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Diabetes-causing gene can be regulated like a rheostat: Studying noncoding RNAs opens new avenues to understand human disease

Researchers at the Centre for Genomic Regulation (CRG) and Imperial College London have found a switch that regulates the activity of a gene that causes diabetes. The findings, published in Nature Cell Biology, highlights potential new vulnerabilities in the disease and could lead to the development of new therapeutic strategies.

HNF1A is a gene that provides instructions for making a protein called hepatocyte nuclear factor-1 alpha. The protein is expressed in many tissues but is particularly important for the pancreas, where it plays a role in developing beta cells. Beta cells produce the hormone insulin, which regulate blood sugar levels.

Mutations in HNF1A cause cells to create a protein that doesn’t work normally, which in turn affects the function of beta cells. This results in individuals developing a disease known as maturity-onset diabetes of the young, where symptoms such as high blood sugar can appear before individuals reach the age of 30.

Though this disease accounts for just 1% of all types of diabetes, it is high in terms of absolute numbers due to the high prevalence of diabetes amongst the worldwide population (5-10%). HNF1A is also known to play a key role in the susceptibility for the more common form of the disease, type 2 diabetes, in concert with other genetic and non-genetic factors.

Understanding how the HNF1A gene is switched on or off in beta cells could have important implications for understanding why defects in this gene lead to diabetes, or how it could be harnessed to correct the underlying problem. Using a combination of mouse and human models, researchers have now focused on an enigmatic part of the genome near HNF1A that has a unique function that has not been described before. This DNA regulatory element works like as rheostat; if the HNF1A gene transcribes too much it dials it down, if the gene is slacking it dials it back up.

“We coined this a stabilizer, in contrast to other DNA regulatory elements such as enhancers, promoters and silencers, and call this particular element HASTER, for HNF1A stabilizer,” explains Jorge Ferrer, Senior Researcher at the CRG and Group Leader at CIBERDEM.

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