Researchers have developed a 3D map of the gene interactions that play a key role in cardiovascular disease, a study in eLife reports.
The map will help researchers identify the most important genes to focus on for the development of new treatments for heart attacks, heart failure and heart rhythm disorders.
More than 500 genetic variants have been linked with increased risk of cardiovascular disease. But most are located in so-called ‘non-coding’ parts of the genome, which means they don’t code for a particular protein molecule. This makes it challenging for researchers to understand the importance of these genetic variants because, until now, there has been no way to study their function.
“The strongest genetic signatures associated with complex human diseases, including many cardiovascular diseases, are actually located outside of genes, scattered throughout the vast 98% of the genome that is ‘non-coding,’” explains lead author Lindsey Montefiori, Graduate Student at the University of Chicago, US. “What we think is happening is that these mutations affect the function of the ‘switches’ of genes, called enhancers, which determine where, when and to what level each gene should be turned on.”
These enhancers can be located anywhere in the genome and are often a considerable distance from the genes they control. But because DNA forms loops inside cells, the enhancers can physically connect with the genes they control and fine-tune their activity.
It has recently become possible to map these enhancers to their target genes using a technique called high-resolution promoter capture, which uses the enhancer region as ‘bait’ to catch its target gene. The team added an extra step to this, so that they only ‘captured’ a region of the genome that contains coding genes. This enabled them to map each mutation to its target gene in human heart cells and examine the precise wiring of all the potential enhancers controlling each gene.
They looked at more than 10,000 genetic mutations that have been linked to cardiovascular diseases and found that 1,999 of them make physical contact with 347 target genes in heart cells. When they studied the genes further, they found that these were well known for their roles in cardiac function.
Because the three diseases analysed involve different processes, the team next studied the interactions between enhancers with genes in other cell types which may be involved in cardiovascular disease. Here they found that mutations linked to heart attacks captured a target gene involved in cholesterol regulation, and mutations in heart failure pulled out a gene known to be important in coronary artery disease.
“Incomplete understanding of long-range gene regulation is a major roadblock in translating genetic variants into understanding of disease biology,” says senior author Marcelo Nóbrega, Professor of Human Genetics at the University of Chicago. “Our 3D map of enhancer–gene interactions in human heart cells will help guide investigators to the most likely causal genes underlying increased cardiovascular disease risk, and could lead to new treatment and prevention strategies.”
eLife aims to help scientists accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours in science. We publish important research in all areas of the life and biomedical sciences, which is selected and evaluated by working scientists and made freely available online without delay. eLife also invests in innovation through open source tool development to accelerate research communication and discovery. Our work is guided by the communities we serve. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, the Wellcome Trust and the Knut and Alice Wallenberg Foundation. Learn more at https://elifesciences.org/about.
About the University of Chicago Medicine & Biological Sciences
The University of Chicago Medicine & Biological Sciences is one of the nation's leading academic medical institutions. It comprises the Pritzker School of Medicine; the University of Chicago Biological Sciences Division; and the University of Chicago Medical Center. Twelve Nobel Prize winners in physiology or medicine have been affiliated with the University of Chicago Medicine. Learn more at uchicagomedicine.org.