2024
Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes
Olfson E, Farhat L, Liu W, Vitulano L, Zai G, Lima M, Parent J, Polanczyk G, Cappi C, Kennedy J, Fernandez T. Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes. Nature Communications 2024, 15: 5870. PMID: 38997333, PMCID: PMC11245598, DOI: 10.1038/s41467-024-50247-7.Peer-Reviewed Original ResearchConceptsDNA sequencesRisk genesHigh-confidence risk genesWhole-exome DNA sequencingSequencing of familiesIdentified de novoLysine demethylase 5BDNA variantsTrio cohortBiological pathwaysGenesSequencing cohortGenetic factorsChildhood neurodevelopmental disordersAttention-deficit/hyperactivity disorderSequenceVariantsADHD riskNeurodevelopmental disordersKDM5BDNAMutationsFamilyLysineDiscoveryTranscriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor
Nakamura T, Yoshihara T, Tanegashima C, Kadota M, Kobayashi Y, Honda K, Ishiwata M, Ueda J, Hara T, Nakanishi M, Takumi T, Itohara S, Kuraku S, Asano M, Kasahara T, Nakajima K, Tsuboi T, Takata A, Kato T. Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor. Molecular Psychiatry 2024, 29: 2888-2904. PMID: 38528071, PMCID: PMC11420081, DOI: 10.1038/s41380-024-02479-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutism Spectrum DisorderAutistic DisorderBehavior, AnimalBrainChromosome DeletionChromosomes, Human, Pair 9Craniofacial AbnormalitiesDisease Models, AnimalFemaleHaploinsufficiencyHeart Defects, CongenitalHistone DemethylasesHistone-Lysine N-MethyltransferaseIntellectual DisabilityMaleMiceMice, Inbred C57BLTranscriptomeConceptsLysine-specific histone demethylase 1Lysine‐specific histone demethylase 1 inhibitorAssociated with autism spectrum disorderHeterozygous loss-of-function variantsHistone H3 lysine 4Autistic-like behaviorsLoss-of-function variantsGenome-wide associationH3 lysine 4ASD risk genesRegulation of chromatinSingle-cell RNA sequencingHeterozygous frameshift mutationWorking memoryMutant miceChIP-seqLysine 4Downregulated DEGsCategories of psychiatric disordersExome sequencingPathogenesis of neurodevelopmental disordersTranscriptome analysisRisk genesDownregulated genesTranscriptomic dysregulation
2023
Lysine Demethylation in Pathogenesis
Cao J, Yan Q. Lysine Demethylation in Pathogenesis. Advances In Experimental Medicine And Biology 2023, 1433: 1-14. PMID: 37751133, DOI: 10.1007/978-3-031-38176-8_1.ChaptersConceptsLysine demethylasesLSD1/KDM1AHistone lysine methylationHistone lysine methyltransferasesMajor epigenetic mechanismsNormal developmentNon-histone substratesSpecific small molecule inhibitorsSmall molecule inhibitorsLysine methylationLysine methyltransferasesHistone methylationHistone lysineLysine demethylationEpigenetic mechanismsDNA repairArginine residuesHuman diseasesMore subfamiliesMolecule inhibitorsLysine modificationDemethylasesMethylationTreatment of cancerEnzymeThe KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression
Wei J, Alfajaro M, Cai W, Graziano V, Strine M, Filler R, Biering S, Sarnik S, Patel S, Menasche B, Compton S, Konermann S, Hsu P, Orchard R, Yan Q, Wilen C. The KDM6A-KMT2D-p300 axis regulates susceptibility to diverse coronaviruses by mediating viral receptor expression. PLOS Pathogens 2023, 19: e1011351. PMID: 37410700, PMCID: PMC10325096, DOI: 10.1371/journal.ppat.1011351.Peer-Reviewed Original ResearchConceptsMouse hepatitis virusReceptor expressionTherapeutic targetMERS-CoVMajor SARS-CoV-2 variantsPrimary human airwaySARS-CoV-2 variantsNovel therapeutic targetViral receptor expressionSARS-CoV-2Histone methyltransferase KMT2DIntestinal epithelial cellsCoronavirus SusceptibilityDiverse coronavirusesHistone demethylase KDM6ADPP4 expressionCoronavirus receptorsHost determinantsHepatitis virusHuman airwaysSARS-CoVSmall molecule inhibitionViral entryPotential drug targetsViral receptors
2022
Systematic identification of biomarker-driven drug combinations to overcome resistance
Rees M, Brenan L, do Carmo M, Duggan P, Bajrami B, Arciprete M, Boghossian A, Vaimberg E, Ferrara S, Lewis T, Rosenberg D, Sangpo T, Roth J, Kaushik V, Piccioni F, Doench J, Root D, Johannessen C. Systematic identification of biomarker-driven drug combinations to overcome resistance. Nature Chemical Biology 2022, 18: 615-624. PMID: 35332332, DOI: 10.1038/s41589-022-00996-7.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkersCell SurvivalDrug CombinationsHistone DemethylasesHumansMonoacylglycerol LipasesConceptsSmall molecule responsesCell linesGSK-J4Gene expression featuresMonoacylglycerol lipaseGene knockoutSerine hydrolaseCancer cell linesSystematic identificationCell viability profileInsensitive cell linesNovel relationshipSmall moleculesMechanism of actionEnzymatic modificationSpecific mechanismsViability profileIntrinsic resistanceVariable responseMechanistic studiesRational candidatesMechanism
2020
Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma
Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, Steinharter J, Sun M, Wind-Rotolo M, Pignon JC, Cherniack AD, Lichtenstein L, Neuberg D, Catalano P, Freeman GJ, Sharpe AH, McDermott DF, Van Allen EM, Signoretti S, Wu CJ, Shukla SA, Choueiri TK. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nature Medicine 2020, 26: 909-918. PMID: 32472114, PMCID: PMC7499153, DOI: 10.1038/s41591-020-0839-y.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntigen PresentationAntineoplastic Agents, ImmunologicalCarcinoma, Renal CellCD8-Positive T-LymphocytesChromosome DeletionChromosomes, Human, Pair 6Chromosomes, Human, Pair 9Class I Phosphatidylinositol 3-KinasesDNA-Binding ProteinsExome SequencingFemaleFluorescent Antibody TechniqueGene DeletionGenomicsHistocompatibility Antigens Class IIHistone DemethylasesHistone-Lysine N-MethyltransferaseHumansKidney NeoplasmsLymphocytes, Tumor-InfiltratingMaleMiddle AgedMutationNivolumabPrognosisProteasome Endopeptidase ComplexPTEN PhosphohydrolaseSequence Analysis, RNATOR Serine-Threonine KinasesTranscription FactorsTuberous Sclerosis Complex 1 ProteinTumor Suppressor ProteinsUbiquitin ThiolesteraseVon Hippel-Lindau Tumor Suppressor ProteinConceptsAdvanced clear cell renal cell carcinomaClear cell renal cell carcinomaPD-1 blockadeCell renal cell carcinomaRenal cell carcinomaCell carcinomaDegree of CD8Numerous chromosomal alterationsProspective clinical trialsSomatic alterationsInfiltrated tumorsClinical responseCell infiltrationTherapeutic responseClinical trialsTherapeutic efficacyBlockadeCcRCC tumorsTumorsPBRM1 mutationsModulates responseCD8Chromosomal alterationsImmunofluorescence analysisCarcinoma
2019
Intergenerational epigenetic inheritance of cancer susceptibility in mammals
Lesch BJ, Tothova Z, Morgan EA, Liao Z, Bronson RT, Ebert BL, Page DC. Intergenerational epigenetic inheritance of cancer susceptibility in mammals. ELife 2019, 8: e39380. PMID: 30963999, PMCID: PMC6456297, DOI: 10.7554/elife.39380.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDisease Models, AnimalEpigenesis, GeneticGenetic Predisposition to DiseaseHistone DemethylasesMiceNeoplasmsWillsConceptsGerm lineEpigenetic changesParental germ lineIntergenerational epigenetic inheritanceRegulation of genesPaternal germ lineCancer susceptibilityChromatin regulatorsEpigenetic inheritanceH3K27me3 marksHypermethylated regionsDNA methylationSomatic tissuesMale gametesElevated tumor incidenceCancer initiationGenetic variantsGermline deletionMutantsHeritabilityDeletionSuccessive generationsSpermOffspringWild-type miceTargeting NOTCH activation in small cell lung cancer through LSD1 inhibition
Augert A, Eastwood E, Ibrahim A, Wu N, Grunblatt E, Basom R, Liggitt D, Eaton K, Martins R, Poirier J, Rudin C, Milletti F, Cheng W, Mack F, MacPherson D. Targeting NOTCH activation in small cell lung cancer through LSD1 inhibition. Science Signaling 2019, 12 PMID: 30723171, PMCID: PMC6530478, DOI: 10.1126/scisignal.aau2922.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic Helix-Loop-Helix Transcription FactorsCell Line, TumorEnzyme InhibitorsGene Expression Regulation, NeoplasticHistone DemethylasesHumansKaplan-Meier EstimateLung NeoplasmsMice, Inbred NODMice, KnockoutMice, SCIDReceptors, NotchSignal TransductionSmall Cell Lung CarcinomaTumor BurdenXenograft Model Antitumor AssaysConceptsSmall cell lung cancerCell lung cancerNonsmall cell lung cancerLung cancerNotch activationLSD1 inhibitionPatient-derived xenograft modelsLSD1 inhibitorsReactivation of NotchFirst-line standardExpression of Ascl1Durable tumor regressionTranscription factor Ascl1Notch pathway activationLineage genesKnockdown studiesNotch pathwayDownstream signalingCare treatmentPDX modelsTumor regressionTargeted therapySCLC tumorigenesisActionable mutationsXenograft model
2018
Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis
Hatzi K, Geng H, Doane AS, Meydan C, LaRiviere R, Cardenas M, Duy C, Shen H, Vidal MNC, Baslan T, Mohammad HP, Kruger RG, Shaknovich R, Haberman AM, Inghirami G, Lowe SW, Melnick AM. Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis. Nature Immunology 2018, 20: 86-96. PMID: 30538335, PMCID: PMC6294324, DOI: 10.1038/s41590-018-0273-1.Peer-Reviewed Original ResearchKDM5 histone demethylases repress immune response via suppression of STING
Wu L, Cao J, Cai WL, Lang SM, Horton JR, Jansen DJ, Liu ZZ, Chen JF, Zhang M, Mott BT, Pohida K, Rai G, Kales SC, Henderson MJ, Hu X, Jadhav A, Maloney DJ, Simeonov A, Zhu S, Iwasaki A, Hall MD, Cheng X, Shadel GS, Yan Q. KDM5 histone demethylases repress immune response via suppression of STING. PLOS Biology 2018, 16: e2006134. PMID: 30080846, PMCID: PMC6095604, DOI: 10.1371/journal.pbio.2006134.Peer-Reviewed Original ResearchConceptsImmune responseSTING expressionCyclic GMP-AMP synthase stimulatorSuppression of STINGCancer cellsCancer immunotherapy agentsHuman papilloma virusAdaptive immune responsesMultiple clinical trialsExpression of STINGBreast cancer cellsInnate immune defenseRobust interferon responseMultiple cancer typesIntratumoral CD8Immunotherapy agentsAnticancer immunotherapyPatient survivalNeck cancerPapilloma virusClinical trialsT cellsSTING agonistsKDM5 histonePositive headLoss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors
Andricovich J, Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors. Cancer Cell 2018, 33: 512-526.e8. PMID: 29533787, PMCID: PMC5854186, DOI: 10.1016/j.ccell.2018.02.003.Peer-Reviewed Original ResearchConceptsPancreatic cancerCOMPASS-like complexesBET inhibitorsMetastatic pancreatic cancerSensitivity to BET inhibitorsSubtypes of tumorsSpectrum of malignanciesPatient-tailored therapySuper-enhancersActivation of super-enhancersSquamous-likeTumor suppressor functionSquamous differentiationRestrained tumor growthTailored therapyTumor growthTherapeutic nicheKDM6A lossSuppressor functionAberrant activationKDM6ACancerCharacterized mechanismsInhibitorsConcomitant loss
2016
Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas
Toledo RA, Qin Y, Cheng ZM, Gao Q, Iwata S, Silva GM, Prasad M, Ocal IT, Rao S, Aronin N, Barontini M, Bruder J, Reddick RL, Chen Y, Aguiar RC, Dahia PL. Recurrent Mutations of Chromatin-Remodeling Genes and Kinase Receptors in Pheochromocytomas and Paragangliomas. Clinical Cancer Research 2016, 22: 2301-2310. PMID: 26700204, PMCID: PMC4854762, DOI: 10.1158/1078-0432.ccr-15-1841.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdrenal Gland NeoplasmsAdultAgedc-Mer Tyrosine KinaseCarcinoma, NeuroendocrineChildChromatinChromatin Assembly and DisassemblyExomeFemaleGerm-Line MutationGiant Cell Tumor of BoneHistone DemethylasesHistone MethyltransferasesHistone-Lysine N-MethyltransferaseHistonesHumansMaleMiddle AgedParagangliomaPheochromocytomaThyroid NeoplasmsYoung AdultConceptsHistone methylation analysisAnalysis of mutantsChromatin-remodeling genesChromatin remodelingHistone demethylasesTranscriptome sequencingFrequent genetic eventKinase geneMolecular basisPPGL susceptibility genesGenesGenetic eventsNeural crest originMethylation analysisSusceptibility genesNew cancer syndromeMost PPGLsMutationsSomatic mutationsProtein expressionCell linesDomain mutationsFGFR1 mutationsWestern blottingDriver mutations
2015
Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors
Dulmovits BM, Appiah-Kubi AO, Papoin J, Hale J, He M, Al-Abed Y, Didier S, Gould M, Husain-Krautter S, Singh SA, Chan KW, Vlachos A, Allen SL, Taylor N, Marambaud P, An X, Gallagher PG, Mohandas N, Lipton JM, Liu JM, Blanc L. Pomalidomide reverses γ-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors. Blood 2015, 127: 1481-1492. PMID: 26679864, PMCID: PMC4797024, DOI: 10.1182/blood-2015-09-667923.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnemia, Sickle Cellbeta-GlobinsCarrier ProteinsErythroid Precursor CellsErythropoiesisFetal Hemoglobingamma-GlobinsGene Expression Regulation, DevelopmentalGenetic VectorsHematopoietic Stem CellsHistone DemethylasesHumansIkaros Transcription FactorKruppel-Like Transcription FactorsLentivirusMultiple MyelomaNeoplasm ProteinsNuclear ProteinsProteasome Endopeptidase ComplexRepressor ProteinsRNA InterferenceRNA, Small InterferingSOXD Transcription FactorsThalidomideTranscription, GeneticConceptsSickle cell anemiaCell anemiaΓ-globinThird-generation immunomodulatory drugAdult human erythroblastsMultiple myeloma patientsHematopoietic progenitorsΓ-globin levelsΓ-globin repressionCurrent therapeutic strategiesErythroid differentiation programFetal hemoglobinAdult hematopoietic progenitorsPomalidomide treatmentImmunomodulatory drugsMyeloma patientsTranscriptional reprogrammingFetal hemoglobin productionTranscription networksTherapeutic strategiesDifferentiation programPomalidomideHuman erythroblastsΒ-hemoglobinopathiesGenetic ablationIntegrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency
Cacchiarelli D, Trapnell C, Ziller MJ, Soumillon M, Cesana M, Karnik R, Donaghey J, Smith ZD, Ratanasirintrawoot S, Zhang X, Sui S, Wu Z, Akopian V, Gifford CA, Doench J, Rinn JL, Daley GQ, Meissner A, Lander ES, Mikkelsen TS. Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency. Cell 2015, 162: 412-424. PMID: 26186193, PMCID: PMC4511597, DOI: 10.1016/j.cell.2015.06.016.Peer-Reviewed Original ResearchConceptsInduced pluripotencyHuman cellsEmbryonic patterning genesComplementary functional analysesPre-implantation stagesPatterning genesDevelopmental regulatorsEpigenomic analysisMolecular principlesNovel regulatorFunctional analysisIntegrative analysisIntercellular heterogeneityMolecular underpinningsPluripotencyDisease modelingCell platformRegulatorCellsDistinct wavesDonor variabilityGenes
2014
Histone Demethylase RBP2 Is Critical for Breast Cancer Progression and Metastasis
Cao J, Liu Z, Cheung WK, Zhao M, Chen SY, Chan SW, Booth CJ, Nguyen DX, Yan Q. Histone Demethylase RBP2 Is Critical for Breast Cancer Progression and Metastasis. Cell Reports 2014, 6: 868-877. PMID: 24582965, PMCID: PMC4014129, DOI: 10.1016/j.celrep.2014.02.004.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorDisease ProgressionEpigenesis, GeneticFemaleGene Expression Regulation, NeoplasticHistone DemethylasesHumansMaleMammary Neoplasms, ExperimentalMiceMice, Inbred NODMice, SCIDMice, TransgenicNeoplasm MetastasisRetinol-Binding Proteins, CellularTransfectionConceptsHistone demethylase RBP2MMTV-neu transgenic miceHuman breast cancer cellsMajor clinical challengeBreast cancer metastasisBreast cancer progressionBreast cancer cellsClinical challengeBreast cancer gene expression data setsTherapeutic targetingTransgenic miceMetastasisMetastatic progressionPutative mediatorsTumor progressionCancer metastasisCancer treatmentCancer progressionTumor metastasisTumor formationCancer cellsProgressionAberrant epigenetic modificationsMetastasis genesMice
2012
Lysine-Specific Demethylase 1: An Epigenetic Regulator of Salt-Sensitive Hypertension
Williams JS, Chamarthi B, Goodarzi MO, Pojoga LH, Sun B, Garza AE, Raby BA, Adler GK, Hopkins PN, Brown NJ, Jeunemaitre X, Ferri C, Fang R, Leonor T, Cui J, Guo X, Taylor KD, Chen Y, Xiang A, Raffel LJ, Buchanan TA, Rotter JI, Williams GH, Shi Y. Lysine-Specific Demethylase 1: An Epigenetic Regulator of Salt-Sensitive Hypertension. American Journal Of Hypertension 2012, 25: 812-817. PMID: 22534796, PMCID: PMC3721725, DOI: 10.1038/ajh.2012.43.Peer-Reviewed Original ResearchConceptsMinor allele carriersSalt-sensitive hypertensionBlood pressureSingle nuclear polymorphismsAllele carriersHypertensive cohortDietary saltWT miceLiberal salt dietLiberal salt intakeSystolic blood pressureSerum aldosterone concentrationHeterozygote knockout miceTranslational research studiesRenovascular responsivenessAldosterone concentrationSalt dietDietary sodiumSalt intakeSystolic BPHuman studiesHypertensionKnockout miceClinical relevanceCaucasian cohortEpigenomics and chromatin dynamics
Akopian V, Chan MM, Clement K, Galonska C, Gifford CA, Lehtola E, Liao J, Samavarchi-Tehrani P, Sindhu C, Smith ZD, Tsankov AM, Webster J, Zhang Y, Ziller MJ, Meissner A. Epigenomics and chromatin dynamics. Genome Biology 2012, 13: 313. PMID: 22364154, PMCID: PMC3334565, DOI: 10.1186/gb-2012-13-2-313.Peer-Reviewed Original Research
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