Translatomics for circadian clock, schizophrenia and amyotrophic lateral sclerosis
Recent Publications Harnessing the Power of Translatomics
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers,
- Zhuang Y et al. find that ATXN and ATXNL2 are master regulators of oscillating translation in the suprachiasmatic nucleus of the mammalian brain.
- Xue, L et al. highlight the role of mRNA acetylation as a therapeutic strategy for correcting pathological gene expression patterns in schizophrenia.
- Stansberry, W et al. discuss how under healthy conditions, motor neurons express muscle-associated genes, potentially contributing to muscle maintenance.
Circadian clocks are modulated by compartmentalized oscillating translation
Cell, 2023
Zhuang, Y., Li, Z., Xiong, S., Sun, C., Li, B., Alivia, W. S., Lyu, J., Shi, X., Yang, L., Chen, Y., Bao, X., Li, X., Sun, C., Chen, Y., Deng, H., Li, T., Wu, Q., Qi, L., Huang, Y., Yang, X., Lin, Y.
The study identifies ATXN2 and ATXN2L as master regulators that form spatiotemporally oscillating condensates orchestrating rhythmic mRNA processing and translation. These condensates recruit and selectively translate core clock transcripts, such as Per2 and Cry1, in a “time-of-day” dependent manner. The authors performed ribosome profiling across circadian time points revealing that translation of many transcripts, particularly core clock and output genes, is highly rhythmic, with distinct phases across the 24-hour cycle. These oscillations closely matched the temporal dynamics of ATXN2/ATXN2L condensate formation, suggesting that these phase-separated granules compartmentalize translation activation. Perturbation experiments reveal that knocking out ATXN2 or ATXN2L separately causes opposing shifts in circadian period length, whereas double knockout abolishes robust translational rhythms and weakens SCN rhythmicity in vivo. Importantly, the rhythmic cycle can be restored by wild-type, but not phase‑separation-defective, ATXN2, emphasizing that dynamic condensate formation is vital for maintaining robust circadian rhythms. The authors propose a model where compartmentalized, oscillatory translation, driven by dynamic condensates, provides a post-transcriptional layer of circadian regulation, fine-tuning the precision and robustness of the mammalian clock. This work extends our understanding of circadian timing by demonstrating that localized translational control via phase-separated organelles is a critical mechanism for temporal regulation in mammals.
Learn more about EIRNABio’s ribosome profiling services here.
MK-801-exposure induces increased translation efficiency and mRNA hyperacetylation of Grin2a in the mouse prefrontal cortex
Epigenetics, 2024
Xue, L., Zhao, J., Liu, X., Zhao, T., Zhang, Y., and Ye, H.
Schizophrenia is a heritable psychiatric disorder manifesting between 18-25 years. Gene expression profiles have been studied in schizophrenic patients and rodent model systems, yet no analysis has been done at the translation level. Acute administration of the NMDA receptor antagonist MK‑801 in juvenile male mice is known to induce schizophrenia-like behaviours. Ribosome profiling (Ribo‑seq) of the prefrontal cortex (PFC) in juvenile male mice following acute MK‑801 exposure revealed 357 genes with significantly altered translational efficiency. Among transcripts with increased translation efficiency, those containing the N⁴‑acetylcytidine (ac⁴C) consensus motif were notably enriched, suggesting a link between this epitranscriptomic mark and translational upregulation. Epitranscriptomic profiling via ac⁴C RNA immunoprecipitation sequencing (acRIP‑seq) revealed 148 differentially acetylated peaks, of which 121 were hyperacetylated and 27 hypoacetylated, mapping to pathways including axon guidance, Hedgehog signalling, neuron differentiation, and memory. Grin2a is a known schizophrenia susceptibility gene that encodes the NMDA receptor subunit NMDAR2A. Its transcript exhibited both hyperacetylation and significantly increased translation efficiency, which correlated with elevated NMDAR2A protein levels in the PFC following MK‑801 exposure. Importantly, pre-treatment with Remodelin, an NAT10 inhibitor, normalized NMDAR2A protein levels and partially rescued the schizophrenia-like behavioural phenotypes, supporting the crucial role of mRNA acetylation in modulating gene expression and behaviour in this model. These findings suggest that targeting mRNA acetylation may offer a novel therapeutic strategy for correcting pathological gene expression patterns in schizophrenia or related conditions.
Learn more about EIRNABio’s ribosome profiling services here.
Analysis of translatomic changes in the Ubqln2ᴾ⁴⁹⁷ˢ model of ALS reveals that motor neurons express muscle-associated genes in non-disease states
Frontiers in Neurology, 2024
Stansberry, W., Fiur, N., Robins, M., and Pierchala, B.
Amyotrophic lateral sclerosis causes progressive worsening of motor symptoms and eventual paralysis. Mutations in the UBQLN2 gene were identified in families with both ALS and frontotemporal dementia. The UBQLN2P497S ALS mouse model exhibits hallmark features such as motor neuron loss and neuromuscular denervation and locomotor deficits by 12 months of age. The authors performed motor-neuron specific RiboTag-based translational analysis at symptom onset, which identified 467 upregulated and 558 downregulated transcripts compared to wild‑type mice. Among the most significantly downregulated were canonical muscle-associated genes, including Actin Alpha-1 (Acta1), Desmin (Des), and Troponin T3 (Tnnt3), highlighting an unexpected expression of muscle-specific transcripts in healthy motor neurons whose loss may contribute to early neuromuscular dysfunction. These findings were validated using fluorescence in situ hybridization (FISH), which confirmed their expression in motor neuron cell bodies in wild-type mice and dramatic reduction in UBQLN2P497S mice. Simultaneously, gene set enrichment and GO analyses revealed that Wnt signaling components were depleted, whereas respiration and metabolic pathways, especially ATP synthesis and energy metabolism, were enriched in disease-state motor neurons.
These unexpected findings suggest that under healthy conditions motor neurons express muscle-associated genes, potentially contributing to muscle maintenance or intercellular support, a mechanism that is disrupted in ALS models exhibiting motor neuron degeneration. The study opens new therapeutic avenues targeting motor neuron–intrinsic programs to preserve muscle connectivity and function in neurodegenerative diseases.
Learn more about EIRNABio’s ribosome profiling services here.
