2025
Sensitive detection of synthetic response to cancer immunotherapy driven by gene paralog pairs
Dong C, Zhang F, He E, Ren P, Verma N, Zhu X, Feng D, Cai J, Zhao H, Chen S. Sensitive detection of synthetic response to cancer immunotherapy driven by gene paralog pairs. Patterns 2025, 6: 101184. DOI: 10.1016/j.patter.2025.101184.Peer-Reviewed Original ResearchParalogous gene pairsParalogous pairsChimeric antigen receptor T cellsResponse to cancer immunotherapyDouble knockoutCancer immunotherapy responseGene pairsCheckpoint blockadeGenome-wide screenImmunotherapy efficacyCancer immunotherapyEnhance immunotherapyImmunotherapy responseImmunotherapy effectT cellsImmunotherapyCancer treatmentIndividual genesCRISPR screensEnrichment analysisParalogsCancerTreatmentCombined targetFunctional significanceNorovirus co-opts NINJ1 for selective protein secretion
Song J, Zhang L, Moon S, Fang A, Wang G, Gheshm N, Loeb S, Cao P, Wallace J, Alfajaro M, Strine M, Beatty W, Jamieson A, Orchard R, Robinson B, Nice T, Wilen C, Orvedahl A, Reese T, Lee S. Norovirus co-opts NINJ1 for selective protein secretion. Science Advances 2025, 11: eadu7985. PMID: 40020060, PMCID: PMC11870086, DOI: 10.1126/sciadv.adu7985.Peer-Reviewed Original ResearchConceptsPlasma membrane ruptureDamage-associated molecular patternsNS1 secretionNinjurin-1Programmed cell deathAmino acid residuesViral replication sitesViral protein NS1CRISPR screensIntracellular viral proteinsMutagenesis studiesMembrane ruptureProtein NS1Unconventional pathwayCaspase-3Protein secretionViral proteinsReplication sitesCell deathMolecular patternsGenetic ablationNS1Pharmaceutical inhibitionDAMP releaseProtein
2024
Epigenomics and single cell CRISPR screening to investigate the risk‐modifying role of microglia in Alzheimer’s disease and multiple sclerosis
Gallagher M, Du W, Hazel K, Aydin Z, Cheng Y, Yuan B, Bell G, Young R, Jaenisch R, Corradin O. Epigenomics and single cell CRISPR screening to investigate the risk‐modifying role of microglia in Alzheimer’s disease and multiple sclerosis. Alzheimer's & Dementia 2024, 20: e093591. PMCID: PMC11710746, DOI: 10.1002/alz.093591.Peer-Reviewed Original ResearchSingle nucleotide polymorphismsRisk lociMS risk lociEnhancer landscapeSingle cell screeningCell type-specific enhancersGenome-wide association studiesMicroglia-specific enhancersH3K27ac ChIP-seqNeurodegenerative diseasesCell type-specificEx vivo microgliaSNP enrichmentChIP-seqHi-C.CRISPRi screenEnhancer/promoter interactionNoncoding regionsRNA-seqAssociation studiesCRISPR screensCRISPRiNucleotide polymorphismsSafe harbor locusCell screeningMetabolic Determinants of Ferroptosis in B-Cell Lymphoma
Leveille E, Bramson E, Robinson M, Bertomeu T, Chatr-Aryamontri A, Kothari S, Müschen M. Metabolic Determinants of Ferroptosis in B-Cell Lymphoma. Blood 2024, 144: 976-976. DOI: 10.1182/blood-2024-209077.Peer-Reviewed Original ResearchB-cell lymphomaB-cell malignanciesB cellsSensitivity to ferroptosisLipid membrane remodelingFerroptosis inducersMyeloid leukemiaSolid tumorsMembrane remodelingCRISPR screensGene dependenciesAssociated with significantly worse survivalTreatment of B-cell lymphomaB-cell lymphoma modelElimination of B cellsPUFA metabolismCysteine-glutamate antiporterCell deathMature splenic B cellsTherapy-resistant tumorsNon-apoptotic form of cell deathAnalysis of clinical dataDominant-negative p53Vulnerability to ferroptosisWhole-genome CRISPR screen42. STRESS EXPOSURE DYNAMICALLY REGULATES EQTL ACTIVITY IN THE POST-MORTEM BRAIN AND IN HIPSC-DERIVED NEURONS
Seah C, Signer R, Young H, Hicks E, Rusielewicz T, Bader H, Xu C, Breen M, Paull D, Yehuda R, Girgenti M, Brennand K, Huckins L. 42. STRESS EXPOSURE DYNAMICALLY REGULATES EQTL ACTIVITY IN THE POST-MORTEM BRAIN AND IN HIPSC-DERIVED NEURONS. European Neuropsychopharmacology 2024, 87: 71-72. DOI: 10.1016/j.euroneuro.2024.08.156.Peer-Reviewed Original ResearchPost-mortem brainsTranscription factor binding sitesAbsence of cellular stressCombat-exposed veteransFactor binding sitesImpact gene expressionBinding sitesGR binding sitesPositive regulatory activityMotif enrichmentSequence readsCRISPRi screenOpen chromatinFunctional annotationBrain regionsTraumatic stressCRISPR screensEQTLTraumatic experiencesLeading locusPTSDPerturbed genesRegulatory architectureTranscriptomic activityTranscriptomic responseMassively parallel approaches for characterizing noncoding functional variation in human evolution
Rong S, Root E, Reilly S. Massively parallel approaches for characterizing noncoding functional variation in human evolution. Current Opinion In Genetics & Development 2024, 88: 102256. PMID: 39217658, PMCID: PMC11648527, DOI: 10.1016/j.gde.2024.102256.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsCis-regulatory elementsFunction of cis-regulatory elementsImpact of sequence variantsHigh-throughput approachNoncoding variationGenome functionNoncoding regionsSequence variantsPhenotypic consequencesCRISPR screensGenetic basisGenetic variantsGenetic differencesDiverse phenotypesGene expressionRegulatory functionsHuman evolutionFunctional variationGenomeUnique phenotypePhenotypeRegulatory impactModel systemVariantsGenesPositive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB
Lampson B, Ramίrez A, Baro M, He L, Hegde M, Koduri V, Pfaff J, Hanna R, Kowal J, Shirole N, He Y, Doench J, Contessa J, Locher K, Kaelin W. Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB. Cell 2024, 187: 2209-2223.e16. PMID: 38670073, PMCID: PMC11149550, DOI: 10.1016/j.cell.2024.03.022.Peer-Reviewed Original ResearchConceptsWhole-genome CRISPR-Cas9 screenCRISPR-Cas9 screensCryoelectron microscopy studiesCell surface localizationLipopolysaccharide receptor Toll-like receptor 4OST complexToll-like receptor 4CRISPR screensNF-kBCatalytic subunitN-glycosylationActivate NF-kBBase editorsUncompetitive inhibition mechanismNGI-1Molecular mechanismsCatalytic siteLPS-treated cellsOligosaccharyltransferaseDruggable pocketSTT3AReceptor Toll-like receptor 4Drug mechanism of actionStructural studiesInflammatory signalingMulticenter integrated analysis of noncoding CRISPRi screens
Yao D, Tycko J, Oh J, Bounds L, Gosai S, Lataniotis L, Mackay-Smith A, Doughty B, Gabdank I, Schmidt H, Guerrero-Altamirano T, Siklenka K, Guo K, White A, Youngworth I, Andreeva K, Ren X, Barrera A, Luo Y, Yardımcı G, Tewhey R, Kundaje A, Greenleaf W, Sabeti P, Leslie C, Pritykin Y, Moore J, Beer M, Gersbach C, Reddy T, Shen Y, Engreitz J, Bassik M, Reilly S. Multicenter integrated analysis of noncoding CRISPRi screens. Nature Methods 2024, 21: 723-734. PMID: 38504114, PMCID: PMC11009116, DOI: 10.1038/s41592-024-02216-7.Peer-Reviewed Original ResearchCis-regulatory elementsCRISPR interferenceSingle guide RNADetection of cis-regulatory elementsGuide RNAsCandidate cis-regulatory elementsNoncoding cis-regulatory elementsDNA strand biasGene regulatory landscapeCis-regulatory mechanismsNoncoding genomeNoncoding elementsTranscribed regionsStrand biasHuman cell linesCRISPR screensFunctional characterizationTranscriptional effectsGenomeK562 cellsRegulatory landscapeCell linesConsortium effortCharacterization CenterRNATherapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery
Chan A, Han L, Delaney C, Wang X, Mukhaleva E, Li M, Yang L, Pokharel S, Mattson N, Garcia M, Wang B, Xu X, Zhang L, Singh P, Elsayed Z, Chen R, Kuang B, Wang J, Yuan Y, Chen B, Chan L, Rosen S, Horne D, Müschen M, Chen J, Vaidehi N, Armstrong S, Su R, Chen C. Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery. Science Advances 2024, 10: eadk3127. PMID: 38394203, PMCID: PMC10889360, DOI: 10.1126/sciadv.adk3127.Peer-Reviewed Original ResearchConceptsTudor domainDrug discoveryRibosomal gene expressionMolecular dynamics simulationsDomain-focused CRISPR screeningDe novo drug discoveryCompound dockingAcetyltransferase complexCRISPR screensGenetic approachesLead inhibitorDynamics simulationsStructural genetics approachGene expressionH3K9 acetylationEpigenetic dysregulationSgf29Tile scansLeukemia progressionMultiple cancersDrug developmentDiscoveryH3K9DockingLeukemia
2023
MASSIVELY PARALLEL CHARACTERIZATION OF CONTEXT SPECIFIC REGULATORY RISK ELEMENTS ACROSS PSYCHIATRIC DISORDERS IN HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED GLUTAMATERGIC NEURONS
Townsley K, Sen A, Lee J, Deans P, Jia M, Fernandez-Garcia M, Cartwright S, Cohen S, Goate A, Brennand K, Huckins L. MASSIVELY PARALLEL CHARACTERIZATION OF CONTEXT SPECIFIC REGULATORY RISK ELEMENTS ACROSS PSYCHIATRIC DISORDERS IN HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED GLUTAMATERGIC NEURONS. European Neuropsychopharmacology 2023, 75: s7-s8. DOI: 10.1016/j.euroneuro.2023.08.022.Peer-Reviewed Original ResearchCandidate regulatory sequencesExpression quantitative trait lociRegulatory sequencesTranscriptional activityGWAS statisticsSingle-cell CRISPR screensCell type-specific mannerParallel reporter assaysQuantitative trait lociPutative regulatory elementsHigh-throughput sequencingFine-mapping approachFine-mapping methodsLarge-scale identificationFunctional impactTranscriptomic imputationTrait lociKey genesCRISPR screensLarge-scale screening techniquesRegulatory elementsNeuropsychiatric traitsCausal SNPsReporter assaysCasual variantsEpigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis
Li M, Yang L, Chan A, Pokharel S, Liu Q, Mattson N, Xu X, Chang W, Miyashita K, Singh P, Zhang L, Li M, Wu J, Wang J, Chen B, Chan L, Lee J, Zhang X, Rosen S, Müschen M, Qi J, Chen J, Hiom K, Bishop A, Chen C. Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis. Advanced Science 2023, 10: 2206584. PMID: 37075745, PMCID: PMC10265057, DOI: 10.1002/advs.202206584.Peer-Reviewed Original ResearchConceptsProtein translation machineryHistone H4 acetylationOncogenic transcription factorNuA4 histoneChromatin remodelersGene bodiesEpigenetic networksTranslation machineryATPase componentEpigenetic controlTumor progressionCRISPR screensTranscription factorsH4 acetylationEpigenetic dysregulationRUVBL1Oncogenic signalingProtein synthesisPatient-derived samplesMYCPharmacological inhibitionEEF1A1 expressionMultiple cancersNovel opportunitiesDynamic interplay3092 – CRISPR OPTIMIZATION TO SCREEN FOR GENES THAT REGULATE FATE SPECIFICATION OF PRIMARY HUMAN HEMATOPOIETIC PROGENITORS
Mancuso R, Thompson E, Wang L, Krause D. 3092 – CRISPR OPTIMIZATION TO SCREEN FOR GENES THAT REGULATE FATE SPECIFICATION OF PRIMARY HUMAN HEMATOPOIETIC PROGENITORS. Experimental Hematology 2023, 124: s96. DOI: 10.1016/j.exphem.2023.06.199.Peer-Reviewed Original ResearchFate specificationMCherry fluorescent reporterFluorescent reportersNumber of genesLarge-scale screenDNA-PK inhibitorPrimary human hematopoietic progenitorsHuman hematopoietic progenitorsCD45-negative cellsPanel of genesCRISPR screensErythroid maturationSingle guideMolecular mechanismsGRNAGRNA sequencesNegative cellsGenesHematopoietic progenitorsLentiviral transductionTotal RNAReporterProgenitorsTransfectionCell number
2022
Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders
Seah C, Huckins L, Brennand K. Stem Cell Models for Context-Specific Modeling in Psychiatric Disorders. Biological Psychiatry 2022, 93: 642-650. PMID: 36658083, DOI: 10.1016/j.biopsych.2022.09.033.Peer-Reviewed Original ResearchConceptsStem cell modelCell typesTarget genesGenome-wide association study (GWAS) lociExpression quantitative trait lociGenome-wide association studiesParallel reporter assaysQuantitative trait lociStem cell-derived cell typesPluripotent stem cell modelsComplex polygenic architectureContext-specific mannerPsychiatric disorder riskTrait lociRegulates transcriptionStudy lociGenetic regulationPolygenic architectureCRISPR screensCell modelCausal variantsRegulated expressionPatient-specific humanReporter assaysAssociation studiesHigh-content CRISPR screening
Bock C, Datlinger P, Chardon F, Coelho M, Dong M, Lawson K, Lu T, Maroc L, Norman T, Song B, Stanley G, Chen S, Garnett M, Li W, Moffat J, Qi L, Shapiro R, Shendure J, Weissman J, Zhuang X. High-content CRISPR screening. Nature Reviews Methods Primers 2022, 2: 8. DOI: 10.1038/s43586-021-00093-4.Peer-Reviewed Original ResearchCRISPR screeningCRISPR screensBiological discoverySingle-cell RNA sequencingPooled CRISPR screensList of genesHigh-content methodBiological challengesGene functionCell competitionUnbiased interrogationGuide RNARNA sequencingBioinformatics analysisDetailed biological insightsTarget genesBasic biologyPool of cellsBiological insightsCRISPR technologyMolecular mechanismsSuch screensGenesMedical GeneticsBroad utility
2021
Tumor immunology CRISPR screening: present, past, and future
Dong MB, Tang K, Zhou X, Zhou JJ, Chen S. Tumor immunology CRISPR screening: present, past, and future. Trends In Cancer 2021, 8: 210-225. PMID: 34920978, PMCID: PMC8854335, DOI: 10.1016/j.trecan.2021.11.009.Peer-Reviewed Original ResearchDiscovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions
Flynn RA, Belk JA, Qi Y, Yasumoto Y, Wei J, Alfajaro MM, Shi Q, Mumbach MR, Limaye A, DeWeirdt PC, Schmitz CO, Parker KR, Woo E, Chang HY, Horvath TL, Carette JE, Bertozzi CR, Wilen CB, Satpathy AT. Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions. Cell 2021, 184: 2394-2411.e16. PMID: 33743211, PMCID: PMC7951565, DOI: 10.1016/j.cell.2021.03.012.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 RNASARS-CoV-2Virus-induced cell deathHost protein interactionsRNA-binding proteinActive infectionRNA virusesHost-virus interfaceGlobal mortalityTherapeutic benefitCRISPR screensAntiviral factorsProtein interactionsAntiviral activityViral specificityHost pathwaysFunctional RNA-binding proteinsFunctional connectionsRNA-centric approachesCell deathHost proteinsVirusFunctional interrogationRNAComprehensive catalog
2020
Genome-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 antagonists
2019
In vivo CRISPR screening in CD8 T cells with AAV–Sleeping Beauty hybrid vectors identifies membrane targets for improving immunotherapy for glioblastoma
Ye L, Park JJ, Dong MB, Yang Q, Chow RD, Peng L, Du Y, Guo J, Dai X, Wang G, Errami Y, Chen S. In vivo CRISPR screening in CD8 T cells with AAV–Sleeping Beauty hybrid vectors identifies membrane targets for improving immunotherapy for glioblastoma. Nature Biotechnology 2019, 37: 1302-1313. PMID: 31548728, PMCID: PMC6834896, DOI: 10.1038/s41587-019-0246-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CDCD8-Positive T-LymphocytesCell Line, TumorCRISPR-Cas SystemsDependovirusFemaleGene EditingGlioblastomaHumansImmunotherapy, AdoptiveLymphocyte Activation Gene 3 ProteinMaleMembrane ProteinsMiceN-AcetylglucosaminyltransferasesNeoplasm ProteinsProtein Disulfide-IsomerasesReceptors, Cell SurfaceRNA, Guide, CRISPR-Cas SystemsTransposasesXenograft Model Antitumor AssaysConceptsRNA cassetteMembrane protein targetsPrimary murine T cellsGenetic screening systemSingle-cell sequencingScreen hitsSleeping Beauty (SB) transposonCRISPR screensMembrane proteinsCell sequencingT cellsAdeno-associated virusGenomic integrationMembrane targetsMurine T cellsProtein targetsEfficient geneHuman GBM cellsGene editingT cell receptor transgenic modelGBM cellsBeauty transposonPDIA3T cell-based immunotherapyAntigen-specific killingNoroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation
Hosmillo M, Lu J, McAllaster MR, Eaglesham JB, Wang X, Emmott E, Domingues P, Chaudhry Y, Fitzmaurice TJ, Tung MK, Panas MD, McInerney G, Locker N, Wilen CB, Goodfellow IG. Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation. ELife 2019, 8: e46681. PMID: 31403400, PMCID: PMC6739877, DOI: 10.7554/elife.46681.Peer-Reviewed Original ResearchConceptsViral positive-sense RNAFirst host factorHost factorsPositive-sense RNAPro-viral activityPositive-sense RNA virusesSense RNA virusesG3BP1 functionsRibosome recruitmentTranslation complexesTranslation initiationCRISPR screensProteomic analysisMurine norovirus infectionReplication complexSense RNANovel functionViral translationRNA virusesG3BP1Data uncoversNorovirus replicationLife cycleVPgGenusSystematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells
Dong MB, Wang G, Chow RD, Ye L, Zhu L, Dai X, Park JJ, Kim HR, Errami Y, Guzman CD, Zhou X, Chen KY, Renauer PA, Du Y, Shen J, Lam SZ, Zhou JJ, Lannin DR, Herbst RS, Chen S. Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells. Cell 2019, 178: 1189-1204.e23. PMID: 31442407, PMCID: PMC6719679, DOI: 10.1016/j.cell.2019.07.044.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCD8-Positive T-LymphocytesCell Line, TumorClustered Regularly Interspaced Short Palindromic RepeatsCytokinesFemaleHumansImmunologic MemoryImmunotherapyMaleMiceMice, KnockoutNF-kappa BProgrammed Cell Death 1 ReceptorRNA HelicasesRNA, Guide, CRISPR-Cas SystemsTranscriptomeConceptsCRISPR screensTarget discoveryGenome-scale CRISPR screensCD8 TRNA helicase DHX37Vivo CRISPR screensGenetic screenGenome scaleTranscriptomic profilingBiochemical interrogationAntigen-specific CD8 TAnti-tumor immune responseFunctional regulatorTriple-negative breast cancerDHX37Essential roleTim-3PD-1Cytokine productionTumor infiltrationImmunotherapy targetImmunotherapy settingsRegulatorBreast cancerT cells
This site is protected by hCaptcha and its Privacy Policy and Terms of Service apply