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 - http://www.scopus.com/inward/record.url?scp=85056260611&partnerID=8YFLogxK
U2 - 10.1093/nar/gky839
DO - 10.1093/nar/gky839
M3 - Article
C2 - 30247717
VL - 46
SP - 10302
EP - 10318
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 19
ER -