Small RNAs derived from tRNA fragmentation regulate the functional maturation of neonatal β cells

Bayazit, Mustafa Bilal; Jacovetti, Cécile; Cristina, Carolina; Sobel, Jonathan; Wu, Kejing; Brozzi, Flora; Rodríguez-Trejo, Adriana; Stoll, Lisa; Guay, Claudiane; Regazzi, Romano

doi:10.1016/j.celrep.2022.111069

Cited by 10 publications

(8 citation statements)

References 52 publications

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“…Furthermore, many reports on tsRNAs abundance, including small RNA sequencing experiments after stress exposure, injury or ANG overexpression, revealed an asymmetric recovery of 5' and 3' tsRNAs from cells with particular ‘jackpot’ tsRNAs such as 5' tsRNA-Gly GCC/CCC and 5' tsRNA-Glu CUC/UUC as overrepresented in various data sets ( 21 , 23 , 28 , 29 ). While biases in cDNA library preparation resulting from RNA modifications could be responsible for these observations ( 30 ), experimental manipulation of biological systems with specific sequences mimicking 5' tsRNAs ( 5 , 8 , 11 , 12 , 21 , 28 , 31 ) or 3' tsRNAs ( 13 , 32–35 ) suggested impact of individual tsRNA moieties on specific cellular processes. If this holds true, this would require the existence of cellular activities with the ability to separate 5′ from 3′ tsRNAs after endonucleolytic attack on parental tRNAs.…”

Section: Introductionmentioning

confidence: 99%

Identification of RNA helicases with unwinding activity on angiogenin-processed tRNAs

Drino

König

Capitanchik

et al. 2023

Nucleic Acids Research

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Stress-induced tRNA fragmentation upon environmental insult is a conserved cellular process catalysed by endonucleolytic activities targeting mature tRNAs. The resulting tRNA-derived small RNAs (tsRNAs) have been implicated in various biological processes that impact cell-to-cell signalling, cell survival as well as gene expression regulation during embryonic development. However, how endonuclease-targeted tRNAs give rise to individual and potentially biologically active tsRNAs remains poorly understood. Here, we report on the in vivo identification of proteins associated with stress-induced tsRNAs-containing protein complexes, which, together with a ‘tracer tRNA’ assay, were used to uncover enzymatic activities that can bind and process specific endonuclease-targeted tRNAs in vitro. Among those, we identified conserved ATP-dependent RNA helicases which can robustly separate tRNAs with endonuclease-mediated ‘nicks’ in their anticodon loops. These findings shed light on the existence of cellular pathways dedicated to producing individual tsRNAs after stress-induced tRNA hydrolysis, which adds to our understanding as to how tRNA fragmentation and the resulting tsRNAs might exert physiological impact.

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Section: Introductionmentioning

confidence: 99%

Identification of RNA helicases with unwinding activity on angiogenin-processed tRNAs

Drino

König

Capitanchik

et al. 2023

Nucleic Acids Research

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“…tiRNAs have been implicated in regulating β-cells, with dysregulation leading to reduced β-cell proliferation and insulin secretion. 15 We also demonstrate that the combined use of 5'ValCAC and miR-23b-3p could potentially help to differentiate between MIDD subjects and type 2 diabetes subjects.…”

Section: Discussionmentioning

confidence: 67%

“…Here we demonstrate for the first time that tiRNAs have lower expression levels in the serum of diabetes subjects compared to healthy controls. tiRNAs have been implicated in regulating β‐cells, with dysregulation leading to reduced β‐cell proliferation and insulin secretion 15 . We also demonstrate that the combined use of 5'ValCAC and miR‐23b‐3p could potentially help to differentiate between MIDD subjects and type 2 diabetes subjects.…”

Section: Discussionmentioning

confidence: 73%

“…Dysregulation of these tiRNAs in islet cells has been shown to increase susceptibility to diabetes. 15 In mitochondrial disease, the expression pattern of several mitochondrial tiRNAs has been shown to be significantly different in cybrid cells from mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) subjects compared to control cells. 16 Here, we performed a small RNAseq analysis of pooled serum samples from MIDD, type 1 diabetes and type 2 diabetes subjects, as well as healthy controls, and identified sncRNAs with altered expression in these samples.…”

Section: Introductionmentioning

confidence: 99%

“…In the pancreas, tiRNAs 5'HIS‐GTG and 5'GLU‐GTC have been found to control mitochondrial respiration, β‐cell proliferation and insulin secretion. Dysregulation of these tiRNAs in islet cells has been shown to increase susceptibility to diabetes 15 . In mitochondrial disease, the expression pattern of several mitochondrial tiRNAs has been shown to be significantly different in cybrid cells from mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) subjects compared to control cells 16 …”

Section: Introductionmentioning

confidence: 99%

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tRNA‐derived fragments are altered in diabetes

Ng,

Gibriel,

Halang

et al. 2023

Diabet Med

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AimsMaternally inherited diabetes and deafness (MIDD) is a rare form of adult‐onset diabetes that can be difficult to diagnose due to its variable clinical phenotype. Transfer RNA‐derived small fragments are a novel, emerging class of small non‐coding RNAs (sncRNAs) that have significant potential as serum biomarkers due to their stress‐induced generation, abundance, stability and ease of detection.MethodsWe investigated the levels of tiRNA 5'ValCAC (alone and in combination with miR‐23b‐3p) identified from small RNA sequencing studies in serum samples from healthy controls, type 1 diabetes, type 2 diabetes and MIDD subjects.ResultsSerum levels of 5'ValCAC were reduced in MIDD and type 2 diabetes subjects compared to controls. Type 2 diabetes subjects had higher serum levels of miR‐23b‐3p compared to all other subjects. Receiver Operating Characteristic analysis showed the potential of 5'ValCAC and miR‐23b‐3p as MIDD biomarkers, with the combination showing excellent separation from type 2 diabetes subjects.ConclusionsThis is the first report showing altered serum levels of tiRNAs in diabetes subjects. The combined use of 5'ValCAC and miR‐23b‐3p as serum biomarkers could potentially differentiate between MIDD subjects and type 2 diabetes subjects.

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tRNA-derived fragments in T lymphocyte–beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice

Brozzi,

Jacovetti,

Cosentino

et al. 2024

Diabetologia

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Aims/hypothesis tRNAs play a central role in protein synthesis. Besides this canonical function, they were recently found to generate non-coding RNA fragments (tRFs) regulating different cellular activities. The aim of this study was to assess the involvement of tRFs in the crosstalk between immune cells and beta cells and to investigate their contribution to the development of type 1 diabetes. Methods Global profiling of the tRFs present in pancreatic islets of 4- and 8-week-old NOD mice and in extracellular vesicles released by activated CD4+ T lymphocytes was performed by small RNA-seq. Changes in the level of specific fragments were confirmed by quantitative PCR. The transfer of tRFs from immune cells to beta cells occurring during insulitis was assessed using an RNA-tagging approach. The functional role of tRFs increasing in beta cells during the initial phases of type 1 diabetes was determined by overexpressing them in dissociated islet cells and by determining the impact on gene expression and beta cell apoptosis. Results We found that the tRF pool was altered in the islets of NOD mice during the initial phases of type 1 diabetes. Part of these changes were triggered by prolonged exposure of beta cells to proinflammatory cytokines (IL-1β, TNF-α and IFN-γ) while others resulted from the delivery of tRFs produced by CD4+ T lymphocytes infiltrating the islets. Indeed, we identified several tRFs that were enriched in extracellular vesicles from CD4+/CD25− T cells and were transferred to beta cells upon adoptive transfer of these immune cells in NOD.SCID mice. The tRFs delivered to beta cells during the autoimmune reaction triggered gene expression changes that affected the immune regulatory capacity of insulin-secreting cells and rendered the cells more prone to apoptosis. Conclusions/interpretation Our data point to tRFs as novel players in the crosstalk between the immune system and insulin-secreting cells and suggest a potential involvement of this novel class of non-coding RNAs in type 1 diabetes pathogenesis. Data availability Sequences are available from the Gene Expression Omnibus (GEO) with accession numbers GSE242568 and GSE256343. Graphical Abstract

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Small RNAs derived from tRNA fragmentation regulate the functional maturation of neonatal β cells

Cited by 10 publications

References 52 publications

Identification of RNA helicases with unwinding activity on angiogenin-processed tRNAs

Identification of RNA helicases with unwinding activity on angiogenin-processed tRNAs

tRNA‐derived fragments are altered in diabetes

tRNA-derived fragments in T lymphocyte–beta cell crosstalk and in type 1 diabetes pathogenesis in NOD mice

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