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,

  • Ni et al. find how ribosome abundance and mRNA translation shapes early human brain development.
  • Kouvela et al. investigate the functional redundancy among tRNA-Gly genes in Staphylococcus aureus.
  • Liu et al. find that intratumoral T cells undergo translatome remodeling.

A programmed decline in ribosome levels governs human early neurodevelopment

Nature Cell Biology, 2025

Ni, C., Wei, Y., Vona, B., Park, D., Schmitz, D.A., Ding, Y., Sakurai, M., Ballard, E., Li, L., Liu, Y. and Kumar, A.

Sunday Paper 1

Ni et al. describe how dynamic regulation of ribosome abundance and mRNA translation shapes early human brain development, and how perturbations in this balance underlie neurodevelopmental disorders. Using cerebral organoids derived from human iPS cells carrying patient-associated variants in the ribosome biogenesis factor AIRIM/C1orf109, the authors performed single-organoid ribosome profiling via microfluidic isotachophoresis (Ribo-ITP), single cell RNA-seq, OPP (O-propargyl puromycin) nascent protein labeling, and proteomics to dissect translation dynamics. They discovered a programmed decline in ribosomal protein abundance during the transition from neuroepithelial to radial glial progenitors, including ribosome levels decline as differentiation proceeds, and that this reduction represents a translational bottleneck. Mutant organoids with AIRIM variants show exacerbated declines in ribosome levels and global protein synthesis at specific developmental timepoints (day 10–15), detectable by OPP labeling and mass spectrometry.

Ribo-ITP revealed that a subset of mRNAs, particularly those encoding translation machinery, mitochondrial proteins, and neurodevelopment regulators, exhibit reduced translational efficiency (TE) in mutant organoids. Many of these sensitive transcripts contain 5′ TOP or TOP-like motifs, rendering them especially vulnerable to modest decreases in ribosome availability. Importantly, boosting mTOR signaling (genetically or pharmacologically) increased global translation and partially rescued cell survival, growth, differentiation, and mitochondrial defects in mutant organoids. Overall, this work leverages state-of-the-art translatomic tools to show that controlled modulation of global translation, and differential sensitivity of specific mRNAs, is critical during neurodevelopment, and that disruptions can lead to selective vulnerability underlying neurodevelopmental disease phenotypes.

Learn more about EIRNABio’s ribosome profiling services here.

Coupling tRNAᴳˡʸ gene redundancy with Staphylococcal cell wall integrity, antibiotic susceptibility, and virulence potential

Nucleic Acids Research, 2025

Kouvela, A., Jaramillo Ponce, J.R., Giarimoglou, N., Chicher, J., Marzi, S., Stathopoulos, C. and Stamatopoulou, V.

Sunday Paper 2

Staphylococcus aureus possesses multiple tRNA-Gly genes, two of which (P1 and P2) are proteinogenic and used in translation, while three others (NP1, NP2, and NEW) are non-proteinogenic and linked to cell wall synthesis. Kouvela et al. investigate the functional redundancy among these tRNA-Gly genes, integrating tRNA biology with translation and cell physiology. Using CRISPR/Cas9, the authors deleted one copy of the proteinogenic tRNA-Gly gene P1, and employed transcriptomics, proteomics, polysome profiling, and tRNA sequencing to assess the consequences.

Polysome profiling under both rich and minimal growth conditions revealed no major differences in the levels of ribosomal subunits, monosomes, or polysomes between the wild type and ΔP1 strains. This suggests that the loss of P1 may be compensated by remaining tRNA-Gly isoacceptors. Northern blot analyses showed that only the proteinogenic tRNAs are associated with actively translating polysomes, whereas non-proteinogenic tRNAs were not recruited to the ribosome, indicating their exclusion from canonical translation. Transcriptomic analyses revealed modest changes: 18 genes were significantly upregulated and 21 downregulated in the mutant. tRNA-seq data demonstrated that the ratios of tRNAs, tRNA halves, and tRNA fragments (tRFs) remained stable. In contrast, proteomic profiling identified 141 differentially expressed proteins, underscoring that loss of P1 affects translation efficiency and decoding beyond transcript-level alterations.

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

LARP4-mediated hypertranslation drives T cell dysfunction in tumors

Nature Immunology, 2025

Liu, Y., Ni, H., Li, J., Yang, J., Sekielyk, I., Snow, B.E., Zhang, Z. et al.

Sunday Paper 3

To study translatome remodelling in intratumoral T cells, the authors developed RPLace-seq, a low input ribosome profiling method that integrates ribosome tagging (RiboTag) with LACE-seq, a method for identifying the RNA bound to specific proteins. Using RPLace-seq, the authors demonstrate that exhausted T cells display broadly increased translation activity and enhanced ribosome engagement across the transcriptome. The underlying mechanism involves the RNA-binding protein LARP4.  LARP4 drives hypertranslation and dysfunction by directly targeting transcripts of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells, selectively upregulating their translation efficiency. This leads to a disruption of OXPHOS subunit balance and causes mitochondrial dysfunction.

Knock out of Larp4 in tumor-specific CD8⁺ T cells dampens their hypertranslation, improves mitochondrial function, alleviates markers of exhaustion, and enhances effector persistence in tumors. Moreover, knocking down LARP4 in chimeric antigen receptor (CAR) T cells reduces terminal exhaustion and improves their anti-tumor performance in both solid and liquid tumor models. This work highlights translation dysregulation—not just transcriptional or epigenetic changes—as a central determinant of T cell fate in cancer. By coupling translatomic profiling with functional perturbations, the study reveals how an RNA‐binding protein can re-wire translational programs to drive immune dysfunction in the tumor microenvironment.

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