Friday, January 27, 2023

Spanish scientists have found that genomic regulation affects the risk of developing diabetes – Formato Site

A research team led by Georg Ferrer, principal investigator at the Center for Genomic Regulation (CRG) and CIBERDEM, has found that genomic regulation of RNA splicing affects the risk of developing diabetes.

There are hundreds of genetic variants that affect a person’s predisposition to type 1 and type 2 diabetes. Individually, each variant has a small effect, but collectively they have a large effect on disease susceptibility.

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. Some DNA variants that affect diabetes risk are also known to affect whether a gene is expressed at high or low levels in the insulin-producing beta cells of pancreatic islets.

Another mechanism by which noncoding DNA variants may affect disease risk is through effects on RNA splicing, 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 controlling RNA splicing may affect the transcription of genes related to type 1 and type 2 diabetes risk.

Previous studies have mapped the location of genetic variants that control 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 overcame this hurdle by obtaining RNA sequence data and genotype information from pancreatic islets from approximately 400 human donors. 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 how both atlases and genetic variants interact, the scientific team discovered new biological mechanisms. For example, previous studies have shown that disruption of ERO1B gene function can lead to 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.

The scientific team hopes that by adding RNA splicing variation to the spectrum of molecular mechanisms underlying type 2 diabetes, the atlas will serve as a useful resource to better understand the complex genetics underlying the biology of diabetes. All with the aim 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 effect of pancreatic islet biology and fractionation on diabetes,” the experts said. Said.

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