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,

  • Medjmedj, A et al. find that 5′UTRs and 3′ UTRs act synergistically in mRNA therapeutic design
  • Zhang, Y et al. find that silencing METTL1 alleviates ischemia/reperfusion injury.
  • Moore, M. et al find evolutionarily-conserved light-intensity-dependent 5′ UTR mRNA motifs in plants.

Evaluation of synthetic mRNA with selected UTR sequences and alternative poly(A) tail, in vitro and in vivo

Mol Ther Nucleic Acids, 2025

Medjmedj, A., Genon, H., Hezili, D., Loth, A.N., Clemençon, R., Guimpied, C., Mollet, L., Bigot, A., Wien, F., Hamacek, J., Chapat, C. and Perche, F.

Sunday Paper 1

The authors systematically evaluated how combinations of 5′/3′ untranslated regions (UTRs) and custom heterologous A/G structures as poly(A) tails regulate synthetic mRNA stability and translation efficiency, benchmarking performance against the Pfizer-BioNTech COVID-19 vaccine baseline.

When screening seven 5′ UTRs and nine 5′/3′ UTR combinations, as well as A/G tails, the human α-globin 5′ UTR (hAg) emerged as a consistently high-performing lead candidate, alongside promising 3′ UTR candidates including VP6 and SOD. Polysome profiling, which separated mRNA by ribosome association quantified via RT-qPCR, revealed the core mechanism behind these results: variance in total protein output was driven primarily by ribosome loading efficiency rather than mRNA half-life, cellular immunogenicity, or UTR thermal stability. High-performing constructs such as hAg-AES, hAg-VP6, and UTR4-AES demonstrated high polysome occupancy, whereas poorly translated designs like UTR3-SOD and UTR4-SOD maintained less than 25% polysome association.

Crucially, UTR performance varied depending on the cell type, proving that 5′ UTRs and 3′ UTRs act synergistically. This emphasizes that effective therapeutic mRNA design requires holistic, full-length optimization rather than selecting isolated regulatory elements. Finally, lipid nanoparticle (LNP) delivery of SARS-CoV-2 spike-encoding mRNA containing the optimized UTR combinations elicited strong antigen expression and robust immunization in mouse models, demonstrating their potential for therapeutic mRNA engineering.

Learn more about EIRNABio’s polysome profiling services here.

METTL1‐Mediated N7‐Methylguanosine tRNA Modification Alleviates Cardiac Ischemia/Reperfusion Injury by Modulating Mitochondrial Energy Metabolism

MedComm, 2026

Zhang, Y., Leng, M., Wang, R., Tang, X., Cai, Z., Wang, L., Shao, X., Diao, H., Long, Q., Li, X., Wu, Y., Jiang, Y., Zhang, H., Liang, H. and Guo, J.

Sunday Paper 2

The study identifies METTL1-mediated m7G tRNA modification as a regulator of cardiac ischemia/reperfusion (I/R) injury and mitochondrial energy metabolism. METTL1 and global m7G tRNA modification were shown to increase following I/R or hypoxia and reoxygenation. Genetic or siRNA-mediated METTL1 suppression reduced infarct size, cardiomyocyte apoptosis and mitochondrial dysfunction, while improving oxidative phosphorylation, ATP production and mitochondrial homeostasis.

tRNA-seq and MeRIP-m7G-tRNA-seq were particularly important for defining the tRNA-level mechanism. tRNA-seq identified changes in tRNA abundance, while MeRIP-m7G-tRNA-seq showed that METTL1 loss markedly reduced m7G modification and the abundance of most m7G-modified tRNAs. Thus, these approaches linked METTL1 activity to changes in the cellular tRNA pool, although the study did not directly demonstrate increased tRNA degradation.

Ribo-seq then connected these tRNA changes to protein synthesis. METTL1 suppression reduced translation efficiency of genes enriched in mitochondrial, ATP-production and oxidative-phosphorylation pathways, including ATPIF1, SLC25A3 and ATP5G3. Notably, ATPIF1 mRNA abundance was not significantly altered, whereas its translational efficiency and protein level decreased, providing evidence for post-transcriptional regulation. Functional rescue experiments further identified ATPIF1 as a key downstream mediator of the mitochondrial and cardiac effects.

Together, tRNA-seq and Ribo-seq provide complementary evidence linking altered m7G-tRNA modification to changes in mRNA translation and, ultimately, mitochondrial dysfunction during cardiac I/R injury.

Learn more about EIRNABio’s ribosome profiling and tRNA-seq services here.

Translation-dependent retrograde signaling coordinates high-light acclimation in plants

Mol Plant, 2026

Moore, M., Smith, A.B., Wegener, M., Khambalkar, P.B., Tyrrell, R.V., Watts, B.C., Nix, S.J., Tsang, H.T., Farooq, M.A., Ganguly, D.R., Furbank, R.T., Ermakova, M., Pogson, B.J. and Dietz, K.J.

Sunday Paper 3

This study shows that Arabidopsis thaliana responds to high light in just 10 minutes by shifting its protein production machinery into emergency mode, a process known as chloroplast retrograde signaling. Although the plant quickly shuts down most of its protein assembly to conserve energy, it selectively speeds up the translation of key mRNAs. These boosted mRNAs encode proteins that protect chloroplasts from light damage, fix damaged photosynthetic machinery, and turn on stress-response genes. The molecular switch behind this selection relies on specific RNA sequences located in the 5′-untranslated region (5′-UTR) of these mRNAs. Under high light, changes in cellular redox state and cofactors cause the metabolic enzyme GAPDH to release from these 5′-UTR motifs (which it binds under low light to repress protein synthesis), directly promoting their translation. The authors verified this same mechanism in green foxtail (Setaria viridis), proving that this stress-response pathway is conserved across crop species.

Polysome profiling and Ribo-Seq were essential to uncover these mechanisms. Polysome profiling showed that heavy polysome complexes rapidly collapsed within 10 minutes of high light exposure, proving the plant instantly represses global protein synthesis to save energy. Meanwhile, Ribo-Seq uncoupled translation efficiency from mRNA abundance, identifying four distinct transcript groups. Crucially, Group 1 transcripts showed increased ribosome loading despite constant or falling mRNA levels, encoding photosynthetic helpers and key transcription factors. Group 2 represented genes whose higher ribosome loading was merely a byproduct of increased mRNA levels, while Groups 3 and 4 reflected the broader translational shutdown. Analyzing the UTRs of both Groups 1 and 2  allowed researchers to pinpoint the shared 5′-UTR motifs that bind GAPDH, proving plants rely on selective translation to survive sudden environmental stress.

Learn more about EIRNABio’s ribosome profiling and polysome profiling services here.