Antwerp, 11 february 2025 – Certain genetic variants can affect gene activity. Curiously, they don’t need to be located within the gene to do this. A new collaborative study by researchers at the Computational Neurobiology lab at the VIB-UAntwerp VIB-UAntwerp Center for Molecular Neurology, MRC Biostatistics Unit at the University of Cambridge and the Functional Gene Control group at MRC Laboratory of Medical Sciences has shed light on how these variants regulate the genes over distance. The study appears in Nature Communications.
Promote and enhance
DNA regions called enhancers help boost the activity of specific genes. Other DNA regions, promotors, are necessary for starting the gene’s expression. Whilst promoters are located near the “start site” of the gene, where the process of making proteins begins, enhancers can be far away in the genome, with some located as far as 1 million bases away from the promoter. The question of how an enhancer passes its activating signal to the gene promoter is a hot topic in genomic research. The answer seems to lie partially in the three-dimensional structure of the genome.
“We know that DNA loops between enhancers and promoters can enable them to communicate in the genome, which is crucial for gene regulation,” said Prof. Valeriya Malysheva (VIB-UAntwerp). “Studying the effect of genetic variation on these three-dimensional loops will not only advance our knowledge of gene regulation but also help us to understand potential pathways through which genetic variants within enhancers can influence disease risk. “
Activity, contact, and expression
The researchers focused on common genetic variants within enhancers that were known to affect the expression of distant genes. They hypothesized that these regulatory variants might modify 1) how strongly the enhancers looped to gene promoters, 2) how “active” the enhancers were, and hence how much of the activating signal could be passed to the gene promoter, or 3) both looping and activity of enhancers. Through a series of experiments in blood cells from 34 human donors, they found that many of the genetic variants were associated with both of the studied properties. This means that the communication and activation of enhancers might be inherently coupled.
Through statistical and computational analyses and genome modification experiments in human cells, the authors went on to identify causal mechanistic pathways between enhancer activation, communication, and gene expression, governed by the DNA code.
Implications for human health
“Several of the causal relationships that we studied,” says Dr. Helen Ray-Jones (VIB-UAntwerp), first author of the study, “involved genetic variants associated with human health and disease. Determining the ways in which these variants affect gene regulation helps us to explain why some individuals are more likely to develop certain health conditions.”
Overall, this work provides valuable insights into the intricate ways that our genes are regulated in three dimensions and brings deeper understanding of how genetics influences health and disease.
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The raw data generated in this study has been made available to the scientific community through the European Genome-Phenome Archive (EGA) and the Open Science Framework (OSF), promoting transparency and collaboration in ongoing research efforts.
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Publication
Genetic coupling of enhancer activity and connectivity in gene expression control. Ray-Jones et al. Nature Communications, 2025.
Funding
This work was supported by the Medical Research Council (MRC), the British Heart Foundation, the BHF Cambridge Centre for Research Excellence, the NIHR Exeter Biomedical Research Centre, the Wellcome Trust (WT220788), the Alan Turing Institute, and the Marmaduke Sheild Fund.