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STAG2 Mutations Drive Development of Myelodysplastic Syndromes by Promoting R-Loop-Mediated Genomic Instability and Activation of cGAS-STING

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Blood 2024年 144卷 4105-4105页

作者： Lin Han Benjamin Braun Caroline A. Conway Amy Wang Johann-Christoph Jann Yihua Wang Kate I. Drachman Qingqing Yan Elodie Hatchi Phillip Wulfridge William Doyle Caroline N. Pitton Kavitha Sarma Zuzana Tothova Department of Medical Oncology Dana-Farber Cancer Institute Boston MA Cancer Program Broad Institute Cambridge MA Gene Expression and Regulation Program The Wistar Institute Philadelphia PA

genes encoding components of the cohesin complex, including STAG2 , are frequently mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and serve as predictors of high-risk disease and poor outcomes. While it is known that cohesin mutations selectively impair DNA damage repair (DDR) and gene-regulatory functions, their role in transcription-coupled DNA damage is unknown. We have previously characterized transcriptional and splicing consequences of STAG2 mutations and identified genetic and pharmacologic dependencies on DDR and splicing. Furthermore, we identified upregulation of type 1 interferon and cGAS/STING pathways in STAG2 knockout (KO) AML cell lines, both known to be triggered by DNA-RNA hybrids (R-loops) in the cytoplasm. We therefore set out to investigate the role of transcription-coupled R-loops in the development of cohesin-mutant MDS and AML, and their potential as a novel therapeutic liability. We first analyzed the effects of STAG2 loss-of-function mutations on transcriptional regulation of a curated set of R-loop regulators and associated proteins, and identified significant differential expression of 109/461 (24%) genes, including downregulation of TOP2A and AQR involved in R-loop resolution. This was associated with increased levels of R-loops, as assessed by immunofluorescence staining and dot blot, G1/S cell cycle arrest and DNA damage accumulation in STAG2 KO cells. R-loop resolution using RNase H1 overexpression restored near-normal levels of dsDNA breaks, as well as cell cycle arrest and apoptosis. To investigate the role of R-loops during MDS development in vivo , we established a new transgenic model of MDS by crossing conditional knockout mice of Tet2 and Stag2 , which are frequently co-mutated in MDS. Bone marrow analysis of Tet2/Stag2 -mutant mice demonstrated multiple features of MDS, including ineffective hematopoiesis, erythroid and megakaryocyte dysplasia, and poor overall survival due to leukemic transformati

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Yeast applied readthrough inducing system (YARIS): an invivo assay for the comprehensive study of translational readthrough

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NUCLEIC ACIDS RESEARCH 2019年第12期47卷 6339-6350页

作者： Beznoskova, Petra Pavlikova, Zuzana Zeman, Jakub Aitken, Colin Echeverria Valasek, Leos S. Laboratory of Regulation of Gene Expression Institute of Microbiology ASCR Videnska 1083 142 20 Prague the Czech Republic Correspondence may also be addressed to Petra Beznosková. Tel: +420 241 062 288 Email: p.beznoskova@seznam.cz Laboratory of Regulation of Gene Expression Institute of Microbiology ASCR Videnska 1083 142 20 Prague the Czech Republic Laboratory of Regulation of Gene Expression Institute of Microbiology ASCR Videnska 1083 142 20 Prague the Czech Republic Biology Department and Biochemistry Program Vassar College 124 Raymond Avenue Poughkeepsie 12601 NY USA Laboratory of Regulation of Gene Expression Institute of Microbiology ASCR Videnska 1083 142 20 Prague the Czech Republic To whom correspondence should be addressed. Email: valasekl@biomed.cas.cz

Stop codon readthrough-the decoding of a stop codon by a near-cognate tRNA-is employed by viruses to balance levels of enzymatic and structural proteins and by eukaryotic cells to enable isoform-specific protein synthesis in response to external stimuli. Owing to the prevalence of premature termination codons in human disease, readthrough has emerged as an attractive therapeutic target. A growing list of various features, for example the +4 nucleotide immediately following the stop codon, modulate readthrough levels, underscoring the need for systematic investigation of readthrough. Here, we identified and described a complete group of yeast tRNAs that induce readthrough in the stop-codon tetranucleotide manner when overexpressed, designated readthrough-inducing tRNAs (rti-tRNAs). These rti-tRNAs are the keystones of YARIS (yeast applied readthrough inducing system), a reporter-based assay enabling simultaneous detection of readthrough levels at all twelve stop-codon tetranucleotides and as a function of the complete set of rti-tRNAs. We demonstrate the utility of YARIS for systematic study of translation readthrough by employing it to interrogate the effects of natural rti-tRNA modifications, as well as various readthrough-inducing drugs(RTIDs). This analysis identified a variety of genetic interactions demonstrating the power of YARIS to characterize existing and identify novel RTIDs.

关键词： Structural Protein keystone Yeast Terminator Codon Nonsense Codon External stimuli Eukaryotic Cells

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MapR: A Method for Identifying Native R-Loops Genome Wide

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Current Protocols in Molecular Biology 2020年第1期130卷 e113页

作者： Yan, Qingqing Sarma, Kavitha Gene Expression and Regulation Program The Wistar Institute Philadelphia PA United States Epigenetics Institute University of Pennsylvania Philadelphia PA United States

R-loops are abundant, RNA-containing chromatin structures that form in the genomes of both eukaryotes and prokaryotes. Devising methods to identify the precise genomic locations of R-loops is critical to understand how these structures regulate numerous cellular processes, including replication, termination, and chromosome segregation, and how their unscheduled formation results in disease. Here, we describe a new, highly sensitive, and antibody-independent method, MapR, to profile native R-loops genome wide. MapR takes advantage of the natural specificity of the RNase H enzyme to recognize DNA:RNA hybrids, a defining feature of R-loops, and combines it with a CUT&RUN approach to target, cleave, and release R-loops that can then be sequenced. MapR has low background, is faster than current R-loop detection technologies, and can be performed in any cell type without the need to generate stable cell lines. © 2020 by John Wiley & Sons, Inc. © 2020 John Wiley & Sons, Inc.

关键词： chromatin DNA:RNA hybrids gene expression R-loops transcription

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Correction: NFκB activation by hypoxic small extracellular vesicles drives oncogenic reprogramming in a breast cancer microenvironment

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Oncogene 2023年第9期42卷 708页

作者： Irene Bertolini Michela Perego Jagadish C Ghosh Andrew V Kossenkov Dario C Altieri Immunology Microenvironment and Metastasis Program The Wistar Institute Philadelphia PA 19104 USA. Bioinformatics Shared Resource The Wistar Institute Philadelphia PA 19104 USA. Gene Expression and Regulation Program The Wistar Institute Philadelphia PA 19104 USA. Immunology Microenvironment and Metastasis Program The Wistar Institute Philadelphia PA 19104 USA. daltieri@***.

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PHARMACOLOGICAL MODULATION OF THE INTEGRATED STRESS RESPONSE ALTERS PATHOLOGY IN AN AMYOTROPHIC LATERAL SCLEROSIS MOUSE MODEL

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IBRO Neuroscience Reports 2023年 15卷 S472-S472页

作者： Nuria Peregrín Pastor Elias Marlin Miguel Valencia Roberto Ferrero Maria Jesus Nicolás Apesteguía Rodrigo Vinueza-Gavilanes Julio Artieda Monserrat Arrasate Tomás Aragón Center for Applied Medical Research (CIMA) Gene Therapy And Regulation Of Gene Expression Program Pamplona Spain Center for Applied Medical Research (CIMA) Neuroscience Program Pamplona Spain IdiSNA Navarra Institute For Health Research Pamplona Spain University of Navarra Institute Of Data Science And Artificial Intelligence (datai) Pamplona Spain Clínica Universidad de Navarra Department Of Neurology Pamplona Spain University of Navarra School Of Medicine Pamplona Spain

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MDEmic in a use case for microscopy metadata harmonization: Facilitating FAIR principles in practical application with metadata annotation tools

arXiv

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arXiv 2021年

作者： Kunis, Susanne Hänsch, Sebastian Schmidt, Christian Wong, Frances Strambio-De-Castillia, Caterina Weidtkamp-Peters, Stefanie Department of Biology/Chemistry Centre for Cellular Nanoanalytics University Osnabrueck Osnabrueck49076 Germany Centre for Advanced Imaging University Duesseldorf Duesseldorf40225 Germany Bioimaging Centre Department of Biology University of Konstanz Konstanz78457 Germany Division of Computational Biology Centre for Gene Regulation and Expression University of Dundee Dundee United Kingdom Program in Molecular Medicine University of Massachusetts Medical School WorcesterMA01605 United States

While the FAIR principles are well accepted in the scientific community, the implementation of appropriate metadata editing and transfer to ensure FAIR research data in practice is significantly lagging behind. On the one hand, it strongly depends on the availability of tools that efficiently support this step in research data management. On the other hand, it depends on the available standards regarding the interpretability of metadata. Here, we introduce a tool, MDEmic, for editing metadata of microscopic imaging data in an easy and comfortable way that provides high flexibility in terms of adjustment of metadata sets. This functionality was in great demand by many researchers applying microscopic techniques. MDEmic has already become a part of the standard installation package of the image database OMERO as ***. This database helps to organize and visualize microscopic image data and keep track of their further processing and linkage to other data sets. For this reason, many imaging core facilities provide OMERO to their users. We present a use case scenario for the tailored application of *** to imaging data of an institutional OMERO-based Membrane Dye Database, which requires specific experimental metadata. Similar to public image data repositories like the Image Data Resource, IDR, this database facilitates image data storage including rich metadata which enables data mining and re-use, one of the major goals of the FAIR principles. © 2021, CC BY-NC-SA.

关键词： Metadata

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Essential metadata for 3D BRAIN microscopy

arXiv

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arXiv 2021年

作者： Ropelewski, Alexander J. Rizzo, Megan A. Swedlow, Jason R. Huisken, Jan Osten, Pavel Khanjani, Neda Weiss, Kurt Bakalov, Vesselina Engle, Michelle Gridley, Lauren Krzyzanowski, Michelle Madden, Tom Maiese, Deborah Waterfield, Justin Williams, David Hamilton, Carol Huggins, Wayne Biomedical Applications Group Pittsburgh Supercomputing Center 300 S Craig Street PittsburghPA15213 United States Department of Physiology University of Maryland School of Medicine 660 West Redwood Street BaltimoreMD21201 United States Centre for Gene Regulation & Expression Division of Computational Biology University of Dundee Nethergate DundeeDD1 4HN United Kingdom Morgridge Institute for Research 330 N Orchard Street MadisonWI53715 United States Cold Spring Harbor Laboratory One Bungtown Road Cold Spring HarborNY11724 United States Mark and Mary Stevens Neuroimaging and Informatics Institute Laboratory of Neuro Imaging Keck School of Medicine of University of Southern California 1975 Zonal Avenue Los AngelesCA90033 United States Bioinformatics and Computational Biology Program RTI International 3040 East Cornwallis Road Research Triangle ParkNC27709 United States

Recent advances in fluorescence microscopy techniques and tissue clearing, labeling, and staining provide unprecedented opportunities to investigate brain structure and function. These experiments’ images make it possible to catalog brain cell types and define their location, morphology, and connectivity in a native context, leading to a better understanding of normal development and disease etiology. Consistent annotation of metadata is needed to provide the context necessary to understand, reuse, and integrate these data. This report describes an effort to establish metadata standards for 3D microscopy datasets for use by the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative and the neuroscience research community. These standards were built on existing efforts and developed with input from the brain microscopy community to promote adoption. The resulting Essential Metadata for 3D BRAIN Microscopy includes 91 fields organized into seven categories: Contributors, Funders, Publication, Instrument, Dataset, Specimen, and Image. Adoption of these metadata standards will ensure that investigators receive credit for their work, promote data reuse, facilitate downstream analysis of shared data, and encourage collaboration. © 2021, CC BY-NC-ND.

关键词： Fluorescence microscopy

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QUAREP-LiMi: a community endeavor to advance quality assessment and reproducibility in light microscopy (vol 18, pg 1423, 2021)

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NATURE METHODS 2022年第2期19卷 256-256页

作者： Boehm, Ulrike Nelson, Glyn Brown, Claire M. Bagley, Steve Bajcsy, Peter Bischof, Johanna Dauphin, Aurelien Dobbie, Ian M. Eriksson, John E. Faklaris, Orestis Fernandez-Rodriguez, Julia Ferrand, Alexia Gelman, Laurent Gheisari, Ali Hartmann, Hella Kukat, Christian Laude, Alex Mitkovski, Miso Munck, Sebastian North, Alison J. Rasse, Tobias M. Resch-Genger, Ute Schuetz, Lucas C. Seitz, Arne Strambio-De-Castillia, Caterina Swedlow, Jason R. Nitschke, Roland Janelia Research Campus Howard Hughes Medical Institute Ashburn VA USA Bioimaging Unit Newcastle University Newcastle upon Tyne UK Advanced BioImaging Facility (ABIF) McGill University Montreal Quebec Canada Visualisation Irradiation & Analysis Cancer Research UK Manchester Institute Alderley Park Macclesfield UK National Institute of Standards and Technology Gaithersburg MD USA Euro-BioImaging ERIC Heidelberg Germany Unite Génétique et Biologie du Développement U934 PICT-IBiSA Institut Curie/Inserm/CNRS/PSL Research University Paris France Department of Biochemistry University of Oxford Oxford UK Turku Bioscience Centre Euro-Bioimaging ERIC Turku Finland BCM University of Montpellier CNRS INSERM Montpellier France Centre for Cellular Imaging Sahlgrenska Academy University of Gothenburg Gothenburg Sweden Imaging Core Facility Biozentrum University of Basel Basel Switzerland Friedrich Miescher Institute for Biomedical Research Basel Switzerland Light Microscopy Facility CMCB Technology Platform TU Dresden Dresden Germany FACS & Imaging Core Facility Max Planck Institute for Biology of Ageing Cologne Germany Light Microscopy Facility Max Planck Institute of Experimental Medicine Goettingen Germany VIB BioImaging Core Leuven Flanders Belgium VIB-KU Leuven Center for Brain and Disease Leuven Flanders Belgium KU Leuven Department for Neuroscience Leuven Flanders Belgium The Rockefeller University New York NY USA Scientific Service Group Microscopy Max Planck Institute for Heart and Lung Research Bad Nauheim Germany Division Biophotonics Federal Institute for Materials Research and Testing (BAM) Berlin Germany European Molecular Biology Laboratory Advanced Light Microscopy Facility Heidelberg Germany Faculty of Life Sciences Ecole Polytechnique Federale de Lausanne Lausanne Switzerland Program in Molecular Medicine University of Massachusetts Medical School Worcester MA USA Divisions of Computational Biology and Gene Regulation and Expre

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Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex

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细胞研究（英文版） 2018年第1期28卷 69-89页

作者： Bo Zhao Weidao Zhang Yixian Cun Jingzheng Li Yan Liu Jing Gao Hongwen Zhu Hu Zhou Rugang Zhang Ping Zheng State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China Yunnan Key Laboratory of Animal Reproduction Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China Yunnan Key Laboratory of Animal Reproduction Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China Kunming College of Life Science University of Chinese Academy of Sciences KunmingYunnan 650204 China State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China Gene Expression and Regulation Program The Wistar Institute Cancer Center The Wistar Institute Philadelphia PA 19104 USA

Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative *** is therefore important to understand the regulatory mechanisms of replication stress response in ***,we report that mouse embryonic stem cells (ESCs) are superior to differentiated cells in resolving replication ***,ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks,therefore maintaining genomic *** ESC-specific Filia-Floped complex resides on replication forks under normal *** stress stimulates their recruitment to stalling forks and the serine 151 residue of Filia is phosphorylated in an ATR-dependent *** modification enables the Filia-Floped complex to act as a functional scaffold,which then promotes the stalling fork restart through a dual mechanism:both enhancing recruitment of the replication fork restart protein,Blm,and stimulating ATR kinase *** the Blm pathway,the scaffolds recruit the E3 ubiquitin ligase,Trim25,to the stalled replication forks,and in turn Trim25 tethers and concentrates Blm at stalled replication forks through *** differentiated cells,the recruitment of the Trim25-Blm complex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specific Filia-Floped ***,our study reveals that ESCs utilize an additional and unique regulatory layer to efficiently promote the stalled fork restart and maintain genomic stability.

关键词： pluripotent stem cells Filia Floped DNA replication stress genomic stability

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Erratum to "A new HDV mouse model identifies mitochondrial antiviral signaling protein (MAVS) as a key player in IFN-β induction" [J Hepatol 67 (2017) 669-679]

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Journal of hepatology 2018年第1期69卷 262-264页

作者： Lester Suárez-Amarán Carla Usai Marianna Di Scala Cristina Godoy Yi Ni Mirja Hommel Laura Palomo Víctor Segura Cristina Olagüe Africa Vales Alicia Ruiz-Ripa Maria Buti Eduardo Salido Jesús Prieto Stephan Urban Francisco Rodríguez-Frias Rafael Aldabe Gloria González-Aseguinolaza Gene Therapy and Regulation of Gene Expression Program Center for Applied Medical Research (CIMA) Pamplona Spain Instituto de Investigación Sanitaria de Navarra (IdiSNA) Calle Irunlarrea 3 Pamplona 31008 Spain. Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd) Instituto de Salud Carlos III Barcelona Spain Liver Pathology Unit Departments of Biochemistry and Microbiology Hospital Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain Virology Unit Department of Microbiology Hospital Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain. Department of Infectious Diseases Molecular Virology University Hospital Heidelberg Heidelberg Germany. Instituto de Investigación Sanitaria de Navarra (IdiSNA) Calle Irunlarrea 3 Pamplona 31008 Spain Bioinformatics Unit Center for Applied Medical Research (CIMA) University of Navarra Pamplona Spain. Department of Pathology Centre for Biomedical Research on Rare Diseases (CIBERER) La Laguna S/C Tenerife Spain. Instituto de Investigación Sanitaria de Navarra (IdiSNA) Calle Irunlarrea 3 Pamplona 31008 Spain Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas ( CIBERehd) Instituto de Salud Carlos III Pamplona Spain. Instituto de Investigación Sanitaria de Navarra (IdiSNA) Calle Irunlarrea 3 Pamplona 31008 Spain. Electronic address: ggasegui@unav.es.

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