|
| Status |
Public on Jul 01, 2021 |
| Title |
Neuronal Nsun2 deficiency is associated with codon-specific epitranscriptomic dysregulation of Gly-tRNAs and corresponding proteomic shift impacting synaptic signaling and behavior |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
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.
|
| |
|
| Overall design |
mRNA and small RNA profiles of adult Nsun2 KO and WT cortex
|
| |
|
| Contributor(s) |
Blaze J, Akbarian S |
| Citation(s) |
34389722, 34880236 |
| |
| Submission date |
Jan 20, 2021 |
| Last update date |
Jan 10, 2022 |
| Contact name |
Jennifer Blaze |
| E-mail(s) |
jennifer.blaze@mssm.edu
|
| Organization name |
Icahn School of Medicine at Mount Sinai
|
| Street address |
1470 Madison Ave 9-202
|
| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10029 |
| Country |
USA |
| |
|
| Platforms (4)
|
| GPL16417 |
Illumina MiSeq (Mus musculus) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
|
| Samples (103)
|
|
| Relations |
| BioProject |
PRJNA693540 |
| SRA |
SRP302576 |
Less...
More...