Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
Molecular Systems Biology
by YiQing Lü, Tiffany Cho, Saptaparna Mukherjee, Carmen Florencia Suarez, Nicolas S Gonzalez-Foutel, Ahmad Malik, Sebastien Martinez, Dzana Dervovic, Robin Hyunseo Oh, Ellen Langille, Khalid N Al-Zahrani, Lisa Hoeg, Zhen Yuan Lin, Ricky Tsai, Geraldine Mbamalu, Varda Rotter, Patricia Ashton-Prolla, Jason Moffat, Lucia Beatriz Chemes, Anne-Claude Gingras, Moshe Oren, Daniel Durocher, Daniel Schramek
1w ago
Genome-wide p53 protein stability screens provide a comprehensive network view of the processes regulating wildtype and mutant p53 and uncover potential targets for reinforcing wild-type p53 or targeting mutant p53 in cancer.AbstractTumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we s ..read more
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Interrogation of RNA-protein interaction dynamics in bacterial growth
Molecular Systems Biology
by Mie Monti, Reyme Herman, Leonardo Mancini, Charlotte Capitanchik, Karen Davey, Charlotte S Dawson, Jernej Ule, Gavin H Thomas, Anne E Willis, Kathryn S Lilley, Eneko Villanueva
2w ago
A dynamic analysis of RNA-protein interaction rewiring across growth phases detects extensive reorganisation of the RBPome and reveals the RNA binding properties for 17 unannotated E. coli proteins and their differential impact on cell growth and evolutionary conservation.AbstractCharacterising RNA–protein interaction dynamics is fundamental to understand how bacteria respond to their environment. In this study, we have analysed the dynamics of 91% of the Escherichia coli expressed proteome and the RNA-interaction properties of 271 RNA-binding proteins (RBPs) at different growth phases. We fin ..read more
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Mutational biases favor complexity increases in protein interaction networks after gene duplication
Molecular Systems Biology
by Angel F Cisneros, Lou Nielly-Thibault, Saurav Mallik, Emmanuel D Levy, Christian R Landry
3w ago
Duplicated self-interacting proteins can interact with themselves (homomers) or one another (heteromers). To understand whether natural selection is required to keep homomers over heteromers (or vice versa), the evolution of such duplicate proteins is simulated in the absence of new functions.AbstractBiological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following ..read more
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Cellular energy regulates mRNA degradation in a codon-specific manner
Molecular Systems Biology
by Pedro Tomaz da Silva, Yujie Zhang, Evangelos Theodorakis, Laura D Martens, Vicente A Yépez, Vicent Pelechano, Julien Gagneur
1M ago
Analysis of GTEx data and perturbation experiments in yeast show that cellular energy regulates the effect of optimal codon usage on mRNA stability.AbstractCodon optimality is a major determinant of mRNA translation and degradation rates. However, whether and through which mechanisms its effects are regulated remains poorly understood. Here we show that codon optimality associates with up to 2-fold change in mRNA stability variations between human tissues, and that its effect is attenuated in tissues with high energy metabolism and amplifies with age. Mathematical modeling and perturbation dat ..read more
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PIFiA: self-supervised approach for protein functional annotation from single-cell imaging data
Molecular Systems Biology
by Anastasia Razdaibiedina, Alexander Brechalov, Helena Friesen, Mojca Mattiazzi Usaj, Myra Paz David Masinas, Harsha Garadi Suresh, Kyle Wang, Charles Boone, Jimmy Ba, Brenda Andrews
1M ago
PIFiA is a self-supervised deep-learning approach for protein functional annotation from single-cell images. It generates feature profiles from images of the yeast ORF-GFP collection that can be used in downstream analyses.AbstractFluorescence microscopy data describe protein localization patterns at single-cell resolution and have the potential to reveal whole-proteome functional information with remarkable precision. Yet, extracting biologically meaningful representations from cell micrographs remains a major challenge. Existing approaches often fail to learn robust and noise-invariant featu ..read more
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AI-guided pipeline for protein–protein interaction drug discovery identifies a SARS-CoV-2 inhibitor
Molecular Systems Biology
by Philipp Trepte, Christopher Secker, Julien Olivet, Jeremy Blavier, Simona Kostova, Sibusiso B Maseko, Igor Minia, Eduardo Silva Ramos, Patricia Cassonnet, Sabrina Golusik, Martina Zenkner, Stephanie Beetz, Mara J Liebich, Nadine Scharek, Anja Schütz, Marcel Sperling, Michael Lisurek, Yang Wang, Kerstin Spirohn, Tong Hao, Michael A Calderwood, David E Hill, Markus Landthaler, Soon Gang Choi, Jean-Claude Twizere, Marc Vidal, Erich E Wanker
1M ago
A new pipeline for prioritizing protein-protein interactions (PPIs) for drug discovery, combines machine learning-based scoring of quantitative PPI data, protein complex structure prediction and virtual drug screening.AbstractProtein–protein interactions (PPIs) offer great opportunities to expand the druggable proteome and therapeutically tackle various diseases, but remain challenging targets for drug discovery. Here, we provide a comprehensive pipeline that combines experimental and computational tools to identify and validate PPI targets and perform early-stage drug discovery. We have devel ..read more
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Integrated annotation prioritizes metabolites with bioactivity in inflammatory bowel disease
Molecular Systems Biology
by Amrisha Bhosle, Sena Bae, Yancong Zhang, Eunyoung Chun, Julian Avila-Pacheco, Ludwig Geistlinger, Gleb Pishchany, Jonathan N Glickman, Monia Michaud, Levi Waldron, Clary B Clish, Ramnik J Xavier, Hera Vlamakis, Eric A Franzosa, Wendy S Garrett, Curtis Huttenhower
1M ago
MACARRoN combines ecological and epidemiological metrics to prioritize metabolic features with potential bioactivity in a phenotype of interest. Its application to inflammatory bowel disease (IBD) prioritizes both previously IBD-linked and less-explored microbiome-associated metabolites.AbstractMicrobial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological prope ..read more
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Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis
Molecular Systems Biology
by Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, Claudia Kutter
1M ago
Integration of genomics datasets and patient data reveals estrogen receptor agonist-mediated restoration of molecular and physiological changes and identifies a TEAD autopalmitoylation inhibitor as a potential therapeutic for metabolic dysfunction-associated steatotic liver disease (MASLD).AbstractSex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an es ..read more
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Network integration of thermal proteome profiling with multi-omics data decodes PARP inhibition
Molecular Systems Biology
by Mira L Burtscher, Stephan Gade, Martin Garrido-Rodriguez, Anna Rutkowska, Thilo Werner, H Christian Eberl, Massimo Petretich, Natascha Knopf, Katharina Zirngibl, Paola Grandi, Giovanna Bergamini, Marcus Bantscheff, Maria Fälth-Savitski, Julio Saez-Rodriguez
1M ago
COSMOS, a network-based framework, can integrate functional proteomics data, such as Thermal Proteome Profiling (TPP), with other omics data modalities. It is used to generate multi-omics mechanistic hypotheses, as showcased in this study for PARP inhibition.AbstractComplex disease phenotypes often span multiple molecular processes. Functional characterization of these processes can shed light on disease mechanisms and drug effects. Thermal Proteome Profiling (TPP) is a mass-spectrometry (MS) based technique assessing changes in thermal protein stability that can serve as proxies of functional ..read more
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Unique transcriptomes of sensory and non-sensory neurons: insights from Splicing Regulatory States
Molecular Systems Biology
by Ludovica Ciampi, Luis Serrano, Manuel Irimia
1M ago
This Review discusses the general rules of cell type- and tissue-specific alternative splicing programs in the brain and in specialized sensory neurons and proposes a new paradigm on how ‘splicing regulatory states’ are established, how they can diversify and how they are linked to human diseases.AbstractAlternative Splicing (AS) programs serve as instructive signals of cell type specificity, particularly within the brain, which comprises dozens of molecularly and functionally distinct cell types. Among them, retinal photoreceptors stand out due to their unique transcriptome, making them a par ..read more
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