Description

résumé en Anglais ici également comme recommandé par l'ED.

Precise control of protein synthesis is essential for brain development and cognitive function. Transfer RNAs (tRNAs) play a central role in this process, and their chemical modifications are increasingly recognized as critical regulators of tRNA stability and translational efficiency.
Growing evidence indicates that post‑transcriptional RNA modifications, including those on tRNAs, play critical roles in human health (1). Mutations in genes encoding human tRNA‑modifying enzymes are strongly associated with specific diseases, most notably neurological disorders (2,3). In addition, tRNA‑derived fragments (tRFs) have emerged as key regulators of gene expression, stress responses, and cellular signaling (4,5). Their biogenesis is tightly controlled by post-transcriptional modifications within tRNAs, which stabilize the anticodon loop and protect against endonucleolytic cleavage. When these modifications are absent or defective, tRNAs become more susceptible to fragmentation, leading to altered pools of tRFs that can profoundly impact translation and cellular homeostasis (6).

Among the most studied modifications influencing tRFs generation are 2'-O-methylation (Nm) mediated by FTSJ1 at position 32 and 34 (7,8,9) and queuosine (Q) incorporation at position 34 (10,11) mediated by the tRNA-guanine transglycosylase (TGT) complex (1). Although both Nm and Q act as protective marks that safeguard tRNAs from uncontrolled cleavage, and their loss has been associated with pathological tRF signatures in cancer and neurological disorders (8,9,11-13), definitive evidence for a causal contribution of tRFs to the phenotypes observed upon loss of these modifications is still lacking.

With our international collaborators, our preliminary data, together with previous studies (2-9, 11-13), indicate that FTSJ1-dependent 2′-O-methylation (Nm) and queuosine (Q), are dynamically regulated in cognition-related brain regions and influence the production of tRNA-derived fragments (tRFs). However, how these modifications shape the tRF landscape and modulate translational programs in the brain remains largely unknown. Moreover, the degree to which these mechanisms are conserved across species and cellular systems has not been systematically investigated.

This PhD project aims to define how tRNA Nm and Q govern tRNA-derived fragments biogenesis and neuronal function across multiple model systems. Using complementary molecular, cellular, and in vivo approaches in mouse, human, and Drosophila melanogaster, the PhD student will:
i) map FTSJ1-dependent Nm and Q incorporation in cognition-related brain regions and determine their impact on translation;
ii) establish how loss of these modifications affects tRNA stability and promotes tRF generation;
iii) determine the functional contribution of tRFs to neuronal and synaptic deficits associated with FTSJ1 loss.

Together, those approaches and studies will allow us to control the production of tRFs in the brain. Importantly, we will unambiguously disentangle the effect of the exogenous and controlled expression of identified tRFs (in i)) in a wild-type context in which tRNA modification pathways remain intact. By defining causal roles for tRFs in neuronal and synaptic dysfunction, the project will advance the field beyond correlative observations and position tRFs as active regulators of brain physiology.

More broadly, the results will offer new mechanistic insight into intellectual disability and neurological disorders associated with altered tRNA metabolism, and may support the future development of biomarkers or therapeutic strategies.
Importantly, those modifications are highly conserved, thus the eukaryotic cross-species comparative design of this PhD project ensures that the findings will identify conserved principles of translational regulation with broad biological relevance.

Compétences requises

En Anglais ici également comme recommandé par l'ED. Master’s student in Molecular and Cellular Biology with strong academic records and solid laboratory experience in gene regulation and molecular genetics. Experienced in plasmid construction, cell culture (L2 ideally), RNA and protein extraction and development of quantitative assays for RNA analysis. Proficient in molecular biology techniques including PCR/qPCR, electrophoresis, Western blot and human cell transformation. Skilled in eukaryotic cell culture. Competent in in silico experiments/ bioinformatic analysis and design and RNA/protein sequence analysis. Multilingual scientist is a plus as our lab is international (English and French spoken), with strong adaptability, autonomy, and analytical rigor. Motivated to pursue a PhD in molecular and cellular biology, focusing on gene expression regulation, RNA and functional genomic approaches.

Bibliographie

1 Sordyl, D. et al. MODOMICS: a database of RNA modifications and related information. 2025 update and 20th anniversary. Nucleic Acids Res, doi:10.1093/nar/gkaf1284 (2025).
2 Guo, W., Russo, S. & Tuorto, F. Lost in translation: How neurons cope with tRNA decoding. Bioessays 46, e2400107, doi:10.1002/bies.202400107 (2024).
3 Suzuki, T. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol 22, 375-392, doi:10.1038/s41580-021-00342-0 (2021).
4 Oberbauer, V. & Schaefer, M. R. tRNA-Derived Small RNAs: Biogenesis, Modification, Function and Potential Impact on Human Disease Development. Genes (Basel) 9, doi:10.3390/genes9120607 (2018).
5 Kocakusak, H., Kok, A. B., Ozturk, B., Karacicek, B. & Genc, S. Deciphering the role of tRNA-derived fragments in neurological and psychiatric disease pathogenesis. Front Cell Neurosci 19, 1663788, doi:10.3389/fncel.2025.1663788 (2025).
6 Chujo, T. & Tomizawa, K. Neurological Diseases Caused by Loss of Transfer RNA Modifications: Commonalities in Their Molecular Pathogenesis. J Mol Biol 437, 169047, doi:10.1016/j.jmb.2025.169047 (2025).
7 Nagayoshi, Y. et al. Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability. Sci Adv 7, doi:10.1126/sciadv.abf3072 (2021).
8 Angelova, M. T. et al. tRNA 2'-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila. Nucleic Acids Res 48, 2050-2072, doi:10.1093/nar/gkaa002 (2020).
9 Brazane, M. et al. The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance. Life Sci Alliance 6, doi:10.26508/lsa.202201877 (2023).
10 Wang, X. et al. Queuosine modification protects cognate tRNAs against ribonuclease cleavage. RNA 24, 1305-1313, doi:10.1261/rna.067033.118 (2018).
11 Cirzi, C. et al. Queuosine-tRNA promotes sex-dependent learning and memory formation by maintaining codon-biased translation elongation speed. EMBO J 42, e112507, doi:10.15252/embj.2022112507 (2023).
12 Tuorto, F. et al. Queuosine-modified tRNAs confer nutritional control of protein translation. EMBO J 37, doi:10.15252/embj.201899777 (2018).
13 Dimitrova, D. G., Teysset, L. & Carre, C. RNA 2'-O-Methylation (Nm) Modification in Human Diseases. Genes (Basel) 10, doi:10.3390/genes10020117 (2019).

Mots clés

methylation de l'ARN, fragment d'ARNt (tRF), control traductionnel, Déficience Intélectuelle, regulation de l'expression des gènes