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Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes

2018; Oxford University Press; Volume: 46; Issue: 19 Linguagem: Inglês

10.1093/nar/gky839

1362-4962

Cristina Cosentino, Sanna Toivonen, Esteban Diaz Villamil, Mohamed Atta, Jean‐Luc Ravanat, Stéphane Demine, Andréa Alex Schiavo, Nathalie Pachera, Jean-Philippe Deglasse, Jean‐Christophe Jonas, Diego Balboa, Timo Otonkoski, Ewan R. Pearson, Piero Marchetti, Décio L. Eizirik, Miriam Cnop, Mariana Igoillo‐Esteve,

Epigenetics and DNA Methylation

Transfer RNAs (tRNAs) are non-coding RNA molecules essential for protein synthesis. Post-transcriptionally they are heavily modified to improve their function, folding and stability. Intronic polymorphisms in CDKAL1, a tRNA methylthiotransferase, are associated with increased type 2 diabetes risk. Loss-of-function mutations in TRMT10A, a tRNA methyltransferase, are a monogenic cause of early onset diabetes and microcephaly. Here we confirm the role of TRMT10A as a guanosine 9 tRNA methyltransferase, and identify tRNAGln and tRNAiMeth as two of its targets. Using RNA interference and induced pluripotent stem cell-derived pancreatic β-like cells from healthy controls and TRMT10A-deficient patients we demonstrate that TRMT10A deficiency induces oxidative stress and triggers the intrinsic pathway of apoptosis in β-cells. We show that tRNA guanosine 9 hypomethylation leads to tRNAGln fragmentation and that 5'-tRNAGln fragments mediate TRMT10A deficiency-induced β-cell death. This study unmasks tRNA hypomethylation and fragmentation as a hitherto unknown mechanism of pancreatic β-cell demise relevant to monogenic and polygenic forms of diabetes.