A research team led by Jorge Ferrer, principal investigator at the Center for Genomic Regulation (CRG) and CIBERDEM, has discovered that genomic regulation splicing de ARN Affects the risk of diabetes.
There are hundreds of genetic variants that affect a person’s predisposition to type 1 and type 2 diabetes. Individually, each type has a small effect, but collectively they have a large effect on diabetes susceptibility. Disease,
The mechanisms of action of these variants are a mystery because the vast majority are located in genomic regions that do not code for proteins, a vast region that covers 98% of the human genome. A better understanding of how these variants contribute to diabetes risk may help identify genes and develop new treatments that address the mechanisms that cause diabetes, a major public health problem worldwide. Is.
In recent years, non-protein-coding sequences have been shown to be important in how genes are regulated and expressed. It is also known that some variants of d n Factors affecting diabetes risk are influenced by whether the gene is expressed at high or low levels in the insulin-producing beta cells of the islets of the pancreas.
Another mechanism by which non-coding DNA variants may affect disease risk is through effects on splicing del arn, A process that allows cells to make more than one type of RNA molecule from a single gene. When regulation of RNA splicing fails, it gives rise to diseases as diverse as cancer and motor neuron disease.
Given this scenario, the team hypothesized that genetic variants that control splicing del arn May affect the transcription of genes related to the risk of type 1 and type 2 diabetes.
Previous studies have mapped the location of genetic variants that regulate splicing in various human tissues. However, these research efforts fell short of comprehensively analyzing pancreatic islets, specialized cells in the pancreas that contain beta cells that produce and secrete the hormone insulin.
Dr. Ferrer’s Team overcome this obstacle by obtaining RNA sequence data from approximately 400 human donors and genotyping information from pancreatic islets. They used these data to develop the most comprehensive atlas of genetic variants that control RNA splicing in pancreatic islets to date. In parallel, they also analyzed an atlas of genetic variants that affect the expression of genes related to the risk of type 1 and type 2 diabetes.
By analyzing both atlases and how they interact genetic variants, the scientific team discovered the new biological mechanism. For example, previous studies have shown that disruption of the function of ERO1B is Can cause glucose intolerance in mouse models. Using the atlas, the study shows that genetic variation affects gene RNA splicing, with some variants predisposing cells to make a version of the ERO1B protein that is truncated and possibly non-functional.
adding the difference of splicing de ARN Looking at the spectrum of underlying molecular mechanisms underlying type 2 diabetes, the scientific team hopes that the atlas will serve as a useful resource to better understand the complex genetics that underlie the biology of diabetes, all With the goal of developing new treatments.
“Proposed gene targets based on human genetic evidence double the chance of success in drug development pipelines. Our work opens the door to new therapeutic approaches that take advantage of the great impact of division in biology Experts have said that pancreatic islets and diabetes.