Anatomy of a decision: mapping early development

A new atlas of gene expression during the earliest stages of life boosts studies of development

In the first genome-scale experiment of its kind, researchers have gained new insights into how a mouse embryo first begins to transform from a ball of unfocussed cells into a small, structured entity. Published on 6 July in Nature, the single-cell genomics study was led by the European Bioinformatics Institute (EMBL-EBI) and the Wellcome Trust–MRC Cambridge Stem Cell Institute.

Gastrulation is the point when an animal’s whole body plan is set, just before individual organs start to develop. Understanding this point in very early development is vital to understanding how animals develop and how things go wrong. One of the biggest challenges in studying gastrulation is the very small number of cells that make up an embryo at this stage.

“If we want to better understand the natural world around us, one of the fundamental questions is, how do animals develop? How do you turn from an egg into an animal, with all sorts of tissues? Many of the things that go wrong, like birth defects, are caused by problems in early development. We need to have an atlas of normal development for comparison when things go wrong.”

Bertie Gottgens Research Group Leader at the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute

Today, thanks to advances in single-cell sequencing, the team was able to analyse over 1000 individual cells of gastrulating mouse embryos. The result is an atlas of gene expression during very early, healthy mammalian development.

“Single-cell technologies are a major change over what we’ve used before – we can now make direct observations to see what’s going on during the earliest stages of development. We can look at individual cells and see the whole set of genes that are active at stages of development, which until now have been very difficult to access. Once we have that, we can take cells from embryos in which some genetic factors are not working properly at a specific developmental stage, and map them to the healthy atlas to better understand what might be happening.”

John Marioni Research Group Leader at EMBL-EBI, University of Cambridge and Associate Faculty at the Wellcome Trust Sanger Institute

To illustrate the usefulness of the atlas, the team studied what happened when a genetic factor essential for the formation of blood cells was removed.

“It wasn’t what we expected at all. We found that cells which in healthy embryos would commit to becoming blood cells would actually become confused in the embryos lacking the key gene, effectively getting stuck. What is so exciting about this is that it demonstrates how we can now look at the very small number of cells that are actually making the decision at the precise time point when the decision is being made. It gives us a completely different perspective on development.”

John Marioni Research Group Leader at EMBL-EBI, University of Cambridge and Associate Faculty at the Wellcome Trust Sanger Institute

“What is really exciting for me is that we can look at things that we know are important but were never able to see before – perhaps like people felt when they got hold of a microscope for the first time, suddenly seeing worlds they’d never thought of. This is just the beginning of how single cell genomics will transform our understanding of early development.”

Bertie Gottgens Research Group Leader at the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute

The study was made possible by a Wellcome Trust Strategic Award to study Gastrulation and by the Sanger Institute/EBI Single Cell Genomics Centre.

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Notes to Editor

Notes to Editors

This work was funded as part of Wellcome Trust Strategic Award ‘Tracing early mammalian lineage decisions by single-cell genomics’ awarded to W. Reik, S. Teichmann, J. Nichols, B. Simons, T. Voet, S. Srinivas, L. Vallier, B. Göttgens and J. Marioni. The work also built on a previous LoLa grant by the BBSRC (Establishment of the haematopoietic transcriptional programme: from systems approaches to molecular mechanisms), and benefited from MRC Clinical Research Infrastructure Investment to establish a single cell genomics facility at the Cambridge Biomedical Research Campus.

Data

RNAseq data are available in Array Express under accession numbers E-MTAB-4079 and E-MTAB-4026. Processed RNAseq data are also available at http://gastrulation.stemcells.cam.ac.uk/scialdone2016.

Publications:

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Selected websites

  • EMBL-EBI

    At the European Bioinformatics Institute (EMBL-EBI), we help scientists realise the potential of ‘big data’ in biology by exploiting complex information to make discoveries that benefit mankind. We manage the world’s public biological data and make it freely available to the scientific community via a range of services and tools, perform basic research and provide professional training in bioinformatics. We are part of EMBL and situated on the Wellcome Genome Campus in Hinxton, UK, one of the world’s largest concentrations of scientific and technical expertise in genomics.

  • EMBL

    EMBL is Europe’s flagship laboratory for the life sciences. We are an intergovernmental organisation established in 1974 and are supported by over 20 member states. EMBL performs fundamental research in molecular biology, studying the story of life. We offer services to the scientific community; train the next generation of scientists and strive to integrate the life sciences across Europe. We are international, innovative and interdisciplinary. We are more than 1600 people, from over 80 countries, operating across five sites in Grenoble (France), Hamburg (Germany), Heidelberg (Germany), Hinxton (UK) and Monterotondo (Italy). Our scientists work in independent groups and conduct research and offer services in all areas of molecular biology. Our research drives the development of new technology and methods in the life sciences. We work to transfer this knowledge for the benefit of society.

  • The Cambridge Stem Cell Institute

    The Cambridge Stem Cell Institute (CSCI) is a world-leading centre for stem cell research. Its mission is to transform the prevention, diagnosis and treatment of disease through a deep understanding of the mechanisms regulating stem and progenitor cells, both normal and pathological. A key strategy is to embed biological, clinical and physical scientists operating across disparate tissues and at multiple scales, thus allowing commonalities and differences to be explored in a cohesive and inter-disciplinary manner. The presence of a critical mass of clinician scientists creates synergistic interactions between basic scientists and those driven by disease-focused questions, and a network of affiliated PIs provides bridges to basic and disease-focused institutes throughout Cambridge, thus ensuring that CSCI represents the heart of a vibrant stem cell community.

  • Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.