Featured Publications
Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casiño C, Powell S, Yashaswini C, LaMarca EA, Kassim B, Javidfar B, Espeso-Gil S, Li A, Won H, Geschwind DH, Ho SM, MacDonald M, Hoffman GE, Roussos P, Zhang B, Hahn CG, Weng Z, Brennand KJ, Akbarian S. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 2018, 362 PMID: 30545851, PMCID: PMC6408958, DOI: 10.1126/science.aat4311.Peer-Reviewed Original ResearchMeSH KeywordsBrainCells, CulturedChromatinChromatin Assembly and DisassemblyChromosomes, HumanConnectomeEpigenesis, GeneticGene Expression Regulation, DevelopmentalGenetic Predisposition to DiseaseGenome, HumanGenome-Wide Association StudyHumansMaleNeural Stem CellsNeurogenesisNeurogliaNeuronsNucleic Acid ConformationProtein Interaction MapsProteomicsRiskSchizophreniaTranscription, GeneticTranscriptomeConceptsCoordinated transcriptional regulationThree-dimensional genomeSpatial genome organizationChromosomal contact mapsNeural progenitor cellsSchizophrenia risk variantsGenome organizationChromatin remodelingChromosomal conformationTranscriptional regulationProteomic interactionsDevelopmental remodelingHeritable riskGlial differentiationRisk variantsContact mapsProgenitor cellsVariant sequencesGenesConformation changeNeuronal connectivitySchizophrenia riskSequenceNeuropsychiatric diseasesDistal targetsModelling schizophrenia using human induced pluripotent stem cells
Brennand K, Simone A, Jou J, Gelboin-Burkhart C, Tran N, Sangar S, Li Y, Mu Y, Chen G, Yu D, McCarthy S, Sebat J, Gage F. Modelling schizophrenia using human induced pluripotent stem cells. Nature 2011, 473: 221-225. PMID: 21490598, PMCID: PMC3392969, DOI: 10.1038/nature09915.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAntipsychotic AgentsCell DifferentiationCells, CulturedCellular ReprogrammingChildDisks Large Homolog 4 ProteinFemaleFibroblastsGene Expression ProfilingGene Expression RegulationHumansIntracellular Signaling Peptides and ProteinsLoxapineMaleMembrane ProteinsModels, BiologicalNeuritesNeuronsPhenotypePluripotent Stem CellsReceptors, GlutamateSchizophreniaYoung Adult
2019
Type I interferon response impairs differentiation potential of pluripotent stem cells
Eggenberger J, Blanco-Melo D, Panis M, Brennand KJ, tenOever BR. Type I interferon response impairs differentiation potential of pluripotent stem cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 1384-1393. PMID: 30606801, PMCID: PMC6347712, DOI: 10.1073/pnas.1812449116.Peer-Reviewed Original Research
2018
GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis
Kajiwara Y, Wang E, Wang M, Sin WC, Brennand KJ, Schadt E, Naus CC, Buxbaum J, Zhang B. GJA1 (connexin43) is a key regulator of Alzheimer’s disease pathogenesis. Acta Neuropathologica Communications 2018, 6: 144. PMID: 30577786, PMCID: PMC6303945, DOI: 10.1186/s40478-018-0642-x.Peer-Reviewed Original ResearchConceptsPost-mortem Alzheimer's diseaseAlzheimer's diseaseTop key driverRNA sequencing analysisDisease pathogenesisProteomic datasetsKey regulatorNormal control brainsGJA1 expressionAlzheimer's disease (AD) pathogenesisApoE protein levelsPromising pharmacological targetSequencing analysisGJA1Wildtype astrocytesWildtype neuronsAβ metabolismAβ phagocytosisProtein levelsControl brainsAD pathogenesisAD amyloidPharmacological targetsAstrocytesCognitive functionChronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder
McCarthy MJ, Wei H, Nievergelt CM, Stautland A, Maihofer AX, Welsh DK, Shilling P, Alda M, Alliey-Rodriguez N, Anand A, Andreasson OA, Balaraman Y, Berrettini WH, Bertram H, Brennand KJ, Calabrese JR, Calkin CV, Claasen A, Conroy C, Coryell WH, Craig DW, D’Arcangelo N, Demodena A, Djurovic S, Feeder S, Fisher C, Frazier N, Frye MA, Gage FH, Gao K, Garnham J, Gershon ES, Glazer K, Goes F, Goto T, Harrington G, Jakobsen P, Kamali M, Karberg E, Kelly M, Leckband SG, Lohoff F, McInnis MG, Mondimore F, Morken G, Nurnberger JI, Obral S, Oedegaard KJ, Ortiz A, Ritchey M, Ryan K, Schinagle M, Schoeyen H, Schwebel C, Shaw M, Shekhtman T, Slaney C, Stapp E, Szelinger S, Tarwater B, Zandi PP, Kelsoe JR. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacology 2018, 44: 620-628. PMID: 30487653, PMCID: PMC6333516, DOI: 10.1038/s41386-018-0273-8.Peer-Reviewed Original ResearchConceptsBipolar disorderEffects of lithiumMaintenance treatmentBD patientsCircadian rhythmMinority of patientsLithium maintenance treatmentMood stabilizer treatmentSerious mood disorderCircadian rhythm abnormalitiesCircadian rhythm parametersClinical responseCircadian rhythm functionLithium monotherapyClinical trialsMood disordersRhythm abnormalitiesMood symptomsPharmacological effectsPatientsEvening chronotypeStabilizer treatmentCommon genetic variationRhythm parametersMonotherapyLandscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS
Dobbyn A, Huckins L, Boocock J, Sloofman L, Glicksberg B, Giambartolomei C, Hoffman G, Perumal T, Girdhar K, Jiang Y, Raj T, Ruderfer D, Kramer R, Pinto D, Akbarian S, Roussos P, Domenici E, Devlin B, Sklar P, Stahl E, Sieberts S, Sklar P, Buxbaum J, Devlin B, Lewis D, Gur R, Hahn C, Hirai K, Toyoshiba H, Domenici E, Essioux L, Mangravite L, Peters M, Lehner T, Lipska B, Cicek A, Lu C, Roeder K, Xie L, Talbot K, Hemby S, Essioux L, Browne A, Chess A, Topol A, Charney A, Dobbyn A, Readhead B, Zhang B, Pinto D, Bennett D, Kavanagh D, Ruderfer D, Stahl E, Schadt E, Hoffman G, Shah H, Zhu J, Johnson J, Fullard J, Dudley J, Girdhar K, Brennand K, Sloofman L, Huckins L, Fromer M, Mahajan M, Roussos P, Akbarian S, Purcell S, Hamamsy T, Raj T, Haroutunian V, Wang Y, Gümüş Z, Senthil G, Kramer R, Logsdon B, Derry J, Dang K, Sieberts S, Perumal T, Visintainer R, Shinobu L, Sullivan P, Klei L. Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS. American Journal Of Human Genetics 2018, 102: 1169-1184. PMID: 29805045, PMCID: PMC5993513, DOI: 10.1016/j.ajhg.2018.04.011.Peer-Reviewed Original ResearchConceptsExpression quantitative trait lociConditional expression quantitative trait lociCommonMind ConsortiumEQTL signalsGenome-wide association study (GWAS) lociSchizophrenia GWASContext-specific regulationQuantitative trait lociCo-localization analysisGene expression levelsGWAS associationsNovel genesTrait lociStudy lociCausal genesEQTL dataFine mappingGenomic featuresGWAS statisticsGene expressionGenesGWASLociExpression levelsHuman brain samples
2017
Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes
Ho S, Hartley B, Flaherty E, Rajarajan P, Abdelaal R, Obiorah I, Barretto N, Muhammad H, Phatnani H, Akbarian S, Brennand K. Evaluating Synthetic Activation and Repression of Neuropsychiatric-Related Genes in hiPSC-Derived NPCs, Neurons, and Astrocytes. Stem Cell Reports 2017, 9: 615-628. PMID: 28757163, PMCID: PMC5550013, DOI: 10.1016/j.stemcr.2017.06.012.Peer-Reviewed Original ResearchConceptsSynthetic activationRisk genesCell typesModulation of transcriptionNeuropsychiatric risk genesCommon single nucleotide variantsCas9 fusion proteinsEndogenous expression levelsNeural cell typesPluripotent stem cell-derived neural progenitor cellsRare copy number variationsCopy number variationsSingle nucleotide variantsNeural progenitor cellsGene functionFunctional annotationGenetic studiesGenesRisk variantsProgenitor cellsExpression levelsTranscriptionRepressionPositional effectsProteinAn Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells
Julia T, Wang M, Pimenova A, Bowles K, Hartley B, Lacin E, Machlovi S, Abdelaal R, Karch C, Phatnani H, Slesinger P, Zhang B, Goate A, Brennand K. An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells. Stem Cell Reports 2017, 9: 600-614. PMID: 28757165, PMCID: PMC5550034, DOI: 10.1016/j.stemcr.2017.06.018.Peer-Reviewed Original ResearchCommon developmental genome deprogramming in schizophrenia — Role of Integrative Nuclear FGFR1 Signaling (INFS)
Narla S, Lee Y, Benson C, Sarder P, Brennand K, Stachowiak E, Stachowiak M. Common developmental genome deprogramming in schizophrenia — Role of Integrative Nuclear FGFR1 Signaling (INFS). Schizophrenia Research 2017, 185: 17-32. PMID: 28094170, PMCID: PMC5507209, DOI: 10.1016/j.schres.2016.12.012.Peer-Reviewed Original ResearchMeSH KeywordsAdultCell DifferentiationCells, CulturedFemaleGene Expression Regulation, DevelopmentalGene Regulatory NetworksGenomeGenomicsHumansInduced Pluripotent Stem CellsMaleMicroRNAsModels, BiologicalMutationReceptor, Fibroblast Growth Factor, Type 1Receptor, Notch1SchizophreniaSignal TransductionTranscriptomeYoung AdultConceptsMRNA networkMajor developmental pathwaysIntegrative nuclear FGFR1MiRNA-mRNA networkHuman gene promotersCommon developmental genomesMiRNA genesMiRNA transcriptomeGene networksUpregulated genesGene promoterNuclear FGFR1Genomic etiologyGene dysregulationDisease ontogenyNuclear formGlobal dysregulationDevelopmental pathwaysGenesNeuron formationDistinct pathwaysConcerted actionPotential therapeutic targetTranscriptomeGenome
2016
Altered proliferation and networks in neural cells derived from idiopathic autistic individuals
Marchetto M, Belinson H, Tian Y, Freitas B, Fu C, Vadodaria K, Beltrao-Braga P, Trujillo C, Mendes A, Padmanabhan K, Nunez Y, Ou J, Ghosh H, Wright R, Brennand K, Pierce K, Eichenfield L, Pramparo T, Eyler L, Barnes C, Courchesne E, Geschwind D, Gage F, Wynshaw-Boris A, Muotri A. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Molecular Psychiatry 2016, 22: 820-835. PMID: 27378147, PMCID: PMC5215991, DOI: 10.1038/mp.2016.95.Peer-Reviewed Original ResearchConceptsNeural progenitor cellsInsulin growth factor-1Pluripotent stem cellsTranscriptional cascadeNeuronal networksAutism spectrum disorderGrowth factor-1Human cell modelsNormal brain sizeEarly brain overgrowthPotential cellular mechanismsMolecular mechanismsGenetic studiesClinical trialsIGF-1Therapeutic effectBrain pathologyAbnormal neurogenesisΒ-cateninCellular mechanismsStem cellsBrain overgrowthProgenitor cellsNeural cellsAltered proliferation
2015
Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells
Ho S, Hartley B, Julia T, Beaumont M, Stafford K, Slesinger P, Brennand K. Rapid Ngn2-induction of excitatory neurons from hiPSC-derived neural progenitor cells. Methods 2015, 101: 113-124. PMID: 26626326, PMCID: PMC4860098, DOI: 10.1016/j.ymeth.2015.11.019.Peer-Reviewed Original ResearchConceptsHuman induced pluripotent stem cellsNeural progenitor cellsHiPSC-derived neural progenitor cellsHigh-throughput drug screeningHiPSC neural progenitor cellsExogenous transcription factorsProgenitor cellsInduced pluripotent stem cellsPatient-specific platformPluripotent stem cellsPatient-derived neuronsSomatic reprogrammingTranscription factorsGenetic variationExcitatory neuronsDrug screeningNeurogenin 2Neuronal inductionFunctional neuronsThroughput drug screeningNeuronal phenotypeLentiviral transductionStem cellsStarting populationDisease etiologyIncreased abundance of translation machinery in stem cell–derived neural progenitor cells from four schizophrenia patients
Topol A, English J, Flaherty E, Rajarajan P, Hartley B, Gupta S, Desland F, Zhu S, Goff T, Friedman L, Rapoport J, Felsenfeld D, Cagney G, Mackay-Sim A, Savas J, Aronow B, Fang G, Zhang B, Cotter D, Brennand K. Increased abundance of translation machinery in stem cell–derived neural progenitor cells from four schizophrenia patients. Translational Psychiatry 2015, 5: e662-e662. PMID: 26485546, PMCID: PMC4930118, DOI: 10.1038/tp.2015.118.Peer-Reviewed Original ResearchMeSH KeywordsCell DifferentiationCells, CulturedHumansInduced Pluripotent Stem CellsNeural Stem CellsNeuronsProsencephalonSchizophreniaConceptsHiPSC neural progenitor cellsNeural progenitor cellsNovel post-transcriptional mechanismProtein synthesisGlobal protein translationElongation factor proteinGlobal protein synthesisPost-transcriptional mechanismsProgenitor cellsHuman-induced pluripotent stem cellsPluripotent stem cellsMass spectrometry evidenceTranslation machineryTranslation initiationProtein translationEpigenetic factorsFactor proteinStem cellsProtein levelsTotal protein levelsCellsUnaffected controlsMachineryProteinAbundanceAltered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients
Topol A, Zhu S, Tran N, Simone A, Fang G, Brennand K. Altered WNT Signaling in Human Induced Pluripotent Stem Cell Neural Progenitor Cells Derived from Four Schizophrenia Patients. Biological Psychiatry 2015, 78: e29-e34. PMID: 25708228, PMCID: PMC4520784, DOI: 10.1016/j.biopsych.2014.12.028.Peer-Reviewed Original Research
2014
Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons
Hook V, Brennand K, Kim Y, Toneff T, Funkelstein L, Lee K, Ziegler M, Gage F. Human iPSC Neurons Display Activity-Dependent Neurotransmitter Secretion: Aberrant Catecholamine Levels in Schizophrenia Neurons. Stem Cell Reports 2014, 3: 531-538. PMID: 25358781, PMCID: PMC4223699, DOI: 10.1016/j.stemcr.2014.08.001.Peer-Reviewed Original ResearchConceptsHiPSC neuronsHuman-induced pluripotent stem cell-derived neuronsPluripotent stem cell-derived neuronsActivity-dependent secretionStem cell-derived neuronsCell-derived neuronsPositive neuronsCatecholamine levelsActivity-dependent mannerTyrosine hydroxylasePeptide neurotransmittersNeuronal culturesBrain disordersNeurotransmitter releaseChemical neurotransmissionKCl stimulationNeuronsNorepinephrineCatecholaminesElevated levelsNeurotransmitter secretionCatecholamine biosynthesisSchizophreniaDopamineNeurotransmittersPhenotypic differences in hiPSC NPCs derived from patients with schizophrenia
Brennand K, Savas J, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont K, Kim H, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao S, Mrksich M, Rakic P, Fang G, Zhang B, Yates J, Gage F. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular Psychiatry 2014, 20: 361-368. PMID: 24686136, PMCID: PMC4182344, DOI: 10.1038/mp.2014.22.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAntipsychotic AgentsCell DifferentiationCell MovementCells, CulturedFemaleGene ExpressionHumansMaleMiceMice, Inbred C57BLMice, TransgenicMitochondriaNeural Cell Adhesion MoleculesNeural Stem CellsOxidative StressPhenotypePluripotent Stem CellsProsencephalonProteomicsReactive Oxygen SpeciesSchizophreniaYoung AdultConceptsHiPSC neural progenitor cellsNeural progenitor cellsHuman-induced pluripotent stem cellsHiPSC-derived neuronsGene expressionGene expression comparisonsStable isotope labelingProteomic mass spectrometry analysisAbnormal gene expressionPluripotent stem cellsOxidative stressCytoskeletal remodelingMass spectrometry analysisCellular phenotypesExpression comparisonsDevelopmental mechanismsIsotope labelingPhenotypic differencesBrainSpan AtlasDisease predispositionAmino acidsScalable assayNPC phenotypeStem cellsProgenitor cells
2008
Reprogramming of Pancreatic β Cells into Induced Pluripotent Stem Cells
Stadtfeld M, Brennand K, Hochedlinger K. Reprogramming of Pancreatic β Cells into Induced Pluripotent Stem Cells. Current Biology 2008, 18: 890-894. PMID: 18501604, PMCID: PMC2819222, DOI: 10.1016/j.cub.2008.05.010.Peer-Reviewed Original ResearchConceptsEmbryonic stem cellsPluripotent stem cellsCell typesIPS cellsStem cellsC-MycTranscription factors Oct4Rare cell typesInduced pluripotent stem cellsCertain cell typesAdult stem cellsInducible lentivirusVitro reprogrammingFactors OCT4Pluripotent cellsEctopic expressionGenetic proofPancreatic β-cellsGerm layersDifferentiated cellsChimeric animalsPluripotency markersDifferentiation stageBeta cellsPancreatic beta cells