2023
Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E
Boddu P, Gupta A, Roy R, De La Pena Avalos B, Herrero A, Zimmer J, Simon M, Chandhok N, King D, Neuenkirchen N, Dray E, Lin H, Kupfer G, Verma A, Neugebauer K, Pillai M. Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E. Blood 2023, 142: 714. DOI: 10.1182/blood-2023-187303.Peer-Reviewed Original ResearchSplicing factorsChIP-seqK562 cell lineKey regulatory genesCell linesSingle mutant alleleNon-denaturing gelsAlternative splicingTranscriptional kineticsRegulatory genesSpliceosome assemblySplicing efficiencyMRNA splicingCRISPR/Progenitor populationsNeomorphic functionsMolecular mechanismsMutant allelesIsoform changesGene editingNovel mechanismMutationsSF mutationsRecurrent mutationsAssembly kinetics3189 – REVISITING THE HEMATOPOIETIC AND ERYTHROPOIETIC DEFECTS IN RPS19 AND RPL5 HAPLOINSUFFICIENCY AT THE DEVELOPMENTAL LEVEL
Tang Y, Ling T, Durand S, Palis J, Steiner L, Mohandas N, Gallagher P, Lipton J, Crispino J, Blanc L. 3189 – REVISITING THE HEMATOPOIETIC AND ERYTHROPOIETIC DEFECTS IN RPS19 AND RPL5 HAPLOINSUFFICIENCY AT THE DEVELOPMENTAL LEVEL. Experimental Hematology 2023, 124: s144. DOI: 10.1016/j.exphem.2023.06.296.Peer-Reviewed Original ResearchRibosomal proteinsDiamond-Blackfan anemiaGlobal protein synthesisTerminal erythroid differentiationStem cell exhaustionHematopoietic stem cell exhaustionKey transcription factorInherited bone marrow failure syndromeFailure of erythropoiesisCell cycle arrestHematopoietic developmentMutant cellsTranscription factorsProgenitor stageCRISPR/Erythroid differentiationVav-iCreMendelian ratioDefective erythropoiesisRPS19Bone marrow failure syndromesLoxP sitesProtein synthesisBone marrow failureHematopoietic progenitors
2022
Live imaging and conditional disruption of native PCP activity using endogenously tagged zebrafish sfGFP-Vangl2
Jussila M, Boswell C, Griffiths N, Pumputis P, Ciruna B. Live imaging and conditional disruption of native PCP activity using endogenously tagged zebrafish sfGFP-Vangl2. Nature Communications 2022, 13: 5598. PMID: 36151137, PMCID: PMC9508082, DOI: 10.1038/s41467-022-33322-9.Peer-Reviewed Original ResearchConceptsPlanar cell polarityVertebrate planar cell polarityTissue-specific functionsNon-canonical Wnt/planar cell polarityWnt/planar cell polarityCore PCP componentsLoss of vangl2Polarity proteinsCell polarityPCP componentsMembrane localizationCytoskeletal organizationGenome editingPowerful experimental paradigmCRISPR/Live imagingDynamic regulationCell lineagesAuthentic regulationPCP activityVangl2Fluorescent reportersEpendymal cell ciliaCell behaviorNormal developmentA multifunctional locus controls motor neuron differentiation through short and long noncoding RNAs
Carvelli A, Setti A, Desideri F, Galfrè SG, Biscarini S, Santini T, Colantoni A, Peruzzi G, Marzi MJ, Capauto D, Di Angelantonio S, Ballarino M, Nicassio F, Laneve P, Bozzoni I. A multifunctional locus controls motor neuron differentiation through short and long noncoding RNAs. The EMBO Journal 2022, 41: embj2021108918. PMID: 35698802, PMCID: PMC9251839, DOI: 10.15252/embj.2021108918.Peer-Reviewed Original ResearchConceptsMN differentiationPost-transcriptional roleSingle-cell sequencingMotor neuron differentiationPostmitotic motor neuronsTranscriptional unitsMESC differentiationTranscription factorsCRISPR/Transcriptional levelMiR-466iNeuron differentiationNeuronal differentiationFunctional relevanceMotor neuronsMiR-384-5pDifferentiationSeries of eventsProliferation-related factorsAdditional layerMutantsMiRNAsLncRNAsLociRNAIn vivo CRISPR‐Cas9‐mediated DNA chop identifies a cochlear outer hair cell‐specific enhancer
Sun Y, Zhang Y, Zhang D, Wang G, Song L, Liu Z. In vivo CRISPR‐Cas9‐mediated DNA chop identifies a cochlear outer hair cell‐specific enhancer. The FASEB Journal 2022, 36: e22233. PMID: 35225354, DOI: 10.1096/fj.202100421rr.Peer-Reviewed Original ResearchConceptsDNA fragment deletionKbp fragmentKbp segmentFragment deletionCell-specific enhancerOuter hair cellsLarge DNA fragment deletionGreen fluorescent proteinCRISPR/Motor proteinsIntron regionsGene therapeutic applicationsFluorescent proteinDifferent speciesCochlear outer hair cellsBp fragmentEnhancerSLC26A5Hair cellsEGFPProteinTransgenic miceDeletionKbpPrestin expression
2021
Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1
Bhat N, Narayanan A, Fathzadeh M, Shah K, Dianatpour M, Abou Ziki MD, Mani A. Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1. Cellular Signalling 2021, 90: 110186. PMID: 34752933, PMCID: PMC8712395, DOI: 10.1016/j.cellsig.2021.110186.Peer-Reviewed Original ResearchConceptsSkeletal muscle differentiationMuscle differentiationC2C12 cellsHuman skeletal muscle developmentSkeletal muscle developmentGlobal gene networksPost-transcriptional targetEmbryonic lethalGene networksZebrafish embryosMyofiber differentiationOverexpression approachesMuscle developmentCRISPR/DYRK1BRare gainDownstream targetsTranslational inhibitorKey regulatorUntargeted proteomicsFunction mutationsAutophagic fluxEnhances AutophagyDifferentiationAutophagySarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination
Chen CC, Chen BR, Wang Y, Curman P, Beilinson HA, Brecht RM, Liu CC, Farrell RJ, de Juan-Sanz J, Charbonnier LM, Kajimura S, Ryan TA, Schatz DG, Chatila TA, Wikstrom JD, Tyler JK, Sleckman BP. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination. Journal Of Experimental Medicine 2021, 218: e20201708. PMID: 34033676, PMCID: PMC8155808, DOI: 10.1084/jem.20201708.Peer-Reviewed Original ResearchConceptsRAG2 gene expressionSarco/endoplasmic reticulum Ca2Gene expressionEndoplasmic reticulum Ca2ER Ca2ER transmembrane proteinExpression of SERCA3Mature B cellsER lumenCytosolic Ca2Transmembrane proteinCRISPR/PreB cellsDNA cleavageB cellsReticulum Ca2SERCA proteinATPase activityProteinProfound blockATP2A2 mutationsRAG1RecombinationProtein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas
Norton J, Augert A, Eastwood E, Basom R, Rudin C, MacPherson D. Protein neddylation as a therapeutic target in pulmonary and extrapulmonary small cell carcinomas. Genes & Development 2021, 35: 870-887. PMID: 34016692, PMCID: PMC8168556, DOI: 10.1101/gad.348316.121.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic Helix-Loop-Helix Transcription FactorsCarcinoma, Small CellCell DeathCell Line, TumorCOP9 Signalosome ComplexCyclopentanesDisease Models, AnimalGene Expression Regulation, NeoplasticHeterograftsHumansLung NeoplasmsMiceNEDD8 ProteinNeuroendocrine CellsProteinsPyrimidinesRepressor ProteinsSequence DeletionConceptsSmall cell lung carcinomaSmall cell carcinomaExtrapulmonary small cell carcinomaNeddylation inhibitionCell carcinomaCell statesGenome-scale CRISPR/Therapeutic targetPatient-derived xenograft modelsCell linesDeletion of componentsSolid tumor malignanciesCell lung carcinomaNovel therapeutic approachesPotential therapeutic targetSuppressor screenSCLC cell linesCOP9 signalosomeProtein neddylationCRISPR/Genetic suppressionPathway genesPDX modelsMajor regulatorLung carcinoma
2020
CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix
Bonet-Fernández J, Aroca-Aguilar J, Corton M, Ramírez A, Alexandre-Moreno S, García-Antón M, Salazar J, Ferre-Fernández J, Atienzar-Aroca R, Villaverde C, Iancu I, Tamayo A, Méndez-Hernández C, Morales-Fernández L, Rojas B, Ayuso C, Coca-Prados M, Martinez-de-la-Casa J, García-Feijoo J, Escribano J. CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix. Human Genetics 2020, 139: 1209-1231. PMID: 32274568, DOI: 10.1007/s00439-020-02164-0.Peer-Reviewed Original ResearchMeSH KeywordsAdultalpha-MacroglobulinsAnimalsAnterior ChamberCase-Control StudiesComplement C3CRISPR-Cas SystemsEmbryo, NonmammalianExtracellular MatrixEye AbnormalitiesFemaleGene EditingGene ExpressionGenes, RecessiveGlaucomaHigh-Throughput Nucleotide SequencingHumansLoss of Function MutationMaleMiddle AgedPedigreeTrabecular MeshworkTrabeculectomyTrypsin Inhibitor, Kazal PancreaticZebrafishConceptsZebrafish embryosAnterior segment dysgenesisExtracellular matrixPrimary congenital glaucomaNext-generation DNA sequencingGross developmental abnormalitiesFunction pathogenic mechanismQuantitative reverse transcription PCRAbnormal extracellular matrixCongenital glaucomaCRISPR/Mesenchyme-like cellsTrabecular meshwork cellsReverse transcription-PCRUnknown functionExtracellular matrix disorganizationDNA sequencingGenesGenetic alterationsEmbryosMeshwork cellsDevelopmental abnormalitiesTranscription-PCRAnterior chamber angleDisease RoleNovel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome
Alharatani R, Ververi A, Beleza-Meireles A, Ji W, Mis E, Patterson QT, Griffin JN, Bhujel N, Chang CA, Dixit A, Konstantino M, Healy C, Hannan S, Neo N, Cash A, Li D, Bhoj E, Zackai EH, Cleaver R, Baralle D, McEntagart M, Newbury-Ecob R, Scott R, Hurst JA, Au PYB, Hosey MT, Khokha M, Marciano DK, Lakhani SA, Liu KJ. Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome. Human Molecular Genetics 2020, 29: 1900-1921. PMID: 32196547, PMCID: PMC7372553, DOI: 10.1093/hmg/ddaa050.Peer-Reviewed Original ResearchConceptsCell-cell junctionsNovel protein-truncating variantsP120-catenin proteinProtein-truncating variantsNext-generation sequencingTranscriptional signalingP120-cateninCRISPR/Epithelial-mesenchymal transitionSubset of phenotypesDevelopmental roleLimb dysmorphologiesAdditional phenotypesHuman diseasesCTNND1Conditional deletionDe novoTruncating mutationsBlepharocheilodontic syndromeEpithelial integrityNovel truncating mutationCraniofacial dysmorphismPhenotypeCleft palateNeurodevelopmental disorders
2019
Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous non-small cell lung cancer
Craig M, Kaveh K, Woosley A, Brown AS, Goldman D, Eton E, Mehta RM, Dhawan A, Arai K, Rahman MM, Chen S, Nowak MA, Goldman A. Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous non-small cell lung cancer. PLOS Computational Biology 2019, 15: e1007278. PMID: 31449515, PMCID: PMC6709889, DOI: 10.1371/journal.pcbi.1007278.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationCoculture TechniquesComputational BiologyComputer SimulationCRISPR-Cas SystemsDEAD-box RNA HelicasesDrug Resistance, MultipleDrug Resistance, NeoplasmHumansLung NeoplasmsModels, BiologicalMutationRibonuclease IIIConceptsCancer cellsCell state transitionsWild-type cellsCooperative adaptationNon-small cell lung cancer cellsInterspecies competitionCell lung cancer cellsCRISPR/Drug-sensitive cellsLung cancer cellsNSCLC patient samplesDruggable targetsDrug pressureMutantsFlow cytometry dataPhenotypic heterogeneitySensitive cellsA Zebrafish Model for Selenoprotein Synthesis and Function (OR11-01-19)
Copeland P, Vetick M. A Zebrafish Model for Selenoprotein Synthesis and Function (OR11-01-19). Current Developments In Nutrition 2019, 3: 3131070. PMCID: PMC6578458, DOI: 10.1093/cdn/nzz044.or11-01-19.Peer-Reviewed Original ResearchZebrafish model systemSelenoprotein expressionSelenoprotein synthesisCo-translational insertionHomozygous mutant animalsModel systemMutant embryosSelenoprotein functionOxidative stressUGA codonMutant animalsZebrafish modelCRISPR/Selenoprotein mRNAsNull animalsOvert phenotypePeroxide exposureProtein 2Radioactive seleniumEmbryosProtein expressionExpressionProteinΜM H2O2Later time pointsProtein kinase Cα–mediated phosphorylation of Twist1 at Ser-144 prevents Twist1 ubiquitination and stabilizes it
Tedja R, Roberts CM, Alvero AB, Cardenas C, Yang-Hartwich Y, Spadinger S, Pitruzzello M, Yin G, Glackin CA, Mor G. Protein kinase Cα–mediated phosphorylation of Twist1 at Ser-144 prevents Twist1 ubiquitination and stabilizes it. Journal Of Biological Chemistry 2019, 294: 5082-5093. PMID: 30733340, PMCID: PMC6442047, DOI: 10.1074/jbc.ra118.005921.Peer-Reviewed Original ResearchConceptsProtein kinase CPhosphorylation sitesHelix transcription factorPhosphorylation of Twist1Candidate phosphorylation sitesProtein kinase CαCombination of immunoblottingUbiquitination eventsTwist1 phosphorylationTranscription factorsEmbryonic developmentKnockout experimentsSer-144CRISPR/Twist1 proteinKinase CInvasive phenotypeAdult cellsPhosphorylationTwist1UbiquitinationCancer developmentCell linesTwist1 expressionPKCα
2018
Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome
Braun DA, Lovric S, Schapiro D, Schneider R, Marquez J, Asif M, Hussain MS, Daga A, Widmeier E, Rao J, Ashraf S, Tan W, Lusk CP, Kolb A, Jobst-Schwan T, Schmidt JM, Hoogstraten CA, Eddy K, Kitzler TM, Shril S, Moawia A, Schrage K, Khayyat AIA, Lawson JA, Gee HY, Warejko JK, Hermle T, Majmundar AJ, Hugo H, Budde B, Motameny S, Altmüller J, Noegel AA, Fathy HM, Gale DP, Waseem SS, Khan A, Kerecuk L, Hashmi S, Mohebbi N, Ettenger R, Serdaroğlu E, Alhasan KA, Hashem M, Goncalves S, Ariceta G, Ubetagoyena M, Antonin W, Baig SM, Alkuraya FS, Shen Q, Xu H, Antignac C, Lifton RP, Mane S, Nürnberg P, Khokha MK, Hildebrandt F. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. Journal Of Clinical Investigation 2018, 128: 4313-4328. PMID: 30179222, PMCID: PMC6159964, DOI: 10.1172/jci98688.Peer-Reviewed Original ResearchConceptsNuclear pore complexSteroid-resistant nephrotic syndromeCRISPR/Cas9 knockoutOrgan-specific phenotypesNephrotic syndromeRing subunitsMorpholino knockdownEssential genesEnd-stage renal diseasePore complexNPC subunitsCoimmunoprecipitation experimentsAllelic effectsNUP85CRISPR/Nup107Hypomorphic mutationsNup133WT mRNAEarly lethalityGenesImportant effectorsSubunitsMutationsRenal diseaseCRISPR/Cas9 F0 Screening of Congenital Heart Disease Genes in Xenopus tropicalis
Deniz E, Mis EK, Lane M, Khokha MK. CRISPR/Cas9 F0 Screening of Congenital Heart Disease Genes in Xenopus tropicalis. Methods In Molecular Biology 2018, 1865: 163-174. PMID: 30151766, DOI: 10.1007/978-1-4939-8784-9_12.Peer-Reviewed Original ResearchConceptsCardiac developmentCRISPR/Candidate genesHigh-density SNP arrayCRISPR/Cas9 systemGenome editing technologyCongenital heart disease genesNew genomic technologiesHeart disease genesCopy number variationsRapid functional assayXenopus tropicalisCas9 systemGenetic basisDevelopmental systemsEditing technologyGenomic technologiesSequence variationDisease genesDifferent genesGenetic analysisSNP arrayDevelopmental mechanismsMolecular mechanismsWhole-exome sequencingCRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors
Liu CX, Li CY, Hu CC, Wang Y, Lin J, Jiang YH, Li Q, Xu X. CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors. Molecular Autism 2018, 9: 23. PMID: 29619162, PMCID: PMC5879542, DOI: 10.1186/s13229-018-0204-x.Peer-Reviewed Original ResearchConceptsMutant zebrafishMutant zebrafish modelGenome editing techniquesGene editing approachesZebrafish genomeOrthologous genesAttractive organismGenomic studiesCRISPR/Cas9 gene editing approachGenetic manipulationZebrafish modelCRISPR/ZebrafishMolecular mechanismsEditing approachesAdult stageFunction mutationsMolecular analysisEditing techniquesMolecular changesAutism-like behaviorsEarly developmentSwimming behaviorPresynaptic synaptophysinMorphological measurements
2017
Increased efficiency of targeted mutagenesis by CRISPR/Cas9 in plants using heat stress
LeBlanc C, Zhang F, Mendez J, Lozano Y, Chatpar K, Irish V, Jacob Y. Increased efficiency of targeted mutagenesis by CRISPR/Cas9 in plants using heat stress. The Plant Journal 2017, 93: 377-386. PMID: 29161464, DOI: 10.1111/tpj.13782.Peer-Reviewed Original ResearchConceptsCRISPR/Green fluorescent protein (GFP) reporter geneCRISPR/Cas9 systemFluorescent protein reporter geneCRISPR/Cas9Off-target mutationsArabidopsis plantsEukaryotic genomesDifferent organismsSomatic tissuesCitrus plantsCas9 systemDNA breaksReporter geneTarget mutagenesisTargeted mutationsMutation rateMutagenesisImportance of temperatureArabidopsisHeat stressPlantsMutationsQuantitative assayEukaryotesPinAPL-Py: A comprehensive web-application for the analysis of CRISPR/Cas9 screens
Spahn P, Bath T, Weiss R, Kim J, Esko J, Lewis N, Harismendy O. PinAPL-Py: A comprehensive web-application for the analysis of CRISPR/Cas9 screens. Scientific Reports 2017, 7: 15854. PMID: 29158538, PMCID: PMC5696473, DOI: 10.1038/s41598-017-16193-9.Peer-Reviewed Original ResearchConceptsCRISPR/Large-scale genetic screensCRISPR/Cas9Publication-ready plotsSequence quality controlPlatform-independent analysisUser-friendly implementationLarge sequencing datasetsGenetic screenAnalysis optionsFunctional genomicsPooled screensSgRNA libraryBioinformatics toolsSequencing datasetsComprehensive functionalityExperimental biologistsBioinformatics expertiseArt toolsCustom libraryLimited functionalityTest datasetSequence extractionGene rankingIncreased popularityApplication of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease
Powell S, Gregory J, Akbarian S, Brennand K. Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease. Molecular And Cellular Neuroscience 2017, 82: 157-166. PMID: 28549865, PMCID: PMC5516945, DOI: 10.1016/j.mcn.2017.05.007.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCRISPR/Cas9 technologyPluripotent stem cellsTranscriptional regulatorsManipulation of DNAEpigenetic pathwaysGenomic editingSpecific lociCRISPR/Basic biologyCas9 technologyGene expressionStem cellsTargeted localizationEnzyme activityBrain developmentEpigenomeNeuropsychiatric diseasesGenomeCRISPRRepressionLociBiologyRegulatorEffectorsDNAA Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo
Yang YP, Ma H, Starchenko A, Huh WJ, Li W, Hickman FE, Zhang Q, Franklin JL, Mortlock DP, Fuhrmann S, Carter BD, Ihrie RA, Coffey RJ. A Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo. Cell Reports 2017, 19: 1257-1267. PMID: 28494873, PMCID: PMC5517093, DOI: 10.1016/j.celrep.2017.04.048.Peer-Reviewed Original ResearchConceptsEGF receptorEGFR localizationEndogenous regulatory elementsDistinct cell populationsReporter miceGenome editingEGFR internalizationRegulatory elementsCRISPR/C-terminusEndogenous EGFRFluorescent reportersDifferentiated compartmentVillus compartmentTraffickingCell populationsReporterExpressionEGFR expressionDisease statesDistinct patternsCompartmentsAdjacent epitheliumIntestinal tumorsAdult mice
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