Gene expression: a snapshot of stem cell development
The power of single-cell genomics is demonstrated in new research from the Wellcome Genome Campus, revealing how it could help scientists understand early development of cells. The study found new genes involved in stem cell regulatory networks and new subpopulations of cells, giving insights into stem cell pluripotency – the ability to develop into almost all different types of cell. The researchers also developed new resources for the stem-cell community, which will help interpret future investigations.
Stem cells exist in a ‘ground’ state before something triggers them to develop into functional cells such as liver, heart or blood cells. What sparks that change has a lot to do with how, when and in what order the genes inside that cell are expressed, or turned on and off. Characterising the gene expression at play in stem cells is essential to understanding the fundamental biology of health and disease. It can also help in detecting genetic factors that figure into a person’s response to a medicine.
Researchers at the Wellcome Trust Sanger Institute and European Bioinformatics Institute (EMBL-EBI) used single-cell RNA sequencing technology to study the expression of thousands of genes in around 700 mouse Embryonic Stem Cells (mESCs), and found there is a signature ‘gene expression mix’ that characterises different cell populations. They also found this mix determines the length of the cell cycle. In other words, heterogeneity in gene expression across cells underpins cellular behaviour.
“You can take a kind of snapshot of this very dynamic process of gene expression, and infer a lot of information from it. It’s a bit like taking a picture of a crowd in Times Square at New Year’s Eve from above, and ordering all of the individuals by age to get a sense of their life cycle, or grouping them by clothing style to infer which party they will go onto next.”
Dr Ola Kolodziejczyk A first author from the Sanger Institute and EMBL-EBI
Single-cell RNA sequencing helps researchers see what makes all the cells in our bodies take on different shapes, predict what they might do and explore the many elements that contribute to their fates. In this study, the team developed novel approaches to characterise how gene expression levels vary, stem cell by stem cell, in three different states.
“One really exciting thing was that we identified new genes involved in the stem-cell regulatory network, and validated our findings using the CRISPR technology. That brings us closer to inferring how the whole network is put together – and that in turn can give us insights into what keeps stem cells in a ground state and what triggers them to change.”
Dr Jong Kyoung Kim of EMBL-EBI
By dissecting the noisy mix of gene expression cell by cell The researchers uncovered a rare subpopulation of cells that express a couple of marker genes also expressed by cells at the two-cell stage of the embryo, which are able to develop into any cell type (‘totipotent’). While the rare mESCs identified in this study only share some molecular features of the two-cell system, they will provide valuable resources to the study of early development.
“Our study really shows the power of single-cell transcriptomics, how it can reveal biologically relevant heterogeneity in expression that is often masked by traditional methods. It adds a whole new dimension to how we find relationships between cultured cells and natural development, which is making a big difference in genomics research.”
Dr Sarah Teichmann, a senior author and group leader at both the Sanger Institute and EMBL-EBI
More information
Funding
This work was supported by the Wellcome Trust and the Biotechnology and Biological Sciences Research Council.
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EMBL-EBI
The European Bioinformatics Institute is part of EMBL, and is a global leader in the storage, analysis and dissemination of large biological datasets. EMBL-EBI helps scientists realise the potential of ‘big data’ in biology by enhancing their ability to exploit complex information to make discoveries that benefit mankind. We are a non-profit, intergovernmental organisation funded by EMBL’s 21 member states and two associate member states. Our 570 staff hail from 57 countries, and we welcome a regular stream of visiting scientists throughout the year. We are located on the Wellcome Genome Campus in Hinxton, Cambridge in the United Kingdom.
The Wellcome Genome Campus
The Wellcome Genome Campus is home to some of the world’s most advanced institutes working at the interface of genomics and computational biology. The campus brings together a diverse and exceptional scientific community in a culture and environment that fosters creativity and rewards bold, ambitious thinking. They are committed to delivering life-changing science with the reach, scale and imagination to deliver solutions to some of humanity’s greatest challenges.
The 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.
The Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.
