Featured Publications
Metabolic signatures of regulation by phosphorylation and acetylation
Smith K, Shen F, Lee H, Chandrasekaran S. Metabolic signatures of regulation by phosphorylation and acetylation. IScience 2022, 25: 103730. PMID: 35072016, PMCID: PMC8762462, DOI: 10.1016/j.isci.2021.103730.Peer-Reviewed Original ResearchPosttranslational modificationsTarget of phosphorylationGenome-scale metabolic networksRational rewiringRegulatory circuitsMammalian cellsCellular metabolismMetabolic networksPhosphorylated enzymeMetabolic regulationPhosphoproteome datasetEnzyme propertiesPhosphorylationAcetylationMetabolic signaturesRegulationAcetylomeTranscriptomeDiverse conditionsProteomePhosphoproteomicsTargetCondition-specific factorsEssentialityOrganismsMultiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF–PI3K pathway
Boyer S, Lee H, Steele N, Zhang L, Sajjakulnukit P, Andren A, Ward M, Singh R, Basrur V, Zhang Y, Nesvizhskii A, di Magliano M, Halbrook C, Lyssiotis C. Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF–PI3K pathway. ELife 2022, 11: e73796. PMID: 35156921, PMCID: PMC8843093, DOI: 10.7554/elife.73796.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell Transformation, NeoplasticGene Expression ProfilingGranulocyte-Macrophage Colony-Stimulating FactorHumansMetabolic Networks and PathwaysMetabolomicsMiceMice, Inbred C57BLPancreatic NeoplasmsProteomicsSignal TransductionTranscription FactorsTumor-Associated MacrophagesConceptsTumor-educated macrophagesSingle-cell RNA sequencing datasetsCancer cellsMultiomics characterizationRNA sequencing datasetsTumor-associated macrophagesPI3K-Akt pathwayPI3K pathwayMetabolic programsSequencing datasetsGene expressionMetabolic crosstalkFunction of TAMsCell typesK pathwayGM-CSFGranulocyte-macrophage colony-stimulating factorTumor promotingModel systemEpithelial cellsPathwayColony-stimulating factorMetabolic signaturesMutant KrasMalignant epithelial cellsCysteine depletion induces pancreatic tumor ferroptosis in mice
Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, Sagalovskiy IR, Ma A, Kapilian J, Firl CEM, Decker AR, Sastra SA, Palermo CF, Andrade LR, Sajjakulnukit P, Zhang L, Tolstyka ZP, Hirschhorn T, Lamb C, Liu T, Gu W, Seeley ES, Stone E, Georgiou G, Manor U, Iuga A, Wahl GM, Stockwell BR, Lyssiotis CA, Olive KP. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020, 368: 85-89. PMID: 32241947, PMCID: PMC7681911, DOI: 10.1126/science.aaw9872.Peer-Reviewed Original ResearchConceptsReactive oxygen speciesLipid reactive oxygen speciesPancreatic ductal adenocarcinomaLipid ROS productionAmino acid cysteineCell deathPDAC growthCysteine depletionCoenzyme APDAC cellsTumor ferroptosisROS productionFerroptosisCysteineOxygen speciesCatastrophic accumulationTranslatable meansCancer mortalityDuctal adenocarcinomaLeading causeSystem xTumor typesSubunitsSpeciesDeletionA large-scale analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics
Lee HJ, Kremer DM, Sajjakulnukit P, Zhang L, Lyssiotis CA. A large-scale analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics. Metabolomics 2019, 15: 103. PMID: 31289941, PMCID: PMC6616221, DOI: 10.1007/s11306-019-1564-8.Peer-Reviewed Original ResearchAuditory metabolomics, an approach to identify acute molecular effects of noise trauma
Ji L, Lee HJ, Wan G, Wang GP, Zhang L, Sajjakulnukit P, Schacht J, Lyssiotis CA, Corfas G. Auditory metabolomics, an approach to identify acute molecular effects of noise trauma. Scientific Reports 2019, 9: 9273. PMID: 31239523, PMCID: PMC6592947, DOI: 10.1038/s41598-019-45385-8.Peer-Reviewed Original ResearchConceptsNoise exposureInner earHearing lossNoise-induced hearing lossHidden hearing lossAnimal-based studiesTemporary threshold shiftLow exposure levelsMouse inner earDuration of exposureAuditory traumaLiquid chromatography-coupled tandem mass spectrometryCochlear damageNoise traumaNovel therapiesCochlear functionMetabolic effectsMajor metabolic pathwaysThreshold shiftOxidative stressExposure levelsLC-MS/Molecular effectsEarExposureAbnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma
Xu J, Reznik E, Lee HJ, Gundem G, Jonsson P, Sarungbam J, Bialik A, Sanchez-Vega F, Creighton CJ, Hoekstra J, Zhang L, Sajjakulnukit P, Kremer D, Tolstyka Z, Casuscelli J, Stirdivant S, Tang J, Schultz N, Jeng P, Dong Y, Su W, Cheng EH, Russo P, Coleman JA, Papaemmanuil E, Chen YB, Reuter VE, Sander C, Kennedy SR, Hsieh JJ, Lyssiotis CA, Tickoo SK, Hakimi AA. Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma. ELife 2019, 8: e38986. PMID: 30924768, PMCID: PMC6459676, DOI: 10.7554/elife.38986.Peer-Reviewed Original ResearchConceptsClear cell papillary renal cell carcinomaMtDNA-encoded proteinsPapillary renal cell carcinomaMetabolic phenotypeRenal cell carcinomaNuclear genomeDistinct metabolic phenotypesMitochondrial DNACell carcinomaRespiratory metabolismGenomic sequencingMolecular phenotypesAbnormal oxidative metabolismSugar alcohol sorbitolPresence of glycogenStudy of cancerMajority of cancersOncogenic alterationsPhenotypeOxidative stressOxidative metabolismCytoplasmic clarityDriver lesionsImmunohistochemical stainingKidney tumorsProteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation
Lee HJ, Jedrychowski MP, Vinayagam A, Wu N, Shyh-Chang N, Hu Y, Min-Wen C, Moore JK, Asara JM, Lyssiotis CA, Perrimon N, Gygi SP, Cantley LC, Kirschner MW. Proteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation. Cell Reports 2017, 20: 721-736. PMID: 28723573, PMCID: PMC5626450, DOI: 10.1016/j.celrep.2017.06.074.Peer-Reviewed Original ResearchConceptsCell cycleCancer-related metabolic pathwaysAmino acid synthesisUpregulation of glycolysisNormal proliferative cellsCellular transitionsMetabolic machineryOxidative phosphorylationLymphocyte cell linesEssential amino acidsMetabolic pathwaysAmino acidsNucleotide synthesisCancer cellsCell linesProteomicsMetabolomic characterizationIL-3Proliferative cellsLipid metabolismUrea cycleCellsMetabolic changesMetabolomic profilingPotential linkControllability analysis of the directed human protein interaction network identifies disease genes and drug targets
Vinayagam A, Gibson TE, Lee HJ, Yilmazel B, Roesel C, Hu Y, Kwon Y, Sharma A, Liu YY, Perrimon N, Barabási AL. Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 4976-4981. PMID: 27091990, PMCID: PMC4983807, DOI: 10.1073/pnas.1603992113.Peer-Reviewed Original ResearchConceptsPPI networkDisease genesProtein-protein interaction networkDrug targetsCellular information processingHuman PPI networkNovel disease genesCopy number alteration dataPotential drug targetsNumber alteration dataDisease-causing mutationsIndispensable proteinsInteraction networksCell deathGenesProteinCell proliferationDifferent cancersHuman virusesPrimary targetAlteration dataDisease statesTargetMutationsNetwork control propertiesSystems-level evidence of transcriptional co-regulation of yeast protein complexes.
Lee JW, Zemojtel T, Shakhnovich E. Systems-level evidence of transcriptional co-regulation of yeast protein complexes. Journal Of Computational Biology : A Journal Of Computational Molecular Cell Biology 2009, 16: 331-9. PMID: 19193150, DOI: 10.1089/cmb.2008.17TT.Peer-Reviewed Original ResearchPrioritization of gene regulatory interactions from large-scale modules in yeast
Lee HJ, Manke T, Bringas R, Vingron M. Prioritization of gene regulatory interactions from large-scale modules in yeast. BMC Bioinformatics 2008, 9: 32. PMID: 18211684, PMCID: PMC2244593, DOI: 10.1186/1471-2105-9-32.Peer-Reviewed Original ResearchConceptsTranscriptional modulesRegulatory interactionsTarget genesTranscription factorsChIP-chip binding dataTF-gene interactionsGene regulatory interactionsCo-regulated proteinsCo-regulated genesNormal growth conditionsGenome-wide dataCell wall synthesisChIP-chip dataRegulatory linkWall synthesisFunctional categoriesRegulatory proteinsYeast dataGenesCoherent modulesGrowth conditionsProteinBiological systemsDifferent reference datasetsNumerous moduleslinc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells
Tornini V, Miao L, Lee H, Gerson T, Dube S, Schmidt V, Kroll F, Tang Y, Du K, Kuchroo M, Vejnar C, Bazzini A, Krishnaswamy S, Rihel J, Giraldez A. linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells. ELife 2023, 12: e82249. PMID: 37191016, PMCID: PMC10188112, DOI: 10.7554/elife.82249.Peer-Reviewed Original ResearchConceptsCell typesIntergenic non-coding RNAsChromatin architectural proteinCryptic open reading frameGene regulatory networksOpen reading frameNon-coding RNAsNew cell typesNeural cell typesBrain cell typesPutative lincRNAsVertebrate genomesArchitectural proteinsChromatin disruptionChromatin accessibilityRegulatory networksGenetic basisCell developmentMicropeptidesBrain cell developmentReceptor-mediated pathwaySystematic identificationLincRNAsNeural cellsCerebellar cellsEarly cellular and molecular signatures correlate with severity of West Nile virus infection
Lee H, Zhao Y, Fleming I, Mehta S, Wang X, Vander Wyk B, Ronca S, Kang H, Chou C, Fatou B, Smolen K, Levy O, Clish C, Xavier R, Steen H, Hafler D, Love J, Shalek A, Guan L, Murray K, Kleinstein S, Montgomery R. Early cellular and molecular signatures correlate with severity of West Nile virus infection. IScience 2023, 26: 108387. PMID: 38047068, PMCID: PMC10692672, DOI: 10.1016/j.isci.2023.108387.Peer-Reviewed Original ResearchWest Nile virusEffective anti-viral responseInnate immune cell typesWest Nile virus infectionPro-inflammatory markersAcute time pointsImmune cell typesAnti-viral responseMolecular signaturesHost cellular activitiesAcute infectionAsymptomatic donorsPeripheral bloodSevere infectionsVirus infectionImmune responseSevere casesCell activityIll individualsSerum proteomicsInfectionInfection severityHigh expressionTime pointsNile virusStrokeClassifier: ischemic stroke etiology classification by ensemble consensus modeling using electronic health records
Lee H, Schwamm L, Sansing L, Kamel H, de Havenon A, Turner A, Sheth K, Krishnaswamy S, Brandt C, Zhao H, Krumholz H, Sharma R. StrokeClassifier: ischemic stroke etiology classification by ensemble consensus modeling using electronic health records. Npj Digital Medicine 2024, 7: 130. PMID: 38760474, PMCID: PMC11101464, DOI: 10.1038/s41746-024-01120-w.Peer-Reviewed Original ResearchElectronic health recordsWeighted F1MIMIC-IIIClinical decision support systemsMulti-class classificationNatural language processingMIMIC-III datasetHealth recordsMachine learning classifiersDecision support systemArtificial intelligence toolsVascular neurologistsLearning classifiersBinary classificationCross-validation accuracyLanguage processingMeta-modelIntelligence toolsStroke prevention effortsAcute ischemic strokeStroke etiologySupport systemStroke etiology classificationClassification toolClassifier
2023
Iron promotes glycolysis to drive colon tumorigenesis
Liu Z, Villareal L, Goodla L, Kim H, Falcon D, Haneef M, Martin D, Zhang L, Lee H, Kremer D, Lyssiotis C, Shah Y, Lin H, Lin H, Xue X. Iron promotes glycolysis to drive colon tumorigenesis. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2023, 1869: 166846. PMID: 37579983, PMCID: PMC10530594, DOI: 10.1016/j.bbadis.2023.166846.Peer-Reviewed Original ResearchConceptsGlucose transporter 1Colorectal cancerColon tumorigenesisIron treatmentProgression of CRCCancer-related deathColon tumor growthCommon cancerGlucose levelsColon carcinogenesisGlucose metabolismTumor growthPharmacological inhibitionIntracellular glucose levelsTumor cellsTransporter 1Iron levelsTumor formationAerobic glycolysisPyruvate dehydrogenase kinase 3Excess ironCancerTreatmentGlycolytic productsTricarboxylic acid cycle intermediatesIDDF2023-ABS-0059 Iron promotes glycolysis to drive colon tumorigenesis
Xue X, Liu Z, Villareal L, Kim H, Falcon D, Haneef M, Martin D, Zhang L, Lee H, Kremer D, Lyssiotis C, Shah Y, Lin H. IDDF2023-ABS-0059 Iron promotes glycolysis to drive colon tumorigenesis. 2023, a72-a73. DOI: 10.1136/gutjnl-2023-iddf.61.Peer-Reviewed Original Research
2022
Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome
Zehentmeier S, Lim VY, Ma Y, Fossati J, Ito T, Jiang Y, Tumanov AV, Lee HJ, Dillinger L, Kim J, Csomos K, Walter JE, Choi J, Pereira JP. Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome. Science Immunology 2022, 7: eabo3170. PMID: 36149943, PMCID: PMC9614684, DOI: 10.1126/sciimmunol.abo3170.Peer-Reviewed Original ResearchConceptsSecondary lymphoid organsWHIM syndromeMesenchymal stem cellsInterleukin-7B lymphopeniaBone marrowBM mesenchymal stem cellsT cell numbersIL-7 productionT-cell lymphopeniaLymphotoxin beta receptorEarly progenitor stageLymphoid organsCell lymphopeniaMouse modelBeta receptorsB cellsB cell developmentLymphopeniaStromal cellsLeukocyte retentionSyndromeGOF mutationsLymphopoietic activityCritical pathways
2021
A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation
Kumar R, Landry A, Guha A, Vitvitsky V, Lee H, Seike K, Reddy P, Lyssiotis C, Banerjee R. A redox cycle with complex II prioritizes sulfide quinone oxidoreductase-dependent H2S oxidation. Journal Of Biological Chemistry 2021, 298: 101435. PMID: 34808207, PMCID: PMC8683732, DOI: 10.1016/j.jbc.2021.101435.Peer-Reviewed Original Research1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development
Wang T, Wang Z, de Fabritus L, Tao J, Saied EM, Lee HJ, Ramazanov BR, Jackson B, Burkhardt D, Parker M, Gleinich AS, Wang Z, Seo DE, Zhou T, Xu S, Alecu I, Azadi P, Arenz C, Hornemann T, Krishnaswamy S, van de Pavert SA, Kaech SM, Ivanova NB, Santori FR. 1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development. Developmental Cell 2021, 56: 3128-3145.e15. PMID: 34762852, PMCID: PMC8628544, DOI: 10.1016/j.devcel.2021.10.018.Peer-Reviewed Original ResearchConceptsLigand-binding domainNuclear hormone receptor activityTranscriptional networksCellular physiologyCOUP-TFDifferentiation programCell-based assaysHormone receptor activityTranscriptional activityMetabolic enzymesCell developmentPhysiological regulatorPhysiological modulatorBindsPhysiological concentrationsReceptor activityLymphatic vesselsTranscriptionNervous systemNR2F1RegulatorPhenocopiesModulatorEnzymePhysiologyMitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology
Fujiwara H, Seike K, Brooks MD, Mathew AV, Kovalenko I, Pal A, Lee HJ, Peltier D, Kim S, Liu C, Oravecz-Wilson K, Li L, Sun Y, Byun J, Maeda Y, Wicha MS, Saunders TL, Rehemtulla A, Lyssiotis CA, Pennathur S, Reddy P. Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology. Nature Immunology 2021, 22: 1440-1451. PMID: 34686860, PMCID: PMC9351914, DOI: 10.1038/s41590-021-01048-3.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCase-Control StudiesCell CommunicationCells, CulturedColitisColonCytotoxicity, ImmunologicDisease Models, AnimalElectron Transport Complex IIEpithelial CellsFemaleGraft vs Host DiseaseHumansImmunity, MucosalIntestinal MucosaMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicMitochondriaOxidative PhosphorylationSuccinic AcidT-LymphocytesConceptsGenetic experimental approachesCell-intrinsic featuresMetabolic flux studiesIntestinal epithelial cellsOxidative phosphorylationDisease severityT cell-mediated immunopathologyT cell-mediated colitisIntestinal epithelial cell damageProtein analysisSuccinate dehydrogenaseCell-mediated immunopathologyInflammatory bowel diseaseEpithelial cell damageHuman clinical samplesSuccinate levelsEpithelial cellsCritical roleSDHAHost diseaseBowel diseaseComplementary chemicalIntestinal diseaseT cellsMetabolic alterations
2020
Differential contributions of sarcomere and mitochondria-related multigene variants to the endophenotype of hypertrophic cardiomyopathy
Chung H, Kim Y, Cho SM, Lee HJ, Park CH, Kim JY, Lee SH, Min PK, Yoon YW, Lee BK, Kim WS, Hong BK, Kim TH, Rim SJ, Kwon HM, Choi EY, Lee KA. Differential contributions of sarcomere and mitochondria-related multigene variants to the endophenotype of hypertrophic cardiomyopathy. Mitochondrion 2020, 53: 48-56. PMID: 32380161, DOI: 10.1016/j.mito.2020.04.010.Peer-Reviewed Original ResearchConceptsNon-apical hypertrophic cardiomyopathyApical hypertrophic cardiomyopathyHypertrophic cardiomyopathyHCM patientsIndividualized risk stratificationComprehensive genetic testAtrium remodelingDiastolic dysfunctionRisk stratificationPoor prognosisSarcomere mutationsPatientsPathogenic variantsRare variant analysisAsian populationsPathogenic mutations