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

TY - JOUR

T1 - Pancreatic β-cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes

AU - Cosentino, Cristina

AU - Toivonen, Sanna

AU - Diaz Villamil, Esteban

AU - Atta, Mohamed

AU - Ravanat, Jean-Luc

AU - Demine, Stéphane

AU - Schiavo, Andrea Alex

AU - Pachera, Nathalie

AU - Deglasse, Jean-Philippe

AU - Jonas, Jean-Christophe

AU - Balboa, Diego

AU - Otonkoski, Timo

AU - Pearson, Ewan R.

AU - Marchetti, Piero

AU - Eizirik, Décio L

AU - Cnop, Miriam

AU - Igoillo-Esteve, Mariana

PY - 2018/11/2

Y1 - 2018/11/2

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85056260611

U2 - 10.1093/nar/gky839

DO - 10.1093/nar/gky839

M3 - Article

C2 - 30247717

SN - 0305-1048

VL - 46

SP - 10302

EP - 10318

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 19

ER -