December 15th, 2024
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, Mittal et al. use ribosome profiling to investigate translation in calorie restricted and rapamycin-treated aging mice. Yang et al. use RNA-Seq and Ribo-Seq data to obtain genome-wide analysis during diapause of the Asian corn borer. Lastly, Li et al. use Ribo-Seq and RNA-Seq to uncover the link between deficiency in the N7-methylguanosine (m7G) tRNA modification and primordial drawfism.
Calorie restriction and rapamycin distinctly restore non-canonical ORF translation in the muscles of aging mice
NPJ Regenerative Medicine, 2024
Mittal, N., Ataman, M., Tintignac, L., Ham, D.J., Jörin, L., Schmidt, A., Sinnreich, M., Ruegg, M.A. and Zavolan, M.
Skeletal muscle wasting, a condition associated with aging and various diseases, leads to sarcopenia when muscle mass and function decline beyond a critical threshold. As the human population ages, sarcopenia has become a major cause of frailty and falls, representing a significant socio-economic challenge. Understanding the mechanisms that mitigate aging-related muscle wasting is crucial for healthcare. Rapamycin (RM) treatment and calorie restriction (CR) are two well-tested interventions that promote lifespan and health span in various organisms. Long-term RM treatment has been found to mitigate sarcopenia, while CR (a diet with 60-70% of ad libitum intake without malnutrition) has been shown to improve muscle mass and locomotor activity in rodents. Early-onset CR counteracts muscle fiber loss and reduces aging-related neuromuscular junction abnormalities. While both RM and CR reduce protein synthesis in different organs, the impact of these treatments on mRNA translation in muscle, especially with long-term use, remains unclear.
To explore this, the authors used ribosome footprinting (Ribo-Seq) on the Quadriceps femoris muscle of mice aged under standard conditions, or under long-term treatment with CR or RM. They revealed that both RM and CR remodeled translation, with RM mainly affecting translation of upstream ORFs (uORFs) and CR influencing translation within 3’UTRs, suggesting distinct translational control mechanisms for these interventions. Proteomics analysis identified peptides predicted to be translated from the expression of numerous non-canonical ORFs. These peptides may be potential biomarkers or entry points for therapies aiming to maintain muscle function and extend health span.
Genome-wide analysis reveals transcriptional and translational changes during diapause of the Asian corn borer (Ostrinia furnacalis)
BMC Biology, 2024
Yang, X., Zhao, X., Zhao, Z. and Du, J.
Diapause is a crucial phase in the insect life cycle that enables survival under harsh environmental conditions. It is essential for the storage of metabolites, including lipids, before winter begins. Additionally, the end of diapause in the spring promotes synchrony within insect populations. Investigating diapause can help identify key targets for the development of more effective insect control strategies. Understanding the gene expression profiles of diapause can reveal the molecular mechanisms behind this adaptation. In this study, RNA-Seq and Ribo-Seq data were used to analyze differentially expressed genes and translational efficiency during diapause in the Asian corn borer (Ostrinia furnacalis, ACB).
The authors identified genes categorized as “forwarded,” “exclusive,” “intensified,” or “buffered” during diapause, providing insights into their transcription and translation regulation. Additionally, long non-coding RNAs (lncRNAs) were explored, with differentially expressed lncRNAs identified, suggesting their role in regulating diapause. A comparative analysis of diapause across different insect species revealed shared and unique KEGG pathways. While common pathways focused on energy balance, exclusive pathways in ACB larvae indicated specific adaptations for nutrient utilization and stress response. Notably, changes in the HSP70 gene family and the proteasome pathway were observed during diapause. Manipulating HSP protein levels and the proteasome pathway using activators, inhibitors, and proteasome inhibitors affected diapause, highlighting their crucial role in the process. In conclusion, these findings provide valuable insights into the molecular mechanisms that allow insects to survive extreme conditions, enhancing our understanding of the intricate processes involved in diapause.
Metabolic rewiring during bone development underlies tRNA m⁷G-associated primordial dwarfism
The Journal of Clinical Investigation, 2024
Li, Q., Jiang, S., Lei, K., Han, H., Chen, Y., Lin, W., Xiong, Q., Qi, X., Gan, X., Sheng, R. and Wang, Y.
The translation of mRNA to protein is regulated by transfer RNAs (tRNAs), which undergo chemical modifications to maintain their structure and function. In mammals, tRNA m7G modification is facilitated by a heterodimeric complex consisting of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4). This modification is essential for the self-renewal and differentiation of mouse embryonic stem cells. A homozygous missense mutation in WDR4 has been identified as the cause of microcephalic primordial dwarfism, characterized by severe growth retardation and brain abnormalities. Recent research has also highlighted the role of dysregulated tRNA m7G modification in cancer. While deficiency in the N7-methylguanosine (m7G) tRNA modification has been linked to primordial dwarfism, its mechanism was unclear.
Using Ribo-Seq and RNA-Seq, this study reveals that loss of m7G reprograms cellular metabolism, contributing to the disorder. Deleting the enzyme Mettl1 or mutating the scaffold protein Wdr4 disrupted endochondral bone formation and reduced bone mass. Mettl1 deletion lowered levels of m7G-modified tRNAs, impairing the translation of mRNAs involved in cytoskeleton and Rho GTPase signaling, crucial for bone development. Paradoxically, Mettl1-deficient cells displayed increased energy metabolism but reduced proliferation and osteogenic potential. This was linked to disrupted Rho GTPase signaling, which elevated branched-chain amino acid transaminase 1 (BCAT1), rewiring metabolism and depleting intracellular α-ketoglutarate (αKG). Supplementing αKG mitigated skeletal defects in Mettl1-deficient mice. Further, Mettl1 deletion broadly affected translation via the integrated stress response (ISR) and mTORC1 signaling pathways. While these mechanisms act as quality control to regulate translation during tRNA dysregulation, targeting ISR or mTORC1 worsened bone defects. This study highlights the critical role of m7G tRNA modification in bone development through metabolic regulation and translation control.