@misc{MTMT:34718081, title = {mulea - an R package for enrichment analysis using multiple ontologies and empirical FDR correction}, url = {https://m2.mtmt.hu/api/publication/34718081}, author = {Turek, Cezary and Olbei, Marton and Stirling, Tamás and Fekete, Gergely and Tasnádi, Ervin Áron and Gul, Leila and Bohár, Balázs and Papp, Balázs and Jurkowski, Wiktor and Ari, Eszter}, unique-id = {34718081}, abstract = {Traditional gene set enrichment analyses are typically limited to a few ontologies and do not account for the interdependence of gene sets or terms, resulting in overcorrected p-values. To address these challenges, we introduce mulea, an R package offering comprehensive overrepresentation and functional enrichment analysis. mulea employs an innovative empirical false discovery rate (eFDR) correction method, specifically designed for interconnected biological data, to accurately identify significant terms within diverse ontologies. mulea expands beyond traditional tools by incorporating a wide range of ontologies, encompassing Gene Ontology, pathways, regulatory elements, genomic locations, and protein domains. This flexibility enables researchers to tailor enrichment analysis to their specific questions, such as identifying enriched transcriptional regulators in gene expression data or overrepresented protein domains in protein sets. To facilitate seamless analysis, mulea provides gene sets (in standardised GMT format) for 27 model organisms, covering 16 databases and various identifiers resulting in almost 900 files. Additionally, the muleaData ExperimentData Bioconductor package simplifies access to these pre-defined ontologies. Finally, mulea's architecture allows for easy integration of user-defined ontologies, expanding its applicability across diverse research areas. Availability and Implementation: Software for the tools demonstrated in this article is available as an R package on GitHub: https://github.com/ELTEbioinformatics/mulea.}, year = {2024}, orcid-numbers = {Stirling, Tamás/0000-0002-8964-6443; Ari, Eszter/0000-0001-7774-1067} } @article{MTMT:34479463, title = {The metabolic domestication syndrome of budding yeast}, url = {https://m2.mtmt.hu/api/publication/34479463}, author = {Tengölics, Roland and Szappanos, Balázs and Mülleder, M and Kalapis, Dorottya and Grézal, Gábor and Sajben, Cs and Agostini, F and Mokochinski, Joao Benhur and Bálint, Balázs and Nagy, LG and Ralser, M and Papp, Balázs}, doi = {10.1073/pnas.2313354121}, journal-iso = {P NATL ACAD SCI USA}, journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, volume = {121}, unique-id = {34479463}, issn = {0027-8424}, year = {2024}, eissn = {1091-6490}, orcid-numbers = {Szappanos, Balázs/0000-0002-5075-1799; Grézal, Gábor/0000-0003-1685-4791} } @article{MTMT:34202172, title = {Principles of metabolome conservation in animals}, url = {https://m2.mtmt.hu/api/publication/34202172}, author = {Liska, Orsolya and Boross, Gábor and Rocabert, Charles and Szappanos, Balázs and Tengölics, Roland and Papp, Balázs}, doi = {10.1073/pnas.2302147120}, journal-iso = {P NATL ACAD SCI USA}, journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, volume = {120}, unique-id = {34202172}, issn = {0027-8424}, abstract = {Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients.}, keywords = {PROTEIN; MODELS; Systems biology; RESOURCE; molecular evolution; Optimality; METABOLIC NETWORKS; Phylogenetic comparative method}, year = {2023}, eissn = {1091-6490}, orcid-numbers = {Boross, Gábor/0000-0002-7208-5678; Szappanos, Balázs/0000-0002-5075-1799} } @article{MTMT:34106372, title = {How selection shapes the short- and long-term dynamics of molecular evolution}, url = {https://m2.mtmt.hu/api/publication/34106372}, author = {Pál, Csaba and Papp, Balázs}, doi = {10.1073/pnas.2311012120}, journal-iso = {P NATL ACAD SCI USA}, journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, volume = {120}, unique-id = {34106372}, issn = {0027-8424}, year = {2023}, eissn = {1091-6490} } @article{MTMT:34067381, title = {Phase-separated ribosome-nascent chain complexes in genotoxic stress response}, url = {https://m2.mtmt.hu/api/publication/34067381}, author = {Szatmári, Orsolya and Nagy-Mikó, Bence and Györkei, Ádám and Varga, Dániel and H. Kovács, Bálint Barna and Igaz, Nóra and Bognár, Bence and Rázga, Zsolt and Nagy, Gábor and Zsindely, Nóra and Bodai, László and Papp, Balázs and Erdélyi, Miklós and Csontné Kiricsi, Mónika and Blastyák, András and Collart, Martine A and Boros, Imre Miklós and Villanyi, Zoltan}, doi = {10.1261/rna.079755.123}, journal-iso = {RNA}, journal = {RNA-A PUBLICATION OF THE RNA SOCIETY}, volume = {29}, unique-id = {34067381}, issn = {1355-8382}, abstract = {Assemblysomes are EDTA- and RNase-resistant ribonucleoprotein (RNP) complexes of paused ribosomes with protruding nascent polypeptide chains. They have been described in yeast and human cells for the proteasome subunit Rpt1, and the disordered N-terminal part of the nascent chain was found to be indispensable for the accumulation of the Rpt1-RNP into assemblysomes. Motivated by this, to find other assemblysome-associated RNPs we used bioinformatics to rank subunits of Saccharomyces cerevisiae protein complexes according to their N-terminal disorder propensity. The results revealed that gene products involved in DNA repair are enriched among the top candidates. The Sgs1 DNA helicase was chosen for experimental validation. We found that indeed nascent chains of Sgs1 form EDTA-resistant RNP condensates, assemblysomes by definition. Moreover, upon exposure to UV, SGS1 mRNA shifted from assemblysomes to polysomes, suggesting that external stimuli are regulators of assemblysome dynamics. We extended our studies to human cell lines. The BLM helicase, ortholog of yeast Sgs1, was identified upon sequencing assemblysome-associated RNAs from the MCF7 human breast cancer cell line, and mRNAs encoding DNA repair proteins were overall enriched. Using the radiation-resistant A549 cell line, we observed by transmission electron microscopy that 1,6-hexanediol, an agent known to disrupt phase-separated condensates, depletes ring ribosome structures compatible with assemblysomes from the cytoplasm of cells and makes the cells more sensitive to X-ray treatment. Taken together these findings suggest that assemblysomes may be a component of the DNA damage response from yeast to human.}, year = {2023}, eissn = {1469-9001}, pages = {1557-1574}, orcid-numbers = {Varga, Dániel/0000-0003-0391-5057; Igaz, Nóra/0000-0003-1580-4397; Rázga, Zsolt/0000-0003-4717-8482; Nagy, Gábor/0000-0001-5464-1135; Zsindely, Nóra/0000-0002-6189-3100; Bodai, László/0000-0001-8411-626X; Erdélyi, Miklós/0000-0002-9501-5752; Csontné Kiricsi, Mónika/0000-0002-8416-2052; Boros, Imre Miklós/0000-0001-8504-9687} } @article{MTMT:33634821, title = {Characterization of antibiotic resistomes by reprogrammed bacteriophage-enabled functional metagenomics in clinical strains}, url = {https://m2.mtmt.hu/api/publication/33634821}, author = {Apjok, Gábor and Számel, Mónika and Christodoulou, Chryso and Seregi, Viktória and Vásárhelyi, Bálint Márk and Stirling, Tamás and Eszenyi, Bálint Dénes and Sári , Tóbiás and Vidovics, Fanni and Nagrand, Erika and Kovács, Dorina and Szili, Petra and Lantos, Ildikó Ilona and Méhi, Orsolya Katinka and Jangir, Pramod Kumar and Herczeg, Róbert and Gálik, Bence and Urbán, Péter and Gyenesei, Attila and Draskovits, Gábor and Nyerges, Ákos and Fekete, Gergely and Bodai, László and Zsindely, Nóra and Dénes, Béla and Yosef, Ido and Qimron, Udi and Papp, Balázs and Pál, Csaba and Kintses, Bálint}, doi = {10.1038/s41564-023-01320-2}, journal-iso = {NAT MICROBIOL}, journal = {NATURE MICROBIOLOGY}, volume = {8}, unique-id = {33634821}, issn = {2058-5276}, abstract = {Functional metagenomics is a powerful experimental tool to identify antibiotic resistance genes (ARGs) in the environment, but the range of suitable host bacterial species is limited. This limitation affects both the scope of the identified ARGs and the interpretation of their clinical relevance. Here we present a functional metagenomics pipeline called Reprogrammed Bacteriophage Particle Assisted Multi-species Functional Metagenomics (DEEPMINE). This approach combines and improves the use of T7 bacteriophage with exchanged tail fibres and targeted mutagenesis to expand phage host-specificity and efficiency for functional metagenomics. These modified phage particles were used to introduce large metagenomic plasmid libraries into clinically relevant bacterial pathogens. By screening for ARGs in soil and gut microbiomes and clinical genomes against 13 antibiotics, we demonstrate that this approach substantially expands the list of identified ARGs. Many ARGs have species-specific effects on resistance; they provide a high level of resistance in one bacterial species but yield very limited resistance in a related species. Finally, we identified mobile ARGs against antibiotics that are currently under clinical development or have recently been approved. Overall, DEEPMINE expands the functional metagenomics toolbox for studying microbial communities.}, year = {2023}, eissn = {2058-5276}, pages = {410-423}, orcid-numbers = {Apjok, Gábor/0000-0002-8627-2378; Vásárhelyi, Bálint Márk/0000-0003-1782-8691; Stirling, Tamás/0000-0002-8964-6443; Méhi, Orsolya Katinka/0009-0004-7918-913X; Jangir, Pramod Kumar/0000-0001-8330-0655; Herczeg, Róbert/0000-0002-5903-0082; Gálik, Bence/0000-0002-3949-7005; Nyerges, Ákos/0000-0002-1581-490X; Bodai, László/0000-0001-8411-626X; Zsindely, Nóra/0000-0002-6189-3100; Dénes, Béla/0000-0002-9889-529X} } @article{MTMT:33632100, title = {Plasticity and stereotypic rewiring of the transcriptome upon bacterial evolution of antibiotic resistance}, url = {https://m2.mtmt.hu/api/publication/33632100}, author = {Grézal, Gábor and Spohn, Réka and Méhi, Orsolya Katinka and Dunai, Anett and Lázár, Viktória and Bálint, Balázs and Nagy, István and Pál, Csaba and Papp, Balázs}, doi = {10.1093/molbev/msad020}, journal-iso = {MOL BIOL EVOL}, journal = {MOLECULAR BIOLOGY AND EVOLUTION}, volume = {40}, unique-id = {33632100}, issn = {0737-4038}, abstract = {Bacterial evolution of antibiotic resistance frequently has deleterious side effects on microbial growth, virulence, and susceptibility to other antimicrobial agents. However, it is unclear how these trade-offs could be utilized for manipulating antibiotic resistance in the clinic, not least because the underlying molecular mechanisms are poorly understood. Using laboratory evolution, we demonstrate that clinically relevant resistance mutations in Escherichia coli constitutively rewire a large fraction of the transcriptome in a repeatable and stereotypic manner. Strikingly, lineages adapted to functionally distinct antibiotics and having no resistance mutations in common show a wide range of parallel gene expression changes that alter oxidative stress response, iron homeostasis, and the composition of the bacterial outer membrane and cell surface. These common physiological alterations are associated with changes in cell morphology and enhanced sensitivity to antimicrobial peptides. Finally, the constitutive transcriptomic changes induced by resistance mutations are largely distinct from those induced by antibiotic stresses in the wild-type. This indicates a limited role for genetic assimilation of the induced antibiotic stress response during resistance evolution. Our work suggests that diverse resistance mutations converge on similar global transcriptomic states that shape genetic susceptibility to antimicrobial compounds.}, year = {2023}, eissn = {1537-1719}, orcid-numbers = {Grézal, Gábor/0000-0003-1685-4791; Méhi, Orsolya Katinka/0009-0004-7918-913X} } @article{MTMT:33552618, title = {Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan}, url = {https://m2.mtmt.hu/api/publication/33552618}, author = {Correia-Melo, C. and Kamrad, S. and Tengölics, Roland and Messner, C.B. and Trebulle, P. and Townsend, S. and Jayasree, Varma S. and Freiwald, A. and Heineike, B.M. and Campbell, K. and Herrera-Dominguez, L. and Kaur, Aulakh S. and Szyrwiel, L. and Yu, J.S.L. and Zelezniak, A. and Demichev, V. and Mülleder, M. and Papp, Balázs and Alam, M.T. and Ralser, M.}, doi = {10.1016/j.cell.2022.12.007}, journal-iso = {CELL}, journal = {CELL}, volume = {186}, unique-id = {33552618}, issn = {0092-8674}, abstract = {Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan. © 2022 The Author(s)}, keywords = {chronological aging; metabolic microenvironment; eukaryotic longevity; metabolite exchange interactions}, year = {2023}, eissn = {1097-4172}, pages = {63-79.e21} } @article{MTMT:33101945, title = {TFLink: an integrated gateway to access transcription factor–target gene interactions for multiple species}, url = {https://m2.mtmt.hu/api/publication/33101945}, author = {Liska, Orsolya and Bohár, Balázs and Hidas, András and Korcsmáros, Tamás and Papp, Balázs and Fazekas, Dávid and Ari, Eszter}, doi = {10.1093/database/baac083}, journal-iso = {DATABASE-OXFORD}, journal = {DATABASE-JOURNAL OF BIOLOGICAL DATABASES AND CURATION}, volume = {2022}, unique-id = {33101945}, issn = {1758-0463}, abstract = {Analysis of transcriptional regulatory interactions and their comparisons across multiple species are crucial for progress in various fields in biology, from functional genomics to the evolution of signal transduction pathways. However, despite the rapidly growing body of data on regulatory interactions in several eukaryotes, no databases exist to provide curated high-quality information on transcription factor–target gene interactions for multiple species. Here, we address this gap by introducing the TFLink gateway, which uniquely provides experimentally explored and highly accurate information on transcription factor–target gene interactions (∼12 million), nucleotide sequences and genomic locations of transcription factor binding sites (∼9 million) for human and six model organisms: mouse, rat, zebrafish, fruit fly, worm and yeast by integrating 10 resources. TFLink provides user-friendly access to data on transcription factor–target gene interactions, interactive network visualizations and transcription factor binding sites, with cross-links to several other databases. Besides containing accurate information on transcription factors, with a clear labelling of the type/volume of the experiments (small-scale or high-throughput), the source database and the original publications, TFLink also provides a wealth of standardized regulatory data available for download in multiple formats. The database offers easy access to high-quality data for wet-lab researchers, supplies data for gene set enrichment analyses and facilitates systems biology and comparative gene regulation studies.}, year = {2022}, eissn = {1758-0463}, orcid-numbers = {Hidas, András/0000-0002-6030-8459; Fazekas, Dávid/0000-0001-7605-592X; Ari, Eszter/0000-0001-7774-1067} } @article{MTMT:33040340, title = {A Single Early Introduction Governed Viral Diversity in the Second Wave of SARS-CoV-2 Epidemic in Hungary}, url = {https://m2.mtmt.hu/api/publication/33040340}, author = {Ari, Eszter and Vásárhelyi, Bálint Márk and Kemenesi, Gábor and Tóth, Gábor Endre and Zana, Brigitta and Somogyi, Balázs Antal and Lanszki, Zsófia and Röst, Gergely and Jakab, Ferenc and Papp, Balázs and Kintses, Bálint}, doi = {10.1093/ve/veac069}, journal-iso = {VIRUS EVOL}, journal = {VIRUS EVOLUTION}, volume = {8}, unique-id = {33040340}, abstract = {Retrospective evaluation of past waves of the SARS-CoV-2 epidemic is key for designing optimal interventions against future waves and novel pandemics. Here we report on analysing genome sequences of SARS-CoV-2 from the first two waves of the epidemic in 2020 in Hungary, mirroring a suppression and a mitigation strategy, respectively. Our analysis reveals that the two waves markedly differed in viral diversity and transmission patterns. Specifically, unlike in several European areas or in the USA, we have found no evidence for early introduction and cryptic transmission of the virus in the first wave of the pandemic in Hungary. Despite the introduction of multiple viral lineages, extensive community spread was prevented by a timely national lockdown in March 2020. In sharp contrast, the majority of the cases in the much larger second wave can be linked to a single transmission lineage of the pan-European B.1.160 variant. This lineage was introduced unexpectedly early, followed by a two-month-long cryptic transmission before a soar of detected cases in September 2020. Epidemic analysis has revealed that the dominance of this lineage in the second wave was not associated with an intrinsic transmission advantage. This finding is further supported by the rapid replacement of B.1.160 by the alpha variant (B.1.1.7) that launched the third wave of the epidemic in February 2021. Overall, these results illustrate how the founder effect in combination with cryptic transmission, instead of repeated international introductions or higher transmissibility, can govern viral diversity.}, year = {2022}, eissn = {2057-1577}, orcid-numbers = {Ari, Eszter/0000-0001-7774-1067; Vásárhelyi, Bálint Márk/0000-0003-1782-8691; Kemenesi, Gábor/0000-0001-9775-3065; Tóth, Gábor Endre/0000-0002-7201-9646; Lanszki, Zsófia/0000-0003-3116-4633; Röst, Gergely/0000-0001-9476-3284} }