2025
Genome-scale CRISPR/Cas9 screening reveals the role of PSMD4 in colibactin-mediated cell cycle arrest
Dougherty M, Hoffmann R, Hernandez M, Airan Y, Gharaibeh R, Herzon S, Yang Y, Jobin C. Genome-scale CRISPR/Cas9 screening reveals the role of PSMD4 in colibactin-mediated cell cycle arrest. MSphere 2025, 10: e00692-24. PMID: 39918307, PMCID: PMC11934320, DOI: 10.1128/msphere.00692-24.Peer-Reviewed Original ResearchMeSH KeywordsCell Cycle CheckpointsCell SurvivalCRISPR-Cas SystemsDNA DamageGene Knockout TechniquesHEK293 CellsHT29 CellsHumansPeptidesPolyketidesConceptsCell cycle arrestCycle arrestCRISPR/Cas9 screenDNA damageGenome-scale CRISPR/Cas9 screensGenome-wide CRISPR/Cas9 knockout screenRegulating cell cycle arrestRNA polymerase IIIRNA processing factorsCRISPR/Cas9 knockout screenG2-M cell cycle arrestGenotoxic secondary metabolitesHT-29 cellsHost response pathwaysPolymerase IIIKnockout screenHost pathwaysCell fateProteasome subunitsColony sizeColibactin-producing bacteriaColibactinRNA sequencingColony formation rateGene expression
2023
Manipulating mitochondrial electron flow enhances tumor immunogenicity
Mangalhara K, Varanasi S, Johnson M, Burns M, Rojas G, Esparza Moltó P, Sainz A, Tadepalle N, Abbott K, Mendiratta G, Chen D, Farsakoglu Y, Kunchok T, Hoffmann F, Parisi B, Rincon M, Vander Heiden M, Bosenberg M, Hargreaves D, Kaech S, Shadel G. Manipulating mitochondrial electron flow enhances tumor immunogenicity. Science 2023, 381: 1316-1323. PMID: 37733872, PMCID: PMC11034774, DOI: 10.1126/science.abq1053.Peer-Reviewed Original ResearchConceptsElectron transport chainMethylation-controlled J proteinMitochondrial electron transport chainElectron flowMitochondrial electron flowJ-proteinsEpigenetic activationTransport chainMitochondrial respirationTumor growthPresentation genesElectron entryNoncancer cellsMelanoma tumor growthCommon mechanismTherapeutic potentialGenesRelative contributionProteinGrowthKnockoutAntigen presentationRespirationT cell-mediated killingExpression
2022
Tracing the cis-regulatory changes underlying the endometrial control of placental invasion
Suhail Y, Maziarz JD, Novin A, Dighe A, Afzal J, Wagner G, Kshitiz. Tracing the cis-regulatory changes underlying the endometrial control of placental invasion. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2111256119. PMID: 35110402, PMCID: PMC8832988, DOI: 10.1073/pnas.2111256119.Peer-Reviewed Original ResearchMeSH KeywordsCell Line, TumorCRISPR-Cas SystemsEndometriumFemaleGATA2 Transcription FactorGene Knockout TechniquesHumansNeoplasm ProteinsNeoplasmsTranscription Factor DP1TrophoblastsConceptsCis-regulatory changesComparative genomic investigationCis-regulatory elementsTranscription factor GATA2Placental invasionCancer cell invasionEutherian mammalsTranscription factorsGenomic investigationsInvasibilityGene knockoutGenomic mechanismsDifferent speciesCell invasionEndometrial controlCancer malignancyDegree of invasionSpecies differencesCancer disseminationMaternal endometriumInterspecies differencesPlacental trophoblastsStromal cellsStromal characteristicsInvasionGasdermin D inhibition confers antineutrophil mediated cardioprotection in acute myocardial infarction
Jiang K, Tu Z, Chen K, Xu Y, Chen F, Xu S, Shi T, Qian J, Shen L, Hwa J, Wang D, Xiang Y. Gasdermin D inhibition confers antineutrophil mediated cardioprotection in acute myocardial infarction. Journal Of Clinical Investigation 2022, 132: e151268. PMID: 34752417, PMCID: PMC8718151, DOI: 10.1172/jci151268.Peer-Reviewed Original ResearchConceptsAcute myocardial infarctionGasdermin DInfarcted heartMyocardial infarctionBone marrow transplantation studiesAMI mouse modelIL-1β releaseMarrow transplantation studiesReduced heart failureBlood leukocytosisDetrimental immunopathologyEarly mobilizationHeart failureInfarct sizePatient survivalVentricular remodelingCardiac functionAMI survivalMouse modelHeart functionExcessive boneNeutrophil productionNeutrophil generationScar sizePharmacological inhibition
2021
Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics
Ding R, Chen P, Rajendran B, Lyu X, Wang H, Bao J, Zeng J, Hao W, Sun H, Wong A, Valecha M, Yang E, Su S, Choi T, Liu S, Chan K, Yang L, Wu J, Miao K, Chen Q, Shim J, Xu X, Deng C. Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics. Nature Communications 2021, 12: 3046. PMID: 34031426, PMCID: PMC8144567, DOI: 10.1038/s41467-021-23379-3.Peer-Reviewed Original ResearchConceptsSarcomatoid carcinomaEpithelial-mesenchymal transitionNasopharyngeal carcinomaCarcinoma subtypesNeck cancer typesPatient-derived organoidCRT regimensDistinct molecular featuresMalignant headHigh morbidityTreatment regimensTherapeutic responseEC subtypesPathogenic mechanismsDrug responsivenessEGFR inhibitorsNPC subtypesCancer typesSubtypesCarcinomaPrecision oncologyDrug testsMolecular landscapeRegimensMicrotubule inhibitorsCell-Autonomous Role of EGFR in Spontaneous Duodenal Tumors in LRIG1 Null Mice
Niitsu H, Lu Y, Huh W, Love A, Franklin J, Coffey R. Cell-Autonomous Role of EGFR in Spontaneous Duodenal Tumors in LRIG1 Null Mice. Cellular And Molecular Gastroenterology And Hepatology 2021, 12: 1159-1162.e4. PMID: 33989815, PMCID: PMC8413138, DOI: 10.1016/j.jcmgh.2021.05.004.Peer-Reviewed Original ResearchConditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury
Benson CA, Olson KL, Patwa S, Reimer ML, Bangalore L, Hill M, Waxman SG, Tan AM. Conditional RAC1 knockout in motor neurons restores H-reflex rate-dependent depression after spinal cord injury. Scientific Reports 2021, 11: 7838. PMID: 33837249, PMCID: PMC8035187, DOI: 10.1038/s41598-021-87476-5.Peer-Reviewed Original ResearchConceptsSpinal cord injuryDendritic spine dysgenesisMotor neuronsSpine dysgenesisSCI animalsHyperexcitability disordersCord injurySpinal alpha motor neuronsVentral horn motor neuronsAbnormal dendritic spine morphologyRac1 knockoutH-reflex pathwayRate-dependent depressionAlpha motor neuronsDevelopment of spasticityAdeno-associated viralMushroom dendritic spinesSpine head sizeOverall spine lengthDendritic spine morphologyRac1 protein expressionNeuronal hyperexcitabilityMajor complicationsClinical symptomsReflex excitabilityAP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer
Beck AC, Cho E, White JR, Paemka L, Li T, Gu VW, Thompson DT, Koch KE, Franke C, Gosse M, Wu VT, Landers SR, Pamatmat AJ, Kulak MV, Weigel RJ. AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer. Molecular Cancer Research 2021, 19: 1156-1167. PMID: 33753551, PMCID: PMC8254761, DOI: 10.1158/1541-7786.mcr-20-0867.Peer-Reviewed Original ResearchMeSH KeywordsAminopyridinesAnimalsBiomarkers, TumorCell Line, TumorCell SurvivalColonic NeoplasmsGene Expression ProfilingGene Expression Regulation, NeoplasticGene Knockout TechniquesHCT116 CellsHumansMiceMorpholinesPhosphoinositide-3 Kinase InhibitorsRNA InterferenceRNA-SeqS PhaseTranscription Factor AP-2Xenograft Model Antitumor AssaysConceptsAP-2αPI3K inhibitorsColon cancer cell linesCell cycleS phasePrimary gene targetsK inhibitorsChromatin immunoprecipitation sequencingCancer cell linesPI3K cascadeProlonged S phaseCell linesActivation of AktShort hairpin RNAPhosphorylation of AktHistone H3Immunoprecipitation sequencingRNA sequencingPI3K inhibitionTarget genesK cascadeGene targetsTumor suppressorHairpin RNAColon cancerMineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload–Induced Heart Failure
Kim S, Biwer L, Moss M, Man J, Aronovitz M, Martin G, Carrillo-Salinas F, Salvador A, Alcaide P, Jaffe I. Mineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload–Induced Heart Failure. Circulation Heart Failure 2021, 14: e007279. PMID: 33517669, PMCID: PMC7887087, DOI: 10.1161/circheartfailure.120.007279.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsMR-intact littermatesAdverse cardiac remodelingMineralocorticoid receptorCardiac remodelingSMC-MRAortic constrictionPressure Overload-Induced Heart FailureInhibition of MRRole of MRPressure overload-induced hypertrophyCardiac blood supplyHeart failure hospitalizationCardiac capillary densityCoronary flow reserveTransverse aortic constrictionIntracardiac pressure measurementsOverload-induced hypertrophyFibrotic gene expressionFetal gene expressionFailure hospitalizationExercise capacityExercise testingEjection fractionHeart failureA simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes
Kroll F, Powell GT, Ghosh M, Gestri G, Antinucci P, Hearn TJ, Tunbak H, Lim S, Dennis HW, Fernandez JM, Whitmore D, Dreosti E, Wilson SW, Hoffman EJ, Rihel J. A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes. ELife 2021, 10: e59683. PMID: 33416493, PMCID: PMC7793621, DOI: 10.7554/elife.59683.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBehavior, AnimalCRISPR-Cas SystemsEmbryo, NonmammalianGene Knockout TechniquesGenetic TestingPhenotypeRNA, Guide, CRISPR-Cas SystemsZebrafishConceptsKnockout methodComplex mutant phenotypesLarge genetic screenRapid genetic screeningGenetic screenMutant phenotypeEffective CRISPRBiallelic knockoutMolecular rhythmsHuman genesInjected embryosCircadian clockLarval zebrafishBehavioral phenotypesMultiple genesComplex phenotypesCurrent CRISPRTriple knockoutAttractive modelGenesGenetic contributionZebrafishPhenotypeKnockoutCRISPRThe Essential Function of SETDB1 in Homologous Chromosome Pairing and Synapsis during Meiosis
Cheng EC, Hsieh CL, Liu N, Wang J, Zhong M, Chen T, Li E, Lin H. The Essential Function of SETDB1 in Homologous Chromosome Pairing and Synapsis during Meiosis. Cell Reports 2021, 34: 108575. PMID: 33406415, PMCID: PMC8513770, DOI: 10.1016/j.celrep.2020.108575.Peer-Reviewed Original ResearchConceptsEarly meiosisEarly meiotic prophase IFunction of SETDB1Homologous chromosome pairingMeiotic prophase IHistone-lysine N-methyltransferaseMeiotic silencingSurvival of spermatocytesGermline developmentBouquet formationHomologous chromosomesLineage genesChromosome pairingBivalent formationPericentromeric regionProphase IApoptosis of spermatocytesSETDB1Essential functionsHomologous bivalentsH3K9me3Meiotic arrestMeiosisSpermatocytesN-methyltransferase
2020
Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids
Trujillo CA, Adams JW, Negraes PD, Carromeu C, Tejwani L, Acab A, Tsuda B, Thomas CA, Sodhi N, Fichter KM, Romero S, Zanella F, Sejnowski TJ, Ulrich H, Muotri AR. Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids. EMBO Molecular Medicine 2020, 13: emmm202012523. PMID: 33501759, PMCID: PMC7799367, DOI: 10.15252/emmm.202012523.Peer-Reviewed Original ResearchMeSH KeywordsBridged Bicyclo Compounds, HeterocyclicFemaleGene Knockout TechniquesHumansMethyl-CpG-Binding Protein 2NeuronsOrganoidsPhenotypePyrrolidinonesQuinuclidinesRett SyndromeConceptsRett syndromeCortical organoidsPredominant etiologyNeurodevelopmental impairmentPharmacological reversalPHA-543613Neuropathologic phenotypeSynaptic dysregulationClinical studiesHuman pluripotent stem cell technologySymptomatic severityHuman neuronsMeCP2 deficiencyCandidate therapeuticsBrain mosaicismNetwork pathologyPharmacological compoundsPluripotent stem cell (iPSC) technologyNeurodevelopmental disordersMECP2 mutationsNeuropathologyMECP2 geneNeuronsCellular mosaicismStem cell technologyGenome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection
Wei J, Alfajaro MM, DeWeirdt PC, Hanna RE, Lu-Culligan WJ, Cai WL, Strine MS, Zhang SM, Graziano VR, Schmitz CO, Chen JS, Mankowski MC, Filler RB, Ravindra NG, Gasque V, de Miguel FJ, Patil A, Chen H, Oguntuyo KY, Abriola L, Surovtseva YV, Orchard RC, Lee B, Lindenbach BD, Politi K, van Dijk D, Kadoch C, Simon MD, Yan Q, Doench JG, Wilen CB. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection. Cell 2020, 184: 76-91.e13. PMID: 33147444, PMCID: PMC7574718, DOI: 10.1016/j.cell.2020.10.028.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsCell LineChlorocebus aethiopsClustered Regularly Interspaced Short Palindromic RepeatsCoronavirusCoronavirus InfectionsCOVID-19Gene Knockout TechniquesGene Regulatory NetworksGenome-Wide Association StudyHEK293 CellsHMGB1 ProteinHost-Pathogen InteractionsHumansSARS-CoV-2Vero CellsVirus InternalizationConceptsSARS-CoV-2 infectionSARS-CoV-2Vesicular stomatitis virusGenome-wide CRISPR screenSWI/SNF chromatinSARS-CoV-2 host factorsAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionTherapeutic targetHost factorsCoronavirus disease 2019 (COVID-19) pathogenesisSyndrome coronavirus 2 infectionCRISPR screensHost genesGene productsMiddle East respiratory syndrome CoVCoronavirus 2 infectionGenetic hitsHuman cellsSARS-CoV-2 spikeNovel therapeutic targetPotential therapeutic targetVero E6 cellsSARS-CoV-1Small molecule antagonistsMembrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice
Abulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsCell MembraneDiglyceridesGene Knockout TechniquesInsulin ResistanceLiverMiceNon-alcoholic Fatty Liver DiseaseConceptsHepatic insulin resistanceInsulin resistanceHepatic insulin sensitivityHepatic steatosisLipid-induced hepatic insulin resistancePKCε activationInsulin sensitivityKnockout miceNormal hepatic insulin sensitivityWild-type control miceHepatic ceramide contentHyperinsulinemic-euglycemic clampComprehensive metabolic phenotypingLipid dropletsHepatic DAG contentDAG contentGlucose intoleranceControl miceMTTP activityHepatic insulinAnimal modelsSteatosisAKT Ser/ThrMiceMetabolic phenotypingPIWIL1 promotes gastric cancer via a piRNA-independent mechanism
Shi S, Yang ZZ, Liu S, Yang F, Lin H. PIWIL1 promotes gastric cancer via a piRNA-independent mechanism. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 22390-22401. PMID: 32848063, PMCID: PMC7486755, DOI: 10.1073/pnas.2008724117.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArgonaute ProteinsCell Line, TumorFemaleGene Knockout TechniquesHumansMaleMiceMice, NudeNonsense Mediated mRNA DecayRNA, Small InterferingStomachStomach NeoplasmsConceptsPIWI-interacting RNAsPIWI proteinsGastric cancer cellsNonsense-mediated mRNA decay mechanismPiRNA-independent mechanismDomain protein familyMRNA decay mechanismMammalian somatic tissuesRNA deep sequencingGastric cancer cell line SNU-1Cancer cellsGastric cancer cell proliferationRNA pathwaysPPD proteinsProtein familyPiwil1 geneSomatic tissuesSomatic cancersCancer cell proliferationDeep sequencingRegulatory mechanismsOncogenic functionPIWIL1Gastric cancer tissuesDetectable functionFam20C regulates protein secretion by Cab45 phosphorylation
Hecht TK, Blank B, Steger M, Lopez V, Beck G, Ramazanov B, Mann M, Tagliabracci V, von Blume J. Fam20C regulates protein secretion by Cab45 phosphorylation. Journal Of Cell Biology 2020, 219: e201910089. PMID: 32422653, PMCID: PMC7265331, DOI: 10.1083/jcb.201910089.Peer-Reviewed Original ResearchRole of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish
Morales-Cámara S, Alexandre-Moreno S, Bonet-Fernández J, Atienzar-Aroca R, Aroca-Aguilar J, Ferre-Fernández J, Méndez C, Morales L, Fernández-Sánchez L, Cuenca N, Coca-Prados M, Martínez-de-la-Casa J, Garcia-Feijoo J, Escribano J. Role of GUCA1C in Primary Congenital Glaucoma and in the Retina: Functional Evaluation in Zebrafish. Genes 2020, 11: 550. PMID: 32422965, PMCID: PMC7288452, DOI: 10.3390/genes11050550.Peer-Reviewed Original ResearchMeSH KeywordsAdultAmino Acid SequenceAnimalsApoptosisBase SequenceCRISPR-Cas SystemsFemaleGene EditingGene Knockout TechniquesGlaucomaGliosisGuanylate Cyclase-Activating ProteinsHigh-Throughput Nucleotide SequencingHumansMaleMiddle AgedPedigreeRetinaReverse Transcriptase Polymerase Chain ReactionSequence AlignmentSequence Homology, Amino AcidZebrafishZebrafish ProteinsConceptsPrimary congenital glaucomaCongenital glaucomaRetinal ganglion cell layerRetinal ganglion cell apoptosisCiliary epitheliumGlial fibrillary acidic proteinWhole-exome sequencing analysisGanglion cell layerGanglion cell apoptosisHuman ocular ciliary epitheliumFibrillary acidic proteinOcular anterior segmentIntraocular pressure regulationOcular ciliary epitheliumNon-pigmented ciliary epitheliumAutosomal recessive fashionOptical neuropathyOcular effectsRetinal damageMüller cellsAnterior segmentPressure regulationAcidic proteinKnockout animalsGuanylate cyclaseTorsin ATPase deficiency leads to defects in nuclear pore biogenesis and sequestration of MLF2
Rampello AJ, Laudermilch E, Vishnoi N, Prophet SM, Shao L, Zhao C, Lusk CP, Schlieker C. Torsin ATPase deficiency leads to defects in nuclear pore biogenesis and sequestration of MLF2. Journal Of Cell Biology 2020, 219: e201910185. PMID: 32342107, PMCID: PMC7265317, DOI: 10.1083/jcb.201910185.Peer-Reviewed Original ResearchConceptsNuclear pore biogenesisMyeloid leukemia factor 2FG nucleoporinsNuclear pore complex biogenesisNuclear envelope herniationsNuclear envelope reformationLive cell imaging platformProteomics-based approachNuclear envelope blebbingComplex biogenesisBleb formationUbiquitin conjugationNuclear envelopeATPase deficiencyBiogenesisHallmark phenotypePhenotypic hallmarksPOM121Factor 2Late markersLuminal componentsNup358CellsUbiquitinBlebbingGABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions
Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, Taylor SR, Duman CH, Delpire E, Picciotto M, Wohleb ES, Duman RS. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. Journal Of Clinical Investigation 2020, 130: 1336-1349. PMID: 31743111, PMCID: PMC7269589, DOI: 10.1172/jci130808.Peer-Reviewed Original ResearchConceptsRapid antidepressant actionsAntidepressant actionGABA interneuronsMedial prefrontal cortexCell-specific knockdownPrinciple neuronsPrefrontal cortexDeletion of GluN2BSingle subanesthetic doseBehavioral actionsAction of ketamineNMDA receptor antagonistExcitatory postsynaptic currentsCellular triggersMajor unmet needKetamine's rapid antidepressant actionsGABA subtypeGluN2B-NMDARsSST interneuronsPostsynaptic currentsReceptor antagonistDepressed patientsSubanesthetic doseExtracellular glutamateMood disordersTreg-Cell-Derived IL-35-Coated Extracellular Vesicles Promote Infectious Tolerance
Sullivan J, Tomita Y, Jankowska-Gan E, Lema D, Arvedson M, Nair A, Bracamonte-Baran W, Zhou Y, Meyer K, Zhong W, Sawant D, Szymczak-Workman A, Zhang Q, Workman C, Hong S, Vignali D, Burlingham W. Treg-Cell-Derived IL-35-Coated Extracellular Vesicles Promote Infectious Tolerance. Cell Reports 2020, 30: 1039-1051.e5. PMID: 31995748, PMCID: PMC7042971, DOI: 10.1016/j.celrep.2019.12.081.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCoculture TechniquesExtracellular VesiclesFemaleForkhead Transcription FactorsGene Knockout TechniquesHeart TransplantationImmune ToleranceImmunosuppression TherapyInterleukin-12 Subunit p35InterleukinsMiceMice, Inbred C57BLMice, Inbred CBAMice, TransgenicMicroscopy, Electron, TransmissionMinor Histocompatibility AntigensReceptors, CytokineT-Lymphocytes, RegulatoryConceptsIL-35Treg cellsInfectious toleranceExtracellular vesiclesExpression of Ebi3T regulatory (Treg) cellsImmunosuppressive cytokinesInterleukin-35Peripheral toleranceRegulatory cellsEpstein-BarrBystander lymphocytesSecondary suppressionReporter miceB lymphocytesEBI3Protein 3Foxp3LymphocytesGene reporterNovel mechanismP35 proteinCellsEV productionTregs
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