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,

  • Murakami et al. shows that m6A-driven mRNA decay is tightly coupled to translation, where ribosome stalling and collision at m6A sites promotes YTHDF-dependent degradation, and translational inhibition stabilizes these transcripts to enable stress responses.
  • Pérez-Roldán et al. find that in Drosophila maternal replication-dependent histone mRNAs are unexpectedly polyadenylated via stem-loop cleavage, and their translation in early embryos is regulated by chromatin state and dBigH1.
  • Park et al. demonstrate that Vaccinia virus rewires host translation during late infection, allowing selective eIF3-independent upregulation of JUN and stress genes that escape shutoff and promote viral spread.

m6A alters ribosome dynamics to initiate mRNA degradation

Cell, 2025

Murakami, S., Olarerin-George, A.O., Liu, J.F., Zaccara, S., Hawley, B. and Jaffrey, S.R.

Sunday Paper 1

N6-methyladenosine (m6A) is a common mRNA modification installed by the METTL3–METTL14 methyltransferase complex and is widely associated with regulation of cell growth, differentiation, and stress responses. Its predominant effect is to promote mRNA degradation via recruitment of YTHDF proteins, keeping many target transcripts—often encoding key regulatory factors—at low abundance. During cellular stress, such as amino acid depletion, many m6A-marked mRNAs involved in metabolism, DNA repair, and autophagy are upregulated, though it remains unclear whether this reflects reduced m6A-mediated decay. In parallel, m6A has been shown to induce ribosome stalling, suggesting a potential link between translation dynamics and mRNA stability. Here, the authors sought to investigate this further.

The authors demonstrate that m6A-mediated mRNA decay is tightly coupled to translation. Mining the toxicogenomic database revealed that the translation inhibitor cycloheximide preferentially increases expression of highly methylated transcripts, a finding supported by DepMap analysis linking m6A machinery to translation-related genes. Using TimeLapse-seq following emetine treatment, they show that inhibition of translation stabilizes m6A-rich mRNAs in an m6A-dependent manner, an effect lost in Mettl14 knockout cells. Ribosome profiling combined with quantitative m6A mapping (GLORI) revealed pronounced ribosome stalling at high-stoichiometry m6A sites, with stalling strength correlating with mRNA destabilization. Reporter assays confirmed that codons inducing stronger m6A-dependent stalling drive greater mRNA decay. Importantly, m6A sites within coding sequences—those encountered by ribosomes—correlate more strongly with degradation than UTR-localized sites. In vitro translation assays and disome profiling demonstrated that m6A induces ribosome collisions, which enhance YTHDF binding (via iCLIP) and promote decay. Perturbation of collision resolution (ASCC3 depletion) further increased degradation. Finally, stress-induced translational repression stabilizes m6A-mRNAs and promotes adaptive responses such as autophagy, linking translational control to m6A-dependent gene regulation.

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

Maternal histone mRNAs are uniquely processed through polyadenylation in a Stem-Loop Binding Protein (SLBP) dependent manner

Nucleic Acids Research, 2025

Pérez-Roldán, J., Henn, L., Bernués, J., Torras-LLort, M., Tamirisa, S., Belloc, E., Rodríguez-Muñoz, L., Timinszky, G., Jiménez, G., Méndez, R., Carbonell, A., and Azorin, F.

Sunday Paper 2

Histones are essential chromatin proteins whose expression is tightly linked to the cell cycle, with replication-dependent (RD) histones (H2A, H2B, H3, H4, and most H1 variants) upregulated during S-phase to support DNA replication. In contrast, replication-independent variants are expressed outside S-phase and include specialised germline- and oocyte-specific linker histones. During early embryogenesis, development relies on maternally deposited histone proteins and mRNAs prior to zygotic genome activation (ZGA), which occurs after several rapid nuclear divisions depending on species. RD histone mRNAs are uniquely non-polyadenylated, instead terminating in a conserved stem-loop bound by SLBP and processed via the U7 snRNP pathway, a feature thought to be universal among metazoans. Unexpectedly, the authors report that Drosophila maternal RD histone mRNAs are polyadenylated, and investigated this further

Using RT-qPCR and PAT assays across developmental stages, they detect poly(A)+ forms in early embryos and ovaries, with sequencing revealing that these transcripts have truncated 3′UTRs due to cleavage within or near the conserved stem-loop. This processing occurs during oogenesis and depends on cytoplasmic polyadenylation machinery, particularly the PAP Wisp and partially the CPEB Orb. SLBP is present during oogenesis but is required to maintain canonical histone 3′-end processing; its perturbation leads to abnormal polyadenylation patterns. In Xenopus, similar polyadenylation is observed but without stem-loop truncation, indicating evolutionary variation. Functionally, polysome profiling shows maternal histone mRNAs are poorly translated in early embryos but become more actively translated upon loss of the linker histone variant dBigH1, linking chromatin state to translational control.

Learn more about EIRNABio’s polysome profiling services here.

Distinct non-canonical translation initiation modes arise for specific host and viral mRNAs during poxvirus-induced shutoff

Nature Microbiology, 2025

Park, C., Ferrell, A.J., Meade, N., Shen, P.S. and Walsh, D.

Sunday Paper 3

Viruses often induce host “shutoff”, suppressing cellular protein synthesis to prioritise viral translation and dampen antiviral responses. This typically involves disruption of cap-dependent initiation, which relies on factors such as eIF3, eIF4F, and the helicase eIF4A. While many RNA viruses bypass this system using IRES elements, DNA viruses usually target mRNA biogenesis instead. Vaccinia virus (VacV) is unusual among DNA viruses because it replicates in the cytoplasm, produces capped mRNAs, and later enforces shutoff via viral decapping enzymes. It also uses non-canonical translation mechanisms, including 5′ poly(A)-leader–driven initiation enhanced by RACK1 phosphorylation. Despite global shutoff, some host mRNAs continue to be translated, though how this reshapes the proteome remains unclear. Here, the authors revisit host translational control during VacV infection, focussing on latter timepoints.

It is first demonstrated that VacV profoundly reprogrammes host translation during late-stage infection (24 h.p.i.), when host shutoff is most pronounced. Using polysome profiling combined with RNA-seq, the authors found that viral mRNAs dominate ribosome-associated pools and that host transcripts lose normal fractionation patterns, reflecting widespread disruption of translational control. Differential expression and GO analysis revealed selective escape of specific host mRNAs, particularly stress and translation-related genes. Notably, JUN and several heat shock proteins showed increased transcript abundance and enhanced translation efficiency, which was validated by qPCR, reporter assays, and Western blotting. By integrating TE calculations with total RNA changes, the authors derived a “predicted protein output” metric that was confirmed experimentally by Western blot and proteomic datasets. Mechanistically, reporter assays and siRNA knockdowns of eIF3 components demonstrated that JUN uses a distinct, largely eIF3-independent initiation mode during infection, unlike canonical or late viral mRNAs. Finally, functional assays showed JUN induction supports efficient viral spread, linking translational rewiring to infection fitness.

Learn more about EIRNABio’s polysome profiling services here.