July 20th, 2025

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,

  • Zuidhof et al. demonstrate the influence of FTO on C/EBPβ‐LIP translation, impacting on downstream breast cancer dynamics.
  • Youn et al. uncover the role translation, metabolism, and stalling in the differentiation of beige adipocytes.
  • Fellmann et al. reveal atypical Diamond-Blackfan anemia mutations, detailing its phenotype at an anatomical and molecular level.

The m6A demethylase FTO promotes C/EBPβ‐LIP translation to perform oncogenic functions in breast cancer cells

The FEBS Journal, 2025

Zuidhof, H.R., Müller, C., Kortman, G., Wardenaar, R., Stepanova, E., Loayza‐Puch, F. and Calkhoven, C.F.

N6-Methyladenosine (m6A) is the most common mRNA modification, regulating gene expression through methylation by METTL3/14-WTAP and removal by FTO or ALKBH5. FTO, linked to obesity and cancer, often acts as an oncogene, including in triple-negative breast cancer (TNBC), a highly aggressive subtype lacking targeted therapies. C/EBPβ-LIP, a translational isoform of CEBPB, promotes TNBC cell migration and EMT, and its production depends on upstream open reading frames and mTORC1 signalling. This study hypothesizes that FTO may regulate TNBC progression by influencing global or specific mRNA translation, particularly of CEBPB, though FTO’s role in these processes remains poorly understood.

Using shRNA knockdown and the inhibitor entacapone, researchers showed that FTO promotes proliferation and migration in both triple-negative (MDA-MB-231) and luminal A (MCF-7) breast cancer cells, as well as in untransformed MCF10A cells. Knockdown increased m6A markers globally and reduced expression of EMT- and ECM-related genes, like FN1 and MMP1, confirmed by qPCR and transcriptomics. Surprisingly, mRNA stability and translation of these genes were largely unaffected, hinting at indirect regulation. Ribosome profiling showed minimal global effects on translation, but pointed toward reduced C/EBPβ-LIP protein levels—an isoform known to drive migration. MeRIP-qPCR and RIP confirmed that FTO demethylates and directly binds CEBPB mRNA. Furthermore, WTAP knockdown (blocking methylation) upregulated C/EBPβ-LIP protein expression, while its overexpression rescued migration defects in FTO-deficient cells. These findings reveal that FTO fine-tunes cancer cell behaviour through isoform-specific translation regulation of CEBPB.

Learn more about EIRNABio’s ribosome profiling services here.

Cross-talks between metabolic and translational controls during beige adipocyte differentiation

Nature Communications, 2025

Youn, D., Kim, B., Jeong, D., Lee, J.Y., Kim, S., Sumberzul, D., Ginting, R.P., Lee, M.W., Song, J.H., Park, Y.S. and Kim, Y et al

Thermogenic adipocytes, including brown and beige fat cells, specialize in heat production and energy expenditure, offering benefits against obesity-related disorders. Their function is linked to unique morphology and metabolism, including multilocular lipid droplets and mitochondria-rich cytoplasm. Differentiation into thermogenic adipocytes involves significant gene expression changes and is influenced by external stimuli like cold. While transcriptional and epigenetic regulation are well-studied, post-transcriptional mechanisms like translation remain underexplored. Metabolism and gene expression are interdependent, with metabolic pathways influencing chromatin modifications and gene regulation. However, it is not currently clear as to how translation and varius metabolic processes influence each other to direct thermogenic adipocyte differentiation, a process the authors aim to investigate.

Utilising ribosome profiling and TMT (tandem mass tag) mass spectrometry, they uncover that, during beige adipocyte differentiation, mRNAs encoding components of the oxidative phosphorylation (OXPHOS) complexes, particularly those derived from mitochondrial DNA, showed reduced ribosome occupancy and protein production despite increased transcript levels. APEX-Seq analysis revealed that these mRNAs were localized to the mitochondrial outer membrane independently of ribosomes . In contrast, Complex II genes, entirely nuclear-encoded, maintained translation and protein expression. Ribosome profiling data at single-nucleotide resolution uncovered increased ribosome stalling at glutamate codons, associated with reduced glutamyl-tRNA charging due to elevated glutamate-ammonia ligase (GLUL) expression and glutamate depletion. Reporter assays and northern blots confirmed impaired translation of glutamate-rich sequences. These translation stalls selectively reduced expression of glutamate-rich cytoskeletal genes, promoting actin disassembly, a known facilitator of adipogenesis. The findings link glutamate metabolism, translational control, and cytoskeletal remodelling in thermogenic fat cell development.

Learn more about EIRNABio’s ribosome profiling services here.

An atypical form of 60S ribosomal subunit in Diamond-Blackfan anemia linked to RPL17 variants

JCI Insight, 2025

Fellmann, F., Saunders, C., O’donohue, M.F., Reid, D.W., McFadden, K.A., Montel-Lehry, N., Yu, C., Fang, M., Zhang, J., Royer-Bertrand, B and Farinelli, P et al

Diamond-Blackfan Anemia (DBA) is a rare genetic disorder marked by congenital anemia and various developmental defects. It stems from haploinsufficiency of ribosomal proteins, disrupting ribosome biogenesis and triggering nucleolar stress, notably stabilizing p53 via the 5S RNP–HDM2 pathway. This impairs erythroid progenitor proliferation, possibly through apoptosis or reduced translation of key proteins like GATA1. DBA exemplifies ribosomopathies—disorders of ribosome dysfunction—whose tissue-specific effects remain poorly understood. Although primarily hematopoietic, ribosomal protein mutations have also been linked to non-hematological diseases such as neurodevelopmental disorders and skeletal dysplasias, highlighting broader consequences of ribosome-related defects. Here, the authors describe a novel form of the 60S subunit in DBA linked to RPL17 variants.

Researchers identified RPL17 mutations as a novel cause of Diamond-Blackfan Anemia (DBA) in two families and a larger DBA cohort. In Family 1, a splice-site mutation (c.217-3C>G) caused exon 4 skipping, confirmed by RT-PCR and immunoblotting, leading to protein instability and haploinsufficiency. Family 2 carried a frameshift mutation (c.452delC), also resulting in reduced RPL17. In vitro cultures of patient-derived CD34+ cells showed impaired erythroid proliferation without excess apoptosis. Zebrafish CRISPR/Cas9 and morpholino models recapitulated anemia and craniofacial defects, which were rescued by wild-type RPL17 mRNA. Northern blotting revealed disrupted rRNA processing and abnormal 5.8S rRNA species (5.8SC), also confirmed by siRNA knockdown. Sucrose gradient centrifugation showed reduced 60S subunits and incorporation of 5.8SC into active ribosomes. Ribosome profiling revealed reduced translation of key developmental and signalling mRNAs (particularly of the Wnt family), with compensatory upregulation of ribosomal protein translation. These findings demonstrate that RPL17 mutations impair ribosome biogenesis and function, contributing to DBA pathogenesis through both quantitative and qualitative translational defects.

Learn more about EIRNABio’s ribosome profiling services here.

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