Biology subjects

Tsagkogeorga, G.

Publications and source records attributed to Tsagkogeorga, G..

5 recordsLinked to original sources

bioRxiv2025

Compensatory tRNA Modification by DUS3L Confers Resistance to METTL1 Loss in Oesophageal Cancer

tRNA N-methylguanosine (mG46), installed by the METTL1/WDR4 methyltransferase, stabilizes the tRNA pool supporting high proliferative rates. Accordingly, many cancer cell lines are vulnerable to METTL1 loss, underscoring its potential as a therapeutic target. We identify a subset of cell lines insensitive to METTL1 depletion and use oesophageal lines as a model to explore the mechanism. The METTL1-resistant adenocarcinoma line OE33 preserves tRNA balance upon mG46 deficiency by elevating dihydrouridylation at position 47 (D47). Depletion of DUS-L enzymes that catalyse D16/D17/D20/D47 on tRNAs sensitises OE33 to METTL1 loss. Concomitant loss of dihydrouridylation and mG46 destabilizes the canonical L-shaped tRNA structure, disrupts coaxial helix stacking and anticodon-loop presentation, and reduces cellular fitness. Notably, METTL1-sensitive cell lines lack this compensatory pathway due to the deleterious effects of increasing their intrinsically low DUS3L levels. These findings reveal a DUS-L-mediated buffering mechanism that supports tRNA homeostasis in METTL1-resistant cancers and highlight DUS3L abundance as a potential biomarker for predicting METTL1 sensitivity. Moreover, they suggest that combined targeting of DUS-L and METTL1 may provide a therapeutic strategy for overcoming resistance in cancers, exemplified in cell lines such as OE33. HighlightsO_LIThe oesophagus cancer line OE33 shows no proliferative defect upon METTL1/WDR4 loss, despite complete lack of m7G46 on its tRNA. C_LIO_LIOE33 coordinates codon usage and abundance of cognate tRNAs in the absence of METTL1/WDR4; the METTL1/WDR4 sensitive line, OE21, fails to do so. C_LIO_LIDepleting dihydrouridine synthases (DUS-L) renders OE33 sensitive to METTL1/WDR4 loss. C_LIO_LIOE33 responds to lack of METTL1/WDR4 activity by upregulating DUS3L and its activity (D47) on tRNA; the sensitive line OE21 fails to do so. C_LIO_LIMETTL1-sensitive lines have intrinsically low DUS3L and cannot sustain higher levels. C_LIO_LIDUS3L reveals as a potential biomarker for METTL1 sensitivity. C_LI

biochemistry↗

bioRxiv2022

Full-length dystrophin is expressed across human tissues and DMD downregulation commonly occurring in tumours coincides with Duchenne-like molecular alterations

Mutations of the DMD gene, encoding dystrophins, cause Duchenne muscular dystrophy (DMD). Some tumors also display altered dystrophin expression and recent studies identified a developmental onset of DMD. Given that embryogenesis and carcinogenesis share many mechanisms, we analyzed a broad spectrum of tumors to establish whether dystrophin loss evokes related outcomes. Transcriptomic, proteomic, and mutation datasets from fifty tumor tissues and matching controls (10,894 samples) and 140 corresponding tumor cell lines were analyzed. Interestingly, DMD expression was widespread across healthy tissues at levels comparable to housekeeping genes. In 80% of tumors, DMD expression was reduced due to transcriptional downregulation and not somatic mutations. The full-length transcript encoding Dp427 was decreased in 68% of tumors, while Dp71 variants showed variability of expression. Hierarchical clustering analysis of DMD transcripts distinguished malignant from control tissues. Transcriptomes of primary tumors and tumor cell lines with low DMD expression showed enrichment of specific pathways in the differentially expressed genes. Pathways consistently identified: ECM-receptor interaction, calcium signaling and PI3K-Akt, are also altered in DMD muscle. Notably, low DMD expression was associated with a more advanced stage, older age of onset, and reduced survival across different tumors. Thus, DMD transcription occurs throughout a spectrum of normal tissues. The molecular signature associated with its frequent downregulation in malignancies is concordant with changes found in Duchenne muscles, even though these malignancies originate from tissues never previously associated with dystrophin expression or function. Therefore, the importance of this largest known gene extends beyond its roles identified in DMD, certainly into oncology.

genetics↗

bioRxiv2021

Predicting genes associated with RNA methylation pathways using machine learning

RNA methylation plays an important role in functional regulation of RNAs, and has thus attracted an increasing interest in biology and drug discovery. Here, we collected and collated transcriptomic, proteomic, structural and physical interaction data from the Harmonizome database, and applied supervised machine learning to predict novel genes associated with RNA methylation pathways in human. We selected five types of classifiers, which we trained and evaluated using cross-validation on multiple training sets. The best models reached 88% accuracy based on cross-validation, and an average 91% accuracy on the test set. Using protein-protein interaction data, we propose six molecular sub-networks linking model predictions to previously known RNA methylation genes, with roles in mRNA methylation, tRNA processing, rRNA processing, but also protein and chromatin modifications. Our study exemplifies how access to large omics datasets joined by machine learning methods can be used to predict gene function.

bioinformatics↗

bioRxiv2020

Reconstitution of Alveolar Regeneration via novel DATPs by Inflammatory Niches

Tissue regeneration involves a multi-step process composed of diverse cellular hierarchies and states that are also implicated in tissue dysfunction and pathogenesis. Here, we leveraged single-cell RNA sequencing analysis in combination with in vivo lineage tracing and organoid models to fine-map trajectories of alveolar lineage cells during injury repair and regeneration. We identified Damage-Associated Transient Progenitors (DATPs) as a distinct AT2-lineaged population arising during alveolar regeneration. Specifically, we found that IL-1{beta}, secreted by interstitial macrophages, primes a subset of Il1r1+AT2 cells for conversion into DATPs, via a Hif1a-mediated glycolysis pathway, that are functional mediators for mature AT1 cell differentiation. Importantly, we show that chronic inflammation mediated by IL-1{beta} prevents differentiation into AT1 cells, leading to aberrant accumulation of DATPs and impaired alveolar differentiation. Our step-wise fine-mapping of cell fate transitions demonstrates how the inflammatory niche impedes alveolar regeneration by directing stem cell fate behavior.

cell biology↗

bioRxiv2017

A phylogenomic framework and timescale for comparative genomics and evolutionary developmental biology of tunicates

BackgroundTunicates are the closest relatives of vertebrates and are widely used as models to study the evolutionary developmental biology of chordates. Their phylogeny, however, remains poorly understood and to date, only the 18S rRNA nuclear gene and mitogenomes have been used to delineate the major groups of tunicates. To resolve their evolutionary relationships and provide a first estimate of their divergence times, we used a transcriptomic approach to build a phylogenomic dataset including all major tunicate lineages, consisting of 258 evolutionarily conserved orthologous genes from representative species.\n\nResultsPhylogenetic analyses using site-heterogeneous CAT mixture models of amino acid sequence evolution resulted in a strongly supported tree topology resolving the relationships among four major tunicate clades: 1) Appendicularia, 2) Thaliacea + Phlebobranchia + Aplousobranchia, 3) Molgulidae, and 4) Styelidae + Pyuridae. Notably, the morphologically derived Thaliacea are confirmed as the sister-group of the clade uniting Phlebobranchia + Aplousobranchia within which the precise position of the model ascidian genus Ciona remains uncertain. Relaxed molecular clock analyses accommodating the accelerated evolutionary rate of tunicates reveal ancient diversification (~450-350 million years ago) among the major groups and allow comparing their evolutionary age with respect to the major vertebrate model lineages.\n\nConclusionsOur study represents the most comprehensive phylogenomic dataset for the main tunicate lineages. It offers a reference phylogenetic framework and first tentative timescale for tunicates, allowing the direct comparison with vertebrate model species in comparative genomics and evolutionary developmental biology studies.

evolutionary biology↗