2024
The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity
Šenigl F, Soikkeli A, Prost S, Schatz D, Slavková M, Hejnar J, Alinikula J. The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity. Tumour Virus Research 2024, 18: 200293. PMID: 39490533, PMCID: PMC11564006, DOI: 10.1016/j.tvr.2024.200293.Peer-Reviewed Original ResearchB cellsSV40 LTMerkel cell polyomavirusAPOBEC familySV40 enhancerCell typesAssociated with several typesAID-induced mutationsLT expressionTumorigenic potentialMalignant developmentSV40 infectionTumorigenic activityHuman cancersSomatic hypermutationAberrant expressionAntibody diversification processesSimian virusKidney cellsMonkey virusSV40Virus enhancerMutationsFrequent sourceSeveral types
2021
Sarco/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 mutationsRAG1Recombination
2020
Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID
Kuhny M, Forbes LR, Çakan E, Vega-Loza A, Kostiuk V, Dinesh RK, Glauzy S, Stray-Pedersen A, Pezzi AE, Hanson IC, Vargas-Hernandez A, Xu ML, Akdemir Z, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR, Chinn IK, Schatz DG, Orange JS, Meffre E. Disease-associated CTNNBL1 mutation impairs somatic hypermutation by decreasing nuclear AID. Journal Of Clinical Investigation 2020, 130: 4411-4422. PMID: 32484799, PMCID: PMC7410074, DOI: 10.1172/jci131297.Peer-Reviewed Original ResearchConceptsB cellsActivation-induced cytidine deaminaseHealthy donor counterpartsIsotype-switched B cellsCommon variable immunodeficiencyMemory B cellsSomatic hypermutationAutoimmune cytopeniasDecreased incidenceVariable immunodeficiencyB cell linesUnderlying molecular defectsNuclear AIDPatient's EBVRamos B cellsPatientsProtein 1Cell linesMolecular defectsCellsCytidine deaminaseMutations
2019
TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer
Lio C, Shukla V, Samaniego-Castruita D, Avalos E, Chakraborty A, Yue X, Schatz D, Rao A. TET enzymes augment AID expression via 5hmC modifications at the Aicda superenhancer. The Journal Of Immunology 2019, 202: 123.15-123.15. DOI: 10.4049/jimmunol.202.supp.123.15.Peer-Reviewed Original ResearchClass switch recombinationChromatin accessibilityTranscription factorsBasic region-leucine zipper (bZIP) transcription factorsBZIP transcription factorsZipper transcription factorAID expressionCytidine deaminase AIDExpression of AicdaTet-responsive elementEpigenetic marksTET enzymesEnhancer dynamicsAicda locusDNA demethylationGenomic regionsAicda expressionMurine B cellsEnhancer activitySwitch recombinationB cellsSuperenhancersTetExpressionCell activationTET 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
2016
Bcl6 Is Required for Somatic Hypermutation and Gene Conversion in Chicken DT40 Cells
Williams AM, Maman Y, Alinikula J, Schatz DG. Bcl6 Is Required for Somatic Hypermutation and Gene Conversion in Chicken DT40 Cells. PLOS ONE 2016, 11: e0149146. PMID: 26900682, PMCID: PMC4762950, DOI: 10.1371/journal.pone.0149146.Peer-Reviewed Original ResearchConceptsDT40 cellsGene conversionTarget genesClass switch recombinationGene bodiesSomatic hypermutationB cell gene expression programChicken DT40 B cellsBCL6 functionCell gene expression programChicken DT40 cellsDT40 B cellsGene expression programsRNA polymerase IIDeficient DT40 cellsTranscription start siteExpression of AIDAbsence of Bcl6High-level expressionB cellsExpression programsPolymerase IIPol IIStart siteTranscriptional features
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
Sin1-mTORC2 Suppresses rag and il7r Gene Expression through Akt2 in B Cells
Lazorchak AS, Liu D, Facchinetti V, Di Lorenzo A, Sessa WC, Schatz DG, Su B. Sin1-mTORC2 Suppresses rag and il7r Gene Expression through Akt2 in B Cells. Molecular Cell 2010, 39: 433-443. PMID: 20705244, PMCID: PMC2957800, DOI: 10.1016/j.molcel.2010.07.031.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsB-LymphocytesCell Line, TransformedDNA-Binding ProteinsForkhead Box Protein O1Forkhead Transcription FactorsGene Expression RegulationGene Rearrangement, B-LymphocyteHomeodomain ProteinsMiceMice, KnockoutPhosphatidylinositol 3-KinasesProto-Oncogene Proteins c-aktReceptors, Interleukin-7Signal TransductionTOR Serine-Threonine KinasesTranscription FactorsConceptsB cell developmentGene expressionCell developmentRAG gene expressionMTOR complex 2FOXO1 transcriptional activityPI3K signalingMTOR inhibitor rapamycinTranscriptional activityKey regulatorB cellsMolecular mechanismsInhibitor rapamycinK signalingCell survivalFoxO1 phosphorylationMammalian targetRecombinase activityPI3KIL-7 receptorAkt2SignalingRapamycinExpressionCells
2008
Two levels of protection for the B cell genome during somatic hypermutation
Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG. Two levels of protection for the B cell genome during somatic hypermutation. Nature 2008, 451: 841-845. PMID: 18273020, DOI: 10.1038/nature06547.Peer-Reviewed Original ResearchConceptsError-free DNA repairB cell genomeGenomic stabilityNumerous oncogenesDNA repairCell genomeBase excisionGenomeMismatch repairImmunoglobulin genesSomatic hypermutationWidespread mutationsHypermutationB-cell tumorsB-cell malignanciesHigh-affinity antibodiesB cellsGenesOncogeneLarge fractionDiversityVital roleMutationsEnzymeRepair
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, ImmunoglobulinSpleenOrigins of peripheral B cells in IL-7 receptor-deficient mice
Hesslein DG, Yang SY, Schatz DG. Origins of peripheral B cells in IL-7 receptor-deficient mice. Molecular Immunology 2006, 43: 326-334. PMID: 16310046, DOI: 10.1016/j.molimm.2005.02.010.Peer-Reviewed Original ResearchConceptsIL-7Ralpha-deficient miceB cell populationsB cellsBone marrowSplenic B cellsIL-7RalphaCell percentageIL-7 receptor-deficient miceCell populationsReceptor-deficient micePeripheral B cellsSplenic B cell populationSpleens of adultBone marrow-derived B cellsReceptor alpha geneEarly lymphoid differentiationAdult bone marrowSplenic populationsPeripheral BNeonatal developmentB cell developmentFollicular cellsMarrowMiceFetal liver
2004
Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors
Horowitz MC, Xi Y, Pflugh DL, Hesslein DG, Schatz DG, Lorenzo JA, Bothwell AL. Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors. The Journal Of Immunology 2004, 173: 6583-6591. PMID: 15557148, DOI: 10.4049/jimmunol.173.11.6583.Peer-Reviewed Original ResearchConceptsNumber of osteoclastsSpleen cellsB cellsOsteoclast developmentB cell-deficient miceCell-deficient miceControl spleen cellsB lymphocyte lineage cellsBone marrow cellsB-cell lineagePro-B cell stageMonocyte phenotypeBone massOsteoclast precursorsMice exhibitOsteoclast progenitorsMarrow cellsGrowth factorMiceOsteoclastsLineage cellsOsteopeniaCell lineagesCellsAdherent cellsB cell–specific loss of histone 3 lysine 9 methylation in the VH locus depends on Pax5
Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K. B cell–specific loss of histone 3 lysine 9 methylation in the VH locus depends on Pax5. Nature Immunology 2004, 5: 853-861. PMID: 15258579, PMCID: PMC1635547, DOI: 10.1038/ni1099.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceB-LymphocytesCell LineageCells, CulturedDNA-Binding ProteinsFlow CytometryGene Rearrangement, B-LymphocyteHematopoietic Stem CellsHistonesImmunoglobulin Heavy ChainsImmunoglobulin Variable RegionLysineMethylationMiceModels, ImmunologicalMolecular Sequence DataPAX5 Transcription FactorPrecipitin TestsReverse Transcriptase Polymerase Chain ReactionTranscription FactorsConceptsH3-K9 methylationDJH recombinationVH locusHistone 3 lysine 9 methylationLysine 9 methylationFunction of Pax5Non-B lineage cellsB cell-specific lossB cell commitmentHistone exchangeInactive chromatinLysine 9Histone H3Transcription factorsCell commitmentCell-specific lossInhibitory modificationMethylationLineage cellsLociPAX5B cellsHeavy chain rearrangementRecombinationChain rearrangementStaggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination
Rush JS, Fugmann SD, Schatz DG. Staggered AID‐dependent DNA double strand breaks are the predominant DNA lesions targeted to Sµ in Ig class switch recombination. International Immunology 2004, 16: 549-557. PMID: 15039385, DOI: 10.1093/intimm/dxh057.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, MonoclonalBlotting, SouthernB-LymphocytesCell DivisionCytidine DeaminaseDeoxyribonucleases, Type II Site-SpecificDNADNA DamageDNA PrimersFlow CytometryGene ExpressionImmunoglobulin Class SwitchingImmunoglobulin DImmunoglobulin GImmunoglobulin Switch RegionInterleukin-4LipopolysaccharidesMiceMice, Inbred C57BLMice, KnockoutPlasmidsPolymerase Chain ReactionRecombination, GeneticConceptsClass switch recombinationDNA double-strand breaksPredominant DNA lesionsDouble-strand breaksActivation-induced cytidine deaminaseDNA lesionsSwitch recombinationAID-dependent DNA double-strand breaksStrand breaksIg class switch recombinationLigation-mediated PCRS mu regionCellular regulationKinetics of inductionMolecular detailsMurine B cellsDNA DSBsStaggered breaksCytidine deaminaseDSBsMu regionMinor speciesB cellsS muEffector propertiesNon‐redundancy of cytidine deaminases in class switch recombination
Fugmann SD, Rush JS, Schatz DG. Non‐redundancy of cytidine deaminases in class switch recombination. European Journal Of Immunology 2004, 34: 844-849. PMID: 14991614, DOI: 10.1002/eji.200324418.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseClass switch recombinationAPOBEC-1Human activation-induced cytidine deaminaseSwitch recombinationCognate substratesCatalytic mutantGene conversionClose homologueProkaryotic cellsInactive mutantMurine B cellsDistinct mRNAsCytidine deaminase activityCytidine deaminasesImmunoglobulin genesDiversification mechanismsCytidine deaminaseSomatic hypermutationUnknown mechanismDeaminase activityMutantsPrecise roleActivated B cellsB cells
1996
Neoteny in Lymphocytes: Rag1 and Rag2 Expression in Germinal Center B Cells
Han S, Zheng B, Schatz D, Spanopoulou E, Kelsoe G. Neoteny in Lymphocytes: Rag1 and Rag2 Expression in Germinal Center B Cells. Science 1996, 274: 2094-2097. PMID: 8953043, DOI: 10.1126/science.274.5295.2094.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesDNA NucleotidyltransferasesDNA-Binding ProteinsFemaleGene ExpressionGene RearrangementGenes, ImmunoglobulinGenes, RAG-1Germinal CenterHomeodomain ProteinsImmunizationImmunoglobulin Class SwitchingLymphocyte ActivationMiceMice, Inbred C57BLPolymerase Chain ReactionProtein BiosynthesisProteinsVDJ RecombinasesConceptsGerminal center B cellsAntigen receptor genesT cell antigen receptor genesRAG2 proteinsB cellsRAG2 geneRAG genesRAG2 expressionFunctional immunoglobulinPeyer's patch germinal centersMessenger RNAGenesRAG1Receptor geneActivated B cellsNormal adult animalsLymphocyte populationsImmature lymphocytesGerminal centersBone marrowMurine splenicAntibody repertoireCellsAdult animalsExpressionThe 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
1991
Selective expression of RAG-2 in chicken B cells undergoing immunoglobulin gene conversion
Carlson L, Oettinger M, Schatz D, Masteller E, Hurley E, McCormack W, Baltimore D, Thompson C. Selective expression of RAG-2 in chicken B cells undergoing immunoglobulin gene conversion. Cell 1991, 64: 201-208. PMID: 1986866, DOI: 10.1016/0092-8674(91)90221-j.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsBlotting, NorthernB-LymphocytesBursa of FabriciusCell LineChickensCloning, MolecularFlow CytometryGene ConversionGene ExpressionGene Expression RegulationGenes, ImmunoglobulinHumansMolecular Sequence DataNucleic Acid HybridizationRecombination, GeneticRNA, MessengerSpleenThymus GlandConceptsIg gene conversionGene conversionChicken B cellsRAG-2 mRNARAG-2Cis-acting DNA elementsChicken B cell lineRAG-1Mammalian B cellsIntrachromosomal gene conversionImmunoglobulin gene conversionRAG-2 expressionB cell developmentIg diversificationRAG-1 mRNADNA elementsCell developmentB cell linesBursa of FabriciusB cellsPhenotypic characteristicsSelective expressionCell linesBursal lymphocytesMRNA