tRNA hypomethylation and fragmentation in pancreatic β-cells – a novel mechanism of diabetes development

We currently do not fully understand what causes certain types of diabetes. This project’s goal is to gain insight into the development of monogenic diabetes, which is caused by mutations in a specific gene, and of type 1 diabetes (which is polygenic).

Earlier research carried out by the laboratory has revealed new biological mechanisms that result in the death or dysfunction of pancreatic β-cells. This project intends to keep exploring these avenues, confirm previous hypotheses, and ultimately suggest new therapeutic approaches for diabetes.

Researchers will thus study the TRMT10A enzyme. They have already shown that mutations of this enzyme trigger early-onset diabetes and microcephaly, and that a deficit of TRT10A causes the death of insulin-producing pancreatic β-cells.
They have also shown that lack of TRMT10A causes a fragmentation of certain cytosolic tRNAs, and that this fragmentation may result in the death of β-cells in cases of diabetes. Lastly, recent data suggest that TRMT10A deficiency may also be associated with type 1 diabetes. This finding has uncovered an entirely new mechanism by which β-cells disappear, which is relevant not only to monogenic diabetes, but also polygenic diabetes.

The researchers now intend, firstly, to understand the molecular mechanisms involved in the biogenesis of tRNA fragments in pancreatic β-cells, as well as their mechanism of action and how they are involved in the function and survival of β-cells. Secondly, they will determine whether environmental factors associated with type 1 diabetes modulate the expression of TRMT10A and the fragmentation of tRNA, and study their involvement in the disease’s pathogenesis.

The project’s results could enable the development of new treatments by targeting the mechanisms discovered. Currently, type 1 and monogenic diabetes can be controlled using insulin, but no treatment can prevent or cure these diseases.

Coordination : Mariana Igoillo Esteve, Centre de recherche sur le diabète, Faculté de Médecine


Created on September 4, 2020