2019
Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire
Shinoda K, Maman Y, Canela A, Schatz DG, Livak F, Nussenzweig A. Intra-Vκ Cluster Recombination Shapes the Ig Kappa Locus Repertoire. Cell Reports 2019, 29: 4471-4481.e6. PMID: 31875554, PMCID: PMC8214342, DOI: 10.1016/j.celrep.2019.11.088.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksRecombination signal sequencesVκ gene segmentsGene segmentsDouble-strand breaksVariable gene segmentsRAG proteinsSignal sequenceV-J rearrangementRecombination eventsSpacer regionVκ-JκRecombinationLevels of breakageComplete absenceProteinLarge fractionDeletionJκSequenceTET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer
Lio CJ, Shukla V, Samaniego-Castruita D, González-Avalos E, Chakraborty A, Yue X, Schatz DG, Ay F, Rao A. TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer. Science Immunology 2019, 4 PMID: 31028100, PMCID: PMC6599614, DOI: 10.1126/sciimmunol.aau7523.Peer-Reviewed Original ResearchMeSH Keywords5-MethylcytosineAnimalsBasic-Leucine Zipper Transcription FactorsB-LymphocytesCell DifferentiationCells, CulturedCytidine DeaminaseDioxygenasesDNA DemethylationDNA-Binding ProteinsGene Expression RegulationGenetic LociImmunoglobulin Class SwitchingLymphocyte ActivationMiceMice, TransgenicPrimary Cell CultureProto-Oncogene ProteinsResponse ElementsConceptsClass switch recombinationTranscription factorsChromatin accessibilityDNA demethylationBasic region-leucine zipper (bZIP) transcription factorsBZIP transcription factorsZipper transcription factorKey transcription factorEpigenetic marksTET enzymesEnhancer dynamicsGenomic regionsDeficient B cellsMurine B cellsEnhancer activityEnzyme essentialEnhancer elementsSwitch recombinationActivation-induced deaminase (AID) expressionAID expressionB cellsSuperenhancersTetDemethylationExpression
2015
Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia
Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon SM, Trageser D, Hasselfeld B, Henke N, Mooster J, Geng H, Schwarz K, Kogan SC, Casellas R, Schatz DG, Lieber MR, Greaves MF, Müschen M. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nature Immunology 2015, 16: 766-774. PMID: 25985233, PMCID: PMC4475638, DOI: 10.1038/ni.3160.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAnimalsAntibody DiversityB-LymphocytesChildChild, PreschoolClonal EvolutionCytidine DeaminaseDNA-Binding ProteinsFemaleFlow CytometryHomeodomain ProteinsHumansImmunoblottingInfantMaleMice, Inbred NODMice, KnockoutMice, SCIDMice, TransgenicMicroscopy, FluorescencePrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidReverse Transcriptase Polymerase Chain ReactionTumor Cells, Cultured
2013
Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes
Duke JL, Liu M, Yaari G, Khalil AM, Tomayko MM, Shlomchik MJ, Schatz DG, Kleinstein SH. Multiple Transcription Factor Binding Sites Predict AID Targeting in Non-Ig Genes. The Journal Of Immunology 2013, 190: 3878-3888. PMID: 23514741, PMCID: PMC3689293, DOI: 10.4049/jimmunol.1202547.Peer-Reviewed Original ResearchConceptsTranscription Factor Binding SitesAID-induced lesionsNon-Ig genesGenome instabilityTranscription factorsAberrant targetingSequence dataCertain genesGenesAID targetingGerminal center B cellsSomatic mutationsLikely targetBinding sitesAID targetsTargetingClassification tree modelMistargetingB cellsLociMechanismTargetMutationsSites
2012
AID-Targeting and Hypermutation of Non-Immunoglobulin Genes Does Not Correlate with Proximity to Immunoglobulin Genes in Germinal Center B Cells
Gramlich HS, Reisbig T, Schatz DG. AID-Targeting and Hypermutation of Non-Immunoglobulin Genes Does Not Correlate with Proximity to Immunoglobulin Genes in Germinal Center B Cells. PLOS ONE 2012, 7: e39601. PMID: 22768095, PMCID: PMC3387148, DOI: 10.1371/journal.pone.0039601.Peer-Reviewed Original ResearchConceptsNon-Ig genesC-MycIg genesAID targetingGerminal center B cellsDouble-strand break endsImportant regulatory elementsNon-immunoglobulin genesMYC transgeneHeavy chain geneRegulatory elementsBreak endsIg heavy chain genesIg lociHuman MYCGenesB cellsSuch translocationsImmunoglobulin lociImmunoglobulin genesTranslocation partnersChain geneHuman Burkitt lymphomaSomatic hypermutationNuclear position
2010
The In Vivo Pattern of Binding of RAG1 and RAG2 to Antigen Receptor Loci
Ji Y, Resch W, Corbett E, Yamane A, Casellas R, Schatz DG. The In Vivo Pattern of Binding of RAG1 and RAG2 to Antigen Receptor Loci. Cell 2010, 141: 419-431. PMID: 20398922, PMCID: PMC2879619, DOI: 10.1016/j.cell.2010.03.010.Peer-Reviewed Original ResearchConceptsJ gene segmentsRAG proteinsGene segmentsSignal sequenceLineage-specific mannerAntigen receptor lociRecombination signal sequencesLysine 4Active chromatinRAG2 bindThousands of sitesHistone 3Receptor locusDevelopmental stagesD gene segmentsDiscrete sitesCritical initial stepVivo patternRAG1BindingRAG2Beta JProteinRecombinationSpecific binding
2009
Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation
Giblin W, Chatterji M, Westfield G, Masud T, Theisen B, Cheng HL, DeVido J, Alt FW, Ferguson DO, Schatz DG, Sekiguchi J. Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation. Blood 2009, 113: 2965-2975. PMID: 19126872, PMCID: PMC2662642, DOI: 10.1182/blood-2008-07-165167.Peer-Reviewed Original ResearchConceptsDouble-strand breaksHypomorphic RAG1 mutationsImmune system dysfunctionDNA rearrangementsKnockin mouse modelP53 mutant backgroundAberrant DNA rearrangementsDNA double-strand breaksPremature immunosenescenceDNA end processingSystem dysfunctionRecombination signal sequencesMouse modelRAG1 mutationsImmune systemMice exhibitAntigen receptor genesThymic lymphomasTumor developmentVivo evidenceMutant backgroundLymphocyte developmentSignal sequenceReceptor geneHypomorphic mutations
2007
Strand-Biased Spreading of Mutations During Somatic Hypermutation
Unniraman S, Schatz DG. Strand-Biased Spreading of Mutations During Somatic Hypermutation. Science 2007, 317: 1227-1230. PMID: 17761884, DOI: 10.1126/science.1145065.Peer-Reviewed Original Research
2006
Roles of the Ig κ Light Chain Intronic and 3′ Enhancers in Igk Somatic Hypermutation
Inlay MA, Gao HH, Odegard VH, Lin T, Schatz DG, Xu Y. Roles of the Ig κ Light Chain Intronic and 3′ Enhancers in Igk Somatic Hypermutation. The Journal Of Immunology 2006, 177: 1146-1151. PMID: 16818772, DOI: 10.4049/jimmunol.177.2.1146.Peer-Reviewed Original ResearchMeSH Keywords3' Untranslated RegionsAnimalsB-LymphocytesCells, CulturedDown-RegulationEnhancer Elements, GeneticGene DeletionGene Expression RegulationGerminal CenterImmunoglobulin kappa-ChainsIntronsLymphocyte ActivationMiceMice, KnockoutMice, TransgenicRNA, MessengerSomatic Hypermutation, ImmunoglobulinSpleen
2005
Histone Modifications Associated with Somatic Hypermutation
Odegard VH, Kim ST, Anderson SM, Shlomchik MJ, Schatz DG. Histone Modifications Associated with Somatic Hypermutation. Immunity 2005, 23: 101-110. PMID: 16039583, DOI: 10.1016/j.immuni.2005.05.007.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsB-LymphocytesChromatinChromatin ImmunoprecipitationCpG IslandsDNA DamageDNA MethylationHistonesImmunoglobulin Class SwitchingImmunoglobulin lambda-ChainsImmunoglobulin Light ChainsMethylationMiceMice, TransgenicPhosphorylationProtein Serine-Threonine KinasesSomatic Hypermutation, ImmunoglobulinConceptsClass switch recombinationSomatic hypermutationDistinct DNA damage responsesPhosphorylation of H2BHistone modification patternsDNA damage responseChromatin modificationsHistone modificationsKinase Mst1Histone H2BDamage responseHistone acetylationAcetylated H3Modification patternsPhosphorylated formIg lociSwitch recombinationImmunoglobulin lociH2BGammaH2AXLociHypermutationRecombinationHistonesH2AXInducible Gene Expression Using an Autoregulatory, Tetracycline‐Controlled System
Shockett P, Schatz D. Inducible Gene Expression Using an Autoregulatory, Tetracycline‐Controlled System. Current Protocols In Cell Biology 2005, 27: 20.8.1-20.8.10. PMID: 18228465, DOI: 10.1002/0471143030.cb2008s27.Peer-Reviewed Original ResearchConceptsInducible gene expressionSelectable markerGene expressionSecond selectable markerCell linesFibroblast cell lineTransient transfectionGene protein expressionResultant clonesStable linesMarker plasmidPlasmidProtein expressionAdherent cellsTransactivatorExpressionTransfectionCellsTargetGenesSupport protocolClonesLinesMarkersAutoregulatory
2004
Partial reconstitution of V(D)J rearrangement and lymphocyte development in RAG-deficient mice expressing inducible, tetracycline-regulated RAG transgenes
Shockett PE, Zhou S, Hong X, Schatz DG. Partial reconstitution of V(D)J rearrangement and lymphocyte development in RAG-deficient mice expressing inducible, tetracycline-regulated RAG transgenes. Molecular Immunology 2004, 40: 813-829. PMID: 14687938, DOI: 10.1016/j.molimm.2003.09.009.Peer-Reviewed Original ResearchConceptsPeripheral lymphoid organsIGK locusInducible gene expressionLymph nodesCell reconstitutionLymphoid organsTransgenic miceTRB locusTRD locusT-cell reconstitutionB-cell reconstitutionMammalian cellsRAG-deficient miceSignal endsTra locusRecombination signalsInducible activationGene expressionTCR beta chainFunctional expressionLymphocyte developmentLociRAG2 mRNALymphocyte reconstitutionTransgeneUp-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression
Zheng WP, Zhao Q, Zhao X, Li B, Hubank M, Schatz DG, Flavell RA. Up-Regulation of Hlx in Immature Th Cells Induces IFN-γ Expression. The Journal Of Immunology 2004, 172: 114-122. PMID: 14688316, DOI: 10.4049/jimmunol.172.1.114.Peer-Reviewed Original ResearchMeSH KeywordsAdjuvants, ImmunologicAdoptive TransferAnimalsCD4-Positive T-LymphocytesCell DifferentiationCells, CulturedHemocyaninsHomeodomain ProteinsInjections, IntravenousInjections, SubcutaneousInterferon-gammaInterphaseMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicTh1 CellsT-Lymphocytes, Helper-InducerTranscription FactorsUp-RegulationConceptsCD4 T cellsTransgenic CD4 T cellsTh2-polarizing conditionsTh1 cell differentiationTh cellsT cellsTh1 cellsIFN-gammaKeyhole limpet hemocyanin immunizationNormal CD4 T cellsTime pointsIntracellular cytokine stainingIFN-γ expressionIFN-gamma expressionEarly time pointsCytokine stainingTh2 cellsNaive precursorsCell differentiationSpecific time pointsThymocyte populationTransgenic miceMarked reductionAberrant expressionRetroviral infection
2002
Inducible, reversible hair loss in transgenic mice
Chen J, Kelz MB, Zeng G, Steffen C, Shockett PE, Terwilliger G, Schatz DG, Nestler EJ. Inducible, reversible hair loss in transgenic mice. Transgenic Research 2002, 11: 241-247. PMID: 12113456, DOI: 10.1023/a:1015619604318.Peer-Reviewed Original ResearchMeSH KeywordsAlopeciaAnimalsDisease Models, AnimalDoxycyclineGene Expression RegulationMiceMice, TransgenicTetracyclineTrans-ActivatorsConceptsTelogen effluviumInducible transgenic miceHair lossTransgenic miceReversible hair lossSkin pathologyHair loss phenotypeAnimal modelsMolecular abnormalitiesDecreased numberMiceHair folliclesAnagen phaseCommon typeEffluviumTelogen phasePresent findingsLoss phenotypeFolliclesPathologyMolecular mechanismsMorphological changesReporter luciferase geneLuciferase geneHigh levels
2000
Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes
Papavasiliou F, Schatz D. Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes. Nature 2000, 408: 216-221. PMID: 11089977, DOI: 10.1038/35041599.Peer-Reviewed Original ResearchConceptsDNA double-strand breaksDouble-strand breaksSomatic hypermutationRepair of DSBsVariable region promotersImmunoglobulin variable region genesDNA replicationHomologous recombinationHeterologous promoterSpecific residuesVariable genesNearby mutationsRegion promoterVariable region genesImmunoglobulin genesHeterologous sequencesChromosomal translocationsPoint mutationsGenesRegion genesMutationsHypermutationTranscriptionPromoterB-cell tumors
1999
Distinct effects of Jak3 signaling on alphabeta and gammadelta thymocyte development.
Eynon E, Livák F, Kuida K, Schatz D, Flavell R. Distinct effects of Jak3 signaling on alphabeta and gammadelta thymocyte development. The Journal Of Immunology 1999, 162: 1448-59. PMID: 9973401, DOI: 10.4049/jimmunol.162.3.1448.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell DivisionCell SurvivalGene ExpressionGene Rearrangement, delta-Chain T-Cell Antigen ReceptorGene Rearrangement, gamma-Chain T-Cell Antigen ReceptorGenes, bcl-2Janus Kinase 3MiceMice, Inbred C57BLMice, KnockoutMice, TransgenicProtein-Tyrosine KinasesReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaSignal TransductionT-Lymphocyte SubsetsConceptsJak3-/- miceGammadelta T cell lineagesThymocyte developmentTransduction of signalsTCRbeta chain gene rearrangementLineage differentiationGammadelta lineageCell lineagesGene resultsKinase 3Developmental blockadeEarly thymocyte differentiationCytokine receptorsGamma locusT-cell lineageTargeted deletionBcl-2 expressionThymocyte differentiationTCRbeta transgeneIL-2 familyLineagesDifferentiationImmature thymocytesTransgeneSevere reduction
1997
αβ Lineage‐committed thymocytes can be rescued by the γδ T cell receptor (TCR) in the absence of TCR β chain
Livák F, Wilson A, MacDonald H, Schatz D. αβ Lineage‐committed thymocytes can be rescued by the γδ T cell receptor (TCR) in the absence of TCR β chain. European Journal Of Immunology 1997, 27: 2948-2958. PMID: 9394823, DOI: 10.1002/eji.1830271130.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationFemaleGene Expression RegulationGene Rearrangement, alpha-Chain T-Cell Antigen ReceptorMiceMice, Inbred AKRMice, Inbred C57BLMice, KnockoutMice, TransgenicModels, ImmunologicalReceptors, Antigen, T-Cell, alpha-betaReceptors, Antigen, T-Cell, gamma-deltaThymus GlandT-Lymphocyte SubsetsTransgenesConceptsT cell receptorLineage commitmentT cell lineage commitmentCell lineage commitmentAlpha beta T cell developmentTCR beta proteinGamma delta T cell lineagesAlpha beta lineageT cell developmentCell receptorTCR-mediated selectionGene rearrangementsCell lineagesT cellsΑβ lineageCell developmentTCR gammaAlpha betaT-cell lineageBeta lineageLineagesGamma delta T-cell receptorTCR β chainGamma delta T cellsDelta T-cell receptorSwitching on gene expression
Shockett P, Schatz D. Switching on gene expression. Nature Biotechnology 1997, 15: 219-221. PMID: 9062915, DOI: 10.1038/nbt0397-219.Commentaries, Editorials and Letters
1996
The half-life of RAG-1 protein in precursor B cells is increased in the absence of RAG-2 expression.
Grawunder U, Schatz DG, Leu TM, Rolink A, Melchers F. The half-life of RAG-1 protein in precursor B cells is increased in the absence of RAG-2 expression. Journal Of Experimental Medicine 1996, 183: 1731-1737. PMID: 8666930, PMCID: PMC2192496, DOI: 10.1084/jem.183.4.1731.Peer-Reviewed Original Research
1995
A modified tetracycline-regulated system provides autoregulatory, inducible gene expression in cultured cells and transgenic mice.
Shockett P, Difilippantonio M, Hellman N, Schatz DG. A modified tetracycline-regulated system provides autoregulatory, inducible gene expression in cultured cells and transgenic mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 1995, 92: 6522-6526. PMID: 7604026, PMCID: PMC41550, DOI: 10.1073/pnas.92.14.6522.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAnimalsBlotting, WesternCells, CulturedDNA NucleotidyltransferasesGene Expression RegulationHerpes Simplex Virus Protein Vmw65MiceMice, TransgenicOpen Reading FramesPlasmidsRecombinant Fusion ProteinsRepressor ProteinsRestriction MappingRNA, MessengerSequence DeletionTetracyclineTrans-ActivatorsTransfectionVDJ RecombinasesConceptsInducible gene expressionGene expressionTetracycline-regulated gene expressionTranscriptional activation domainCultured cellsTetracycline-regulated systemTransgenic miceExpression of tTAAutoregulatory systemActivation domainTTA geneInducible promoterTetracycline repressorInducible expressionFusion proteinTransactivator proteinConstitutive expressionTransgenic animalsGene 1Induced levelsRecombination activityMost tissuesConstitutive systemProteinCell lines