate the differences between cells during symmetry breaking.

Co-senior author Professor Jennifer Nichols at the Wellcome Trust-Medical Research Council Stem Cell Institute, said: “Our data allow us to study gene activity in individual cells to an unprecedented level of precision. This detail has allowed us to observe substantial differences between cells. Regulating noisy gene activity during development may be a key part of how cells make decisions about their future. In the future we hope to discover how this process is controlled to better understand how noise shapes early development.”

As the lead computational scientist on the paper, Dr John Marioni at EMBL-EBI, said: "Making sense of the data generated in studies like this is only possible thanks to ongoing advances in computational biology. With more than 10,000 pieces of data being collected about each individual cell, modern computers are essential in achieving the level of sensitivity needed for this type of research.”

Notes to Editors:

Publication Reference
Mohammed H, Hernando-Herraez I, Savino A, Scialdone A, Macaulay I, Mulas C, Chandra T, Voet T, Dean W, Nichols W, Marioni J, Reik W (2017) A single cell landscape of transcriptome heterogeneity and cell fate decisions during mouse early gastrulation. Cell Reports. http://dx.doi.org/10.1016/j.celrep.2017.07.009

Research Funding
This project was primarily supported by a Wellcome Trust Strategic Award to W. Reik, S. Teichmann, J. Nichols, B. Simons, T. Voet, S. Srinivas, L. Vallier, B. Göttgens and J. Marioni with additional funding from the BBSRC, Wellcome Trust and KU Leuven.

The Wellcome Trust Strategic Award led by Professor Wolf Reik is a multidisciplinary scheme spanning experts in embryology and theoretical physics based mainly in Cambridge and Oxford. The goal is to combine skills and techniques to systematicall study how individual cells change during embryonic development to produce all of the different cells needed in the body. Ultimately the team hope to produce a comprehensive map of early embryonic development.

Press Contact
Dr Jonathan Lawson, Babraham Institute Communications Manager jonathan.lawson@babraham.ac.uk

Image Credit
Image, an artistic interpretation of a mammalian embryo, acquired from ShutterStock.

Affiliated Authors (in author order):
Hisham Mohammed, Epigenetics Programme, Babraham Institute
Irene Hernando-Herraez, Epigenetics Programme, Babraham Institute
Aurora Savino, Epigenetics Programme, Babraham Institute
Tamir Chandra, Epigenetics Programme, Babraham Institute
Wendy Dean, Epigenetics Programme, Babraham Institute
Wolf Reik, Group Leader, Epigenetics Programme, Babraham Institute

Animal Statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. Animals are only used in Babraham Institute research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the Babraham Research Campus for research purposes.

The use of animals in this study was approved by the Babraham Institute Animal Welfare and Ethical Review Body, and carried out in accordance with the Animals (Scientific Procedures) Act 1986, under a UK Home Office project licence. The study used stem cells collected from mouse embryos of the C57 black 6 strain housed at the Babraham Institute Biological Support Unit.

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About the Babraham Institute:
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing.