Featured Publications
HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation
Wu L, Shukla V, Yadavalli AD, Dinesh RK, Xu D, Rao A, Schatz DG. HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation. Genes & Development 2022, 36: 433-450. PMID: 35450882, PMCID: PMC9067407, DOI: 10.1101/gad.349438.122.Peer-Reviewed Original ResearchTopologically Associated Domains Delineate Susceptibility to Somatic Hypermutation
Senigl F, Maman Y, Dinesh RK, Alinikula J, Seth RB, Pecnova L, Omer AD, Rao SSP, Weisz D, Buerstedde JM, Aiden EL, Casellas R, Hejnar J, Schatz DG. Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation. Cell Reports 2019, 29: 3902-3915.e8. PMID: 31851922, PMCID: PMC6980758, DOI: 10.1016/j.celrep.2019.11.039.Peer-Reviewed Original Research
2022
Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences.
Tarsalainen A, Maman Y, Meng FL, Kyläniemi MK, Soikkeli A, Budzyńska P, McDonald JJ, Šenigl F, Alt FW, Schatz DG, Alinikula J. Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences. The Journal Of Immunology 2022, 208: 143-154. PMID: 34862258, PMCID: PMC8702490, DOI: 10.4049/jimmunol.2100923.Peer-Reviewed Original ResearchConceptsPol IIMutating geneSomatic hypermutationTarget genesChicken DT40 B cellsRNA polymerase II stallingIg genesHistone variant H3.3Locus-specific targetingPol II occupancyAID-mediated mutationsDT40 B cellsRNA polymerase IILevels of H3K27acFull-length transcriptsVariant H3.3Antisense transcriptionTranscriptional outputPolymerase IIGenetic diversityMechanistic basisBurkitt's lymphoma cellsGeneration of AbsGenesDIVAC
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 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
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
2014
Targeting Of Somatic Hypermutation By immunoglobulin Enhancer And Enhancer-Like Sequences
Buerstedde JM, Alinikula J, Arakawa H, McDonald JJ, Schatz DG. Targeting Of Somatic Hypermutation By immunoglobulin Enhancer And Enhancer-Like Sequences. PLOS Biology 2014, 12: e1001831. PMID: 24691034, PMCID: PMC3972084, DOI: 10.1371/journal.pbio.1001831.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodiesBinding SitesB-LymphocytesCell LineChickensCytidine DeaminaseE-Box ElementsEnhancer Elements, GeneticGene Knockout TechniquesGreen Fluorescent ProteinsHumansImmunoglobulin kappa-ChainsImmunoglobulin lambda-ChainsLymphocyte ActivationMEF2 Transcription FactorsMiceMutationNF-kappa BSequence AlignmentSomatic Hypermutation, ImmunoglobulinTranscription, GeneticUracil-DNA GlycosidaseConceptsSomatic hypermutationIg enhancersNovel regulatory functionStimulation of transcriptionEnhancer-like elementCytidine deaminase proteinEnhancer-like sequenceActivation-induced cytidine deaminase proteinGene specificityTranscriptional roleHeavy chain intron enhancerTranscription unitGenetic diversityEts familyE-boxChicken cellsRegulatory functionsIntron enhancerFull activationImmunoglobulin genesTarget sequenceImmunoglobulin enhancerPoint mutationsEnhancerTranscriptionInduction of homologous recombination between sequence repeats by the activation induced cytidine deaminase (AID) protein
Buerstedde JM, Lowndes N, Schatz DG. Induction of homologous recombination between sequence repeats by the activation induced cytidine deaminase (AID) protein. ELife 2014, 3: e03110. PMID: 25006166, PMCID: PMC4080448, DOI: 10.7554/elife.03110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceB-LymphocytesCell LineChickensCrossing Over, GeneticCytidine DeaminaseGene ConversionGenes, ReporterGreen Fluorescent ProteinsHomologous RecombinationHumansImmunoglobulin Switch RegionLuminescent ProteinsMiceModels, GeneticMolecular Sequence DataNucleic Acid HeteroduplexesRecombinational DNA RepairRepetitive Sequences, Nucleic AcidSequence DeletionSequence Homology, Nucleic AcidSomatic Hypermutation, ImmunoglobulinConceptsHomologous recombinationCytidine deaminase proteinSequence repeatsCytidine deaminationDNA end resectionHundreds of basesAnalysis of recombinantsVertebrate cellsGene conversionRepeat recombinationEnd resectionHolliday junctionsHomologous sequencesSequence homologyReporter transgeneStrand invasionIntergenic deletionRecombinogenic activityImmunoglobulin lociRepeatsSomatic hypermutationHeteroduplex formationRecombinationProteinDeamination
2013
A Critical Context-Dependent Role for E Boxes in the Targeting of Somatic Hypermutation
McDonald JJ, Alinikula J, Buerstedde JM, Schatz DG. A Critical Context-Dependent Role for E Boxes in the Targeting of Somatic Hypermutation. The Journal Of Immunology 2013, 191: 1556-1566. PMID: 23836058, PMCID: PMC3735716, DOI: 10.4049/jimmunol.1300969.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesB-LymphocytesCells, CulturedChickensCytidine DeaminaseDNA, RecombinantE-Box ElementsEnhancer Elements, GeneticGenes, Immunoglobulin Light ChainGenes, ReporterGreen Fluorescent ProteinsImmunoglobulin Variable RegionMutationProtein BindingSomatic Hypermutation, ImmunoglobulinTranscription Factor 3TransfectionTransgenesConceptsE-boxSomatic hypermutationChicken DT40 B cellsDT40 B cellsNon-Ig lociOff-target mutationsActivation-induced cytidine deaminaseContext-dependent roleShort DNA sequencesSequence motifsDNA sequencesTarget genesIg genesSequence contextAffinity of AbsDNA damageCytidine deaminaseRepertoire diversificationMutationsGenesMotifSequenceFunctional hierarchyHypermutationAg stimulationMultiple 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
Identification of Core DNA Elements That Target Somatic Hypermutation
Kohler KM, McDonald JJ, Duke JL, Arakawa H, Tan S, Kleinstein SH, Buerstedde JM, Schatz DG. Identification of Core DNA Elements That Target Somatic Hypermutation. The Journal Of Immunology 2012, 189: 5314-5326. PMID: 23087403, PMCID: PMC3664039, DOI: 10.4049/jimmunol.1202082.Peer-Reviewed Original ResearchMeSH Keywords3' Flanking RegionAnimalsB-LymphocytesCells, CulturedChickensChromatin ImmunoprecipitationCytidine DeaminaseDNAEnhancer Elements, GeneticGenes, ImmunoglobulinGenetic LociImmunoassayImmunoglobulin Variable RegionMutationPhosphorylationRNA Polymerase IISerineSomatic Hypermutation, ImmunoglobulinTranscription, GeneticConceptsActivation-induced deaminaseDNA elementsSomatic hypermutationChicken DT40 B cellsIg lociChromatin immunoprecipitation experimentsDT40 B cellsRNA polymerase IISystematic deletion analysisL chain lociNon-Ig genesCore DNA elementSerine 5Epigenetic marksPolymerase IITranscriptional elongationMutational machineryDeletion analysisReporter cassetteImmunoprecipitation experimentsDeoxycytosine residuesIg genesDNA damageChain locusLociAID-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 positionDendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma
Koduru S, Wong E, Strowig T, Sundaram R, Zhang L, Strout MP, Flavell RA, Schatz DG, Dhodapkar KM, Dhodapkar MV. Dendritic cell–mediated activation-induced cytidine deaminase (AID)–dependent induction of genomic instability in human myeloma. Blood 2012, 119: 2302-2309. PMID: 22234692, PMCID: PMC3311257, DOI: 10.1182/blood-2011-08-376236.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell Line, TumorCell SurvivalCells, CulturedCoculture TechniquesCytidine DeaminaseDendritic CellsDNA Breaks, Double-StrandedFemaleGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticGenomic InstabilityHumansInterleukin Receptor Common gamma SubunitMiceMice, Inbred NODMice, KnockoutMice, SCIDMultiple MyelomaNF-kappa BRANK LigandReverse Transcriptase Polymerase Chain ReactionTransplantation, HeterologousTumor Cells, CulturedConceptsInduction of AIDMultiple myelomaTumor microenvironmentTumor cellsReceptor activatorActivation-induced cytidine deaminaseDendritic cell infiltrationCapacity of DCPrimary MM cellsNF-κB/receptor activatorGenetics of tumorsGrowth of tumorsGenomic damageMyeloma cell linesRANKL inhibitionPlasmacytoid DCsIndolent behaviorCell infiltrationMM cellsHuman myelomaCytidine deaminaseMyelomaDNA double-strand breaksGenomic instabilityCell lines
2010
Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions
Maul RW, Saribasak H, Martomo SA, McClure RL, Yang W, Vaisman A, Gramlich HS, Schatz DG, Woodgate R, Wilson DM, Gearhart PJ. Uracil residues dependent on the deaminase AID in immunoglobulin gene variable and switch regions. Nature Immunology 2010, 12: 70-76. PMID: 21151102, PMCID: PMC3653439, DOI: 10.1038/ni.1970.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigenic VariationB-LymphocytesCells, CulturedCytidine DeaminaseDNA-(Apurinic or Apyrimidinic Site) LyaseImmunoglobulin Class SwitchingImmunoglobulin Variable RegionInterleukin-4LipopolysaccharidesLymphocyte ActivationMiceMice, Inbred C57BLMice, KnockoutModels, ChemicalSpleenUracilUracil-DNA Glycosidase
2009
Imatinib Resistance and Progression of CML to Blast Crisis: Somatic Hypermutation AIDing the Way
Strout MP, Schatz DG. Imatinib Resistance and Progression of CML to Blast Crisis: Somatic Hypermutation AIDing the Way. Cancer Cell 2009, 16: 174-176. PMID: 19732715, DOI: 10.1016/j.ccr.2009.08.012.Peer-Reviewed Original ResearchConceptsChronic myeloid leukemiaProgression of CMLColleagues present evidenceDisease progressionImatinib resistanceMyeloid leukemiaDrug resistanceCancer cellsOncogenic mutationsProgressionEnzyme activation-induced deaminaseGeneration of mutationsLeukemiaMutationsActivation-induced deaminasePresent evidenceBalancing AID and DNA repair during somatic hypermutation
Liu M, Schatz DG. Balancing AID and DNA repair during somatic hypermutation. Trends In Immunology 2009, 30: 173-181. PMID: 19303358, DOI: 10.1016/j.it.2009.01.007.Peer-Reviewed Original Research
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
2007
Role of Activation-Induced Deaminase Protein Kinase A Phosphorylation Sites in Ig Gene Conversion and Somatic Hypermutation
Chatterji M, Unniraman S, McBride KM, Schatz DG. Role of Activation-Induced Deaminase Protein Kinase A Phosphorylation Sites in Ig Gene Conversion and Somatic Hypermutation. The Journal Of Immunology 2007, 179: 5274-5280. PMID: 17911613, DOI: 10.4049/jimmunol.179.8.5274.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAmino Acid SubstitutionAnimalsAvian ProteinsCell LineChickensCyclic AMP-Dependent Protein KinasesCytidine DeaminaseEnzyme ActivationGene ConversionGenes, ImmunoglobulinHumansMiceMolecular Sequence DataPhosphorylationSerineSomatic Hypermutation, ImmunoglobulinZebrafish ProteinsConceptsReplication protein AActivation-induced deaminaseProtein kinase AClass switch recombinationGene conversionDT40 cellsPhosphorylation sitesSomatic hypermutationProtein kinase A (PKA) phosphorylation siteChicken DT40 cellsIg gene conversionEfficient gene conversionConsensus target siteIg gene diversificationGene diversificationSerine 38Cytosine residuesKinase ASwitch recombinationIg genesResidue interferesFish proteinTarget siteProtein AS38Strand-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