2019
Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting
Dinesh RK, Barnhill B, Ilanges A, Wu L, Michelson DA, Senigl F, Alinikula J, Shabanowitz J, Hunt DF, Schatz DG. Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting. European Journal Of Immunology 2019, 50: 380-395. PMID: 31821534, PMCID: PMC7202714, DOI: 10.1002/eji.201948357.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseGene conversionSomatic hypermutationIg genesTranscription factor family membersTrans-acting factorsFactor family membersClass switch recombinationEnhancer-like sequenceRamos B cell lineIgH intronic enhancerSecondary diversificationTranscription factorsE-boxFactor bindingChIP assaysIntronic enhancerReporter assaysB cell linesSpecific DNASwitch recombinationSHM targetingIg enhancersCytidine deaminaseNovel insightsTET 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
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 AS38Targeting of AID‐Mediated Sequence Diversification by cis‐Acting Determinants
Yang SY, Schatz DG. Targeting of AID‐Mediated Sequence Diversification by cis‐Acting Determinants. Advances In Immunology 2007, 94: 109-125. PMID: 17560273, DOI: 10.1016/s0065-2776(06)94004-8.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseSequence diversificationFeatures of chromatinTranscriptional control elementsCis-acting determinantsClass switch recombinationGene conversionDiversification processMolecular mechanismsIg lociSwitch recombinationIg genesAntibody diversityImmunoglobulin genesCytidine deaminaseSomatic hypermutationControl elementsTranscriptionGenesDiversificationRecombinationChromatinLociDiversityPermissive
2005
Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination
Rush JS, Liu M, Odegard VH, Unniraman S, Schatz DG. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proceedings Of The National Academy Of Sciences Of The United States Of America 2005, 102: 13242-13247. PMID: 16141332, PMCID: PMC1201576, DOI: 10.1073/pnas.0502779102.Peer-Reviewed Original ResearchConceptsClass switch recombinationCell divisionAID expressionSwitch recombinationFrequency of CSRSingle cell divisionSubsequent cell divisionSuccessive cell divisionsActivation-induced cytidine deaminaseConstitutive AID expressionIg heavy chain constant regionsEffector function propertiesHeavy chain constant regionActivation-induced cytidine deaminase mRNAMolecular explanationMechanistic basisDifferent molecular featuresSuccessive divisionsChain constant regionCytidine deaminaseB cell activationCytokine exposureExpressionConstant regionCell activationHistone 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 lociH2BGammaH2AXLociHypermutationRecombinationHistonesH2AX
2004
Staggered 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