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Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

ABSTRACT: Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

PROVIDER: PRJNA693540 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13491285_1.fastq.gz	Fastqsanger.gz
	SRR13491285_2.fastq.gz	Fastqsanger.gz
	SRR13491286_1.fastq.gz	Fastqsanger.gz
	SRR13491286_2.fastq.gz	Fastqsanger.gz
	SRR13491287_1.fastq.gz	Fastqsanger.gz

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Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

Project description:The role of transfer (t)RNA cytosine methyl-transferases as epitranscriptomic regulators of brain proteomes remains unexplored. We report that fear memory and antidepressant-like behaviors are highly sensitive to bi-directional changes in Nsun2 tRNA methyltransferase activity in prefrontal cortex (PFC) neurons. Nsun2-deficient mutant cortex showed a selective deficit in multiple glycine tRNAs, resulting in codon-specific shifts in translational efficiencies and a distorted proteomic landscape with deficits in glycine-rich neuronal proteins impacting synaptic signaling and behavior.

2021-07-02 | PXD023437 | Pride

Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior

Project description:Epitranscriptomic mechanisms linking the brain proteome to cognition and complex behaviors essentially remain unexplored. Here, we describe bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of NOL1/NOP2/SUN domain 2 (Nsun2) in the prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a sharp drop in tRNA m5C levels, resulting in significant deficits in expression of 70% (7/10) of tRNAGlyGCC, GlyCCC GlyTCC isodecoders, while expression changes in non-glycinergic tRNAs were minimal (4/152). Altogether, 1488/5820 proteins were sensitive to neuronal Nsun2-deficiency, in conjunction with GCC and CCC codon-specific defects in translational efficiencies and loss of Gly-rich proteins critical for glutamatergic neurotransmission, resulting in impaired synaptic signaling at PFC pyramidal neurons and impairments in contextual fear memory. These distortions in the neuronal translatome were associated with an adaptive, 2.46-fold up-regulation in PFC glycine levels with increased expression of multiple enzymes in the glycine biosynthetic pathway. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC and link synaptic plasticity and complex behaviors to epitranscriptomic regulation of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

2021-07-01 | GSE165202 | GEO

NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs

Project description:We show that NSUN2 in necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs

2019-06-19 | GSE132020 | GEO

NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs

Project description:NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs

| PRJNA545637 | ENA

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Project description:Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.

| S-EPMC8363735 | biostudies-literature

Author Correction: Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior.

Project description: Not available

| S-EPMC8654860 | biostudies-literature

NSun2-mediated cytosine-5 methylation in Vault non-coding RNA determines its processing into small RNAs [iCLIP]

Project description:Autosomal-recessive loss of the NSUN2 gene has been recently identified as a causative link to intellectual disability disorders in humans. NSun2 is an RNA methyltransferase modifying cytosine-5 in transfer RNAs (tRNA). Whether NSun2 methylates additional RNA species is currently debated. Here, we adapted the individual-nucleotide resolution UV cross-linking and immunoprecipitation method (iCLIP) to identify NSun2-mediated methylation in RNA transcriptome. We confirm site-specific methylation in tRNA and identify messenger and non-coding RNAs as potential methylation targets for NSun2. Using RNA bisulfite sequencing we establish Vault non-coding RNAs as novel substrates for NSun2 and identified six cytosine-5 methylated sites. Furthermore, we show that loss of cytosine-5 methylation in Vault RNAs causes aberrant processing into argonaute-associating small RNA fragments (svRNA). Thus, impaired Vault non-coding RNA processing may be an important contributor to the etiology of NSUN2-deficieny human disorders. Identification of Nsun2 targets by miCLIP in Embryonic kidney (HEK293) cells

2013-07-23 | E-GEOD-44385 | biostudies-arrayexpress

NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs.

Project description:Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation-knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells-we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.

| S-EPMC6822013 | biostudies-literature

Mammalian NSUN2 introduces 5-methylcytidines into mitochondrial tRNAs.

Project description:Post-transcriptional modifications in mitochondrial tRNAs (mt-tRNAs) play critical roles in mitochondrial protein synthesis, which produces respiratory chain complexes. In this study, we took advantage of mass spectrometric analysis to map 5-methylcytidine (m5C) at positions 48-50 in eight mouse and six human mt-tRNAs. We also confirmed the absence of m5C in mt-tRNAs isolated from Nsun2 knockout (KO) mice, as well as from NSUN2 KO human culture cells. In addition, we successfully reconstituted m5C at positions 48-50 of mt-tRNA in vitro with NSUN2 protein in the presence of S-adenosylmethionine. Although NSUN2 is predominantly localized to the nucleus and introduces m5C into cytoplasmic tRNAs and mRNAs, structured illumination microscopy clearly revealed NSUN2 foci inside mitochondria. These observations provide novel insights into the role of NSUN2 in the physiology and pathology of mitochondrial functions.

| S-EPMC6895283 | biostudies-literature

NSun2-mediated cytosine-5 methylation in Vault non-coding RNA determines its processing into small RNAs [RNA-seq]

Project description:Autosomal-recessive loss of the NSUN2 gene has been recently identified as a causative link to intellectual disability disorders in humans. NSun2 is an RNA methyltransferase modifying cytosine-5 in transfer RNAs (tRNA). Whether NSun2 methylates additional RNA species is currently debated. Here, we adapted the individual-nucleotide resolution UV cross-linking and immunoprecipitation method (iCLIP) to identify NSun2-mediated methylation in RNA transcriptome. We confirm site-specific methylation in tRNA and identify messenger and non-coding RNAs as potential methylation targets for NSun2. Using RNA bisulfite sequencing we establish Vault non-coding RNAs as novel substrates for NSun2 and identified six cytosine-5 methylated sites. Furthermore, we show that loss of cytosine-5 methylation in Vault RNAs causes aberrant processing into argonaute-associating small RNA fragments (svRNA). Thus, impaired Vault non-coding RNA processing may be an important contributor to the etiology of NSUN2-deficieny human disorders. mRNA-seq in Embryonic kidney (HEK293) cells transfected with siRNA against Nsun2 vs control

2013-07-23 | E-GEOD-44384 | biostudies-arrayexpress

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