Mapping Gene Regulatory Sites to Understand Islet Biology and Diabetes
Scientists have developed a new technique for identifying regions of the genome that influence gene activity and generated insight into how a specific sequence variant can affect risk for type 2 diabetes. Regions of the genome called “open chromatin” contain genes currently being used within a cell, as well as regulatory DNA elements that influence the way cells utilize those genes. Using a new technique, the investigators isolated open chromatin from human pancreatic islet cells, which produce insulin and other important hormones, and created a map of these sites in the genome. They hypothesized that islet-specific open chromatin was likely to contain sequences that influence the activity of islet-specific genes and, therefore, sequences that may be associated with diabetes risk. They found that most islet-specific open chromatin sites were in or near genes with known functions in islets. In addition, they compared previously identified type 2 diabetes-associated DNA sequence variants to their map and discovered that a number of disease-associated variants are linked to islet-specific open chromatin sites.
Notably, a variant in the gene TCF7L2, which has been consistently associated with type 2 diabetes across diverse ethnic groups, was determined to overlap with an islet-specific open chromatin site. Importantly, the disease-associated variation is not within the part of the gene that codes for a protein, so the type 2 diabetes risk associated with TCF7L2 cannot be explained by an alteration in the protein encoded by the gene. The scientists then demonstrated that the risk-associated sequence variant was more likely than the non-risk sequence variant to be found in open chromatin, meaning that people with the risk version may produce more of the protein encoded by TCF7L2. Indeed, they found that the risk-associated variant can affect gene activity. These results suggest that the risk variant may affect activity of TCF7L2 by opening the site to allow more of the protein to be made, and provide a potential mechanism for the type 2 diabetes susceptibility.
The islet-specific map generated in this study provides a new tool for understanding the regulation of genes important for islet cell biology and for narrowing genomic locations likely to harbor unidentified sequence variants that influence type 2 diabetes suceptibility. This study also validates a new technique for identifying regions of the genome that regulate gene activity. The technique provides an additional means to move beyond identification of disease-associated sequence variants to an understanding of their influence on disease risk, particularly for variants that do not affect the code for a protein. Determining the mechanism by which genetic factors contribute to diabetes is key to understanding both type 1 and type 2 diabetes, identifying individuals at risk, developing and testing prevention strategies, and generating more personalized interventions for people with or at risk for disease.
Gaulton KJ, Nammo T, Pasquali L, et al. A map of open chromatin in human pancreatic islets. Nat Gen 42: 255-259, 2010.