The UK’s Biotechnology and Biological Sciences Research Council (BBSRC) has awarded funding to a new project, which aims to improve our understanding of the impact of order and orientation of enhancers in vertebrate gene regulation.
The project brings together experts at the University of Birmingham, EMBL’s European Bioinformatics Institute (EMBL-EBI), the University of Manchester, the Francis Crick Institute, the University of Edinburgh, and Imperial College London.
The team aims to produce detailed single-cell enhancer maps for a few key genomic regions – also called loci – in zebrafish. They will use these maps to build and test novel, synthetic arrangements of these enhancers to understand how the specific layout and organisation of enhancers ensures that the correct genes are used in the right cell at the right time.
Enhancers are short stretches of the genome that control when and where genes are expressed – a process that is essential for specifying the different cell types of an organism and in guiding development from fertilised egg to adult. It’s estimated that the human genome contains hundreds of thousands of enhancers. Researchers have some understanding of what individual enhancers do, but the significance of enhancer order, orientation, and interaction remains a mystery.
“This is science at the forefront,” said Garth Ilsley, Ensembl Regulation Project Leader and project participant. “As a primary research project, this is unlikely to produce immediate health breakthroughs, but the implications could be profound. Because enhancers work in similar ways across vertebrate species, this research will give us important insights into how enhancer arrangements and genetic differences affect our biology and health.”
EMBL-EBI will contribute data management expertise and support to the project. The resulting data will be made freely available through EMBL-EBI data resources, including:
“There is great synergy between this cutting-edge research and the added value of open data resources, which enable scientists to go deeper in exploring and reusing the data this project will generate,” said Ilsley.
“There’s an underlying assumption that the mechanisms we see in zebrafish will be similar in higher-order organisms, including humans,” said Andy Yates, EMBL-EBI Team Leader and project participant. “We already know there are many diseases linked to gene expression, which can cause developmental issues. For example, mutations in the CAMK1D gene, which is associated with insulin signalling, can affect how strongly the gene is expressed in certain tissues, influencing Type 2 Diabetes risk. Understanding enhancers will provide more context for diseases that are incredibly complex.”
“The 3D aspect is very important to this project. It’s easy to consider the genome as linear, but that’s not true, because it bends and twists to such an extent that elements or genes that are far apart, are a lot closer in 3D space,” he added.
“Enhancers sit at the core of gene regulation,” said Eileen Furlong, Head of the Genome Biology Unit at EMBL, who is not involved in this project. “A deeper understanding of the ‘language’ of enhancers could reveal fundamental principles of development and, in time, disease. Therefore, making these enhancer maps freely available is an essential step that will empower scientists everywhere to explore the data and uncover new connections between gene regulation, development, and disease.”
The project is funded by UKRI-BBSRC’s strategic Longer and Larger (sLoLa) grants.
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