2023
SREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6
Fowler J, Boutagy N, Zhang R, Horikami D, Whalen M, Romanoski C, Sessa W. SREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6. Journal Of Lipid Research 2023, 64: 100411. PMID: 37437844, PMCID: PMC10407908, DOI: 10.1016/j.jlr.2023.100411.Peer-Reviewed Original ResearchMeSH KeywordsCholesterolCytokinesEndothelial CellsHumansKruppel-Like Factor 6Sterol Regulatory Element Binding Protein 2Transcription FactorsTranscriptional ActivationConceptsDirect transcriptional activationTranscriptional activationEndothelial cellsChemokine expressionChromatin immunoprecipitation sequencingCholesterol homeostasisSterol-responsive genesPro-inflammatory chemokinesLipid-lowering drugsAdaptive immune responsesPro-inflammatory genesTranscription factor SREBP2Endogenous cholesterol synthesisImmunoprecipitation sequencingResponsive genesMechanism of actionPromoter regionCardiovascular riskAtherosclerotic diseaseInflammatory phenotypeImmune modulationCardiovascular diseaseImmune responseInflammatory stimuliI interferon
2022
A transcriptional cycling model recapitulates chromatin-dependent features of noisy inducible transcription
Bullock ME, Moreno-Martinez N, Miller-Jensen K. A transcriptional cycling model recapitulates chromatin-dependent features of noisy inducible transcription. PLOS Computational Biology 2022, 18: e1010152. PMID: 36084132, PMCID: PMC9491597, DOI: 10.1371/journal.pcbi.1010152.Peer-Reviewed Original ResearchMeSH KeywordsChromatinHIV InfectionsHIV-1HumansNF-kappa BTranscription, GeneticTranscriptional ActivationVirus LatencyConceptsGene expression noiseExpression noiseTranscriptional burstingPromoter statesDifferent chromatin environmentsChromatin environmentChromatin statePause releaseTranscription factor NFChromatin accessibilityChromatin remodelingTranscriptional noiseChromatin locationsInducible transcriptionSubstantial phenotypic heterogeneityTranscriptional activationTranscription factorsTranscript distributionPolymerase complexTarget genesPolymerase bindingGene expressionPromoter activityViral activationBiological processes
2021
Renal plasticity revealed through reversal of polycystic kidney disease in mice
Dong K, Zhang C, Tian X, Coman D, Hyder F, Ma M, Somlo S. Renal plasticity revealed through reversal of polycystic kidney disease in mice. Nature Genetics 2021, 53: 1649-1663. PMID: 34635846, PMCID: PMC9278957, DOI: 10.1038/s41588-021-00946-4.Peer-Reviewed Original ResearchConceptsPKD genesAutosomal dominant polycystic kidney diseaseCyst cell proliferationGene functionPolycystic kidney diseaseCell shapeGenesKidney diseaseExtracellular matrix depositionCell proliferationKidney tubule cellsNormal lumensDominant polycystic kidney diseaseUnexpected capacityPhenotypic featuresCyst progressionMatrix depositionCellsPlasticityCyst formationCystic tubulesMyofibroblast activationProliferationSquamoid cellsKidney resultsFunctional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation
Khetan S, Kales S, Kursawe R, Jillette A, Ulirsch JC, Reilly SK, Ucar D, Tewhey R, Stitzel ML. Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation. Nature Communications 2021, 12: 5242. PMID: 34475398, PMCID: PMC8413311, DOI: 10.1038/s41467-021-25514-6.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesSingle nucleotide polymorphismsTranscriptional activationEndoplasmic reticulum (ER) stress conditionsTranscriptional stress responseCis-regulatory effectsParallel reporter assaysT2D single nucleotide polymorphismsHigh linkage disequilibriumMultiple single nucleotide polymorphismsT2D genetic riskT2D-associated single nucleotide polymorphismsMIN6 β-cellsChromatin accessibilityCandidate single nucleotide polymorphismsT2D geneticsHuman genomeAssociation signalsRepetitive elementsFunctional characterizationNuclear elementsMolecular mechanismsReporter assaysStress responseAssociation studiesYAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation
He L, Pratt H, Gao M, Wei F, Weng Z, Struhl K. YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation. ELife 2021, 10: e67312. PMID: 34463254, PMCID: PMC8463077, DOI: 10.7554/elife.67312.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingCell Line, TumorCell Transformation, NeoplasticDatabases, GeneticFemaleGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsProtein BindingProtein Interaction Domains and MotifsSignal TransductionSTAT3 Transcription FactorTranscription Factor AP-1Transcription FactorsTranscriptional ActivationTranscriptional Coactivator with PDZ-Binding Motif ProteinsTriple Negative Breast NeoplasmsYAP-Signaling ProteinsConceptsTranscriptional co-activatorAP-1 proteinsAP-1Cellular transformationTarget siteNon-overlapping genesStimulated transcriptional activityAssociated with poor survival of breast cancer patientsPoor survival of breast cancer patientsSTAT3 motifTEAD proteinsSequence motifsGene classesWW domainEpigenetic switchTaz paralogTAZ-specificTranscriptional activityTranscription factorsTEADYAP/TAZSTAT3MotifTAZJunBHyperosmotic stress alters the RNA polymerase II interactome and induces readthrough transcription despite widespread transcriptional repression
Rosa-Mercado NA, Zimmer JT, Apostolidi M, Rinehart J, Simon MD, Steitz JA. Hyperosmotic stress alters the RNA polymerase II interactome and induces readthrough transcription despite widespread transcriptional repression. Molecular Cell 2021, 81: 502-513.e4. PMID: 33400923, PMCID: PMC7867636, DOI: 10.1016/j.molcel.2020.12.002.Peer-Reviewed Original ResearchMeSH KeywordsDown-RegulationEndoribonucleasesHEK293 CellsHumansOsmotic PressureRNARNA Polymerase IISalt StressTime FactorsTranscription, GeneticTranscriptional ActivationConceptsWidespread transcriptional repressionTranscriptional repressionPol IIIntegrator complex subunitsRNA polymerase IIGenome-wide lossStress-induced redistributionParental genesTranscriptional outputDoG inductionPolymerase IIChIP sequencingHuman cell linesUpstream geneComplex subunitsPolyadenylation factorsTranscription profilesReadthrough transcriptsCatalytic subunitIntegrator activityCellular stressHyperosmotic stressTranscriptional levelTranscription resultsGenes
2020
Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.
Schupp JC, Khanal S, Gomez JL, Sauler M, Adams TS, Chupp GL, Yan X, Poli S, Zhao Y, Montgomery RR, Rosas IO, Dela Cruz CS, Bruscia EM, Egan ME, Kaminski N, Britto CJ. Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2020, 202: 1419-1429. PMID: 32603604, PMCID: PMC7667912, DOI: 10.1164/rccm.202004-0991oc.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAirway ResistanceCystic FibrosisFemaleHumansInflammationMaleMiddle AgedSingle-Cell AnalysisTranscriptional ActivationConceptsCF lung diseaseHealthy control subjectsImmune dysfunctionLung diseaseCystic fibrosisControl subjectsSputum cellsAbnormal chloride transportLung mononuclear phagocytesInnate immune dysfunctionDivergent clinical coursesImmune cell repertoireMonocyte-derived macrophagesCF monocytesAirway inflammationClinical courseProinflammatory featuresCell survival programInflammatory responseTissue injuryCell repertoireImmune functionTranscriptional profilesAlveolar macrophagesMononuclear phagocytesHorizontally acquired regulatory gene activates ancestral regulatory system to promote Salmonella virulence
Choi J, Groisman EA. Horizontally acquired regulatory gene activates ancestral regulatory system to promote Salmonella virulence. Nucleic Acids Research 2020, 48: 10832-10847. PMID: 33045730, PMCID: PMC7641745, DOI: 10.1093/nar/gkaa813.Peer-Reviewed Original ResearchConceptsPhoP/PhoQAncestral regulatorNucleoid structuring protein H-NSProtein H-NSS. bongoriSalmonella enterica serovar TyphimuriumAncestral genomesH-NSTarget promotersEnterica serovar TyphimuriumRegulatory genesBacterial virulenceSalmonella virulencePromoter regionSsrBOpposite regulationGenesS. typhimuriumPhoQRegulatory systemSerovar TyphimuriumVirulenceTranscriptionPromoterRegulatorIdentification of a 22 bp DNA cis Element that Plays a Critical Role in Colony Stimulating Factor 1-Dependent Transcriptional Activation of the SPHK1 Gene
Yao GQ, Zhu M, Walker J, Insogna K. Identification of a 22 bp DNA cis Element that Plays a Critical Role in Colony Stimulating Factor 1-Dependent Transcriptional Activation of the SPHK1 Gene. Calcified Tissue International 2020, 107: 52-59. PMID: 32246175, PMCID: PMC7274855, DOI: 10.1007/s00223-020-00685-4.Peer-Reviewed Original ResearchConceptsColony stimulating factor 1Sphingosine kinase 1Bp fragmentSPHK1 promoterBp sequenceSphK1 geneDNA cis elementsProtein binding regionsSPHK1 gene expressionBp DNA fragmentStimulating factor 1Dual-luciferase reporterPutative DNATranscriptional activationTranscription factorsNuclear proteinsDNA sequencesCis elementsDNA bindingGene expressionPromoter activityDNA fragmentsKinase 1EMSAsProtein bindingHepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform
Da Li, Cao T, Sun X, Jin S, Di Xie, Huang X, Yang X, Carmichael GG, Taylor HS, Diano S, Huang Y. Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform. Nature Communications 2020, 11: 342. PMID: 31953394, PMCID: PMC6969024, DOI: 10.1038/s41467-019-14185-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiabetes Mellitus, Type 2DioxygenasesDisease Models, AnimalDNA DemethylationDNA MethylationDNA-Binding ProteinsFastingGene Expression RegulationGlucagonGlucoseHepatocyte Nuclear Factor 3-betaHepatocyte Nuclear Factor 4LiverMaleMiceMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticProtein IsoformsTranscriptional ActivationTranscriptomeUp-RegulationConceptsHepatic glucose productionType 2 diabetesGlucose homeostasisAdult liverSystemic glucose homeostasisPotential therapeutic targetGenetic mouse modelsFetal versionKey gluconeogenic genesMouse modelTherapeutic targetHNF4α functionGlucose productionFetal isoformsLiverT2D.DiabetesPromoter demethylationGluconeogenic genesTET3 overexpressionHNF4αHomeostasisTET3Regulatory mechanismsIsoforms
2019
Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation
Zhao P, Han SN, Arumugam S, Yousaf MN, Qin Y, Jiang JX, Torok NJ, Chen Y, Mankash MS, Liu J, Li J, Iwakiri Y, Ouyang X. Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. AJP Gastrointestinal And Liver Physiology 2019, 317: g387-g397. PMID: 31411894, PMCID: PMC6842989, DOI: 10.1152/ajpgi.00054.2019.Peer-Reviewed Original ResearchConceptsHigh-fat dietSignificant clinical applicabilityHuman nonalcoholic steatohepatitisNonalcoholic steatohepatitisOral digoxinLiver injuryCell subsetsPathway activationMouse modelHigh-fat diet mouse modelLiver injury mouse modelHepatocyte mitochondrial dysfunctionClinical applicabilityDiet mouse modelInjury mouse modelDifferential involvementLarge clinical experienceNLRP3 inflammasome activationSignificant protective effectHIF-1α transactivationHepatic oxidative stress responseHypoxia-inducible factorLiver inflammationHFD miceWide dosage rangeThe Ulp2 SUMO protease promotes transcription elongation through regulation of histone sumoylation
Ryu H, Su D, Wilson‐Eisele N, Zhao D, López‐Giráldez F, Hochstrasser M. The Ulp2 SUMO protease promotes transcription elongation through regulation of histone sumoylation. The EMBO Journal 2019, 38: embj2019102003. PMID: 31313851, PMCID: PMC6694223, DOI: 10.15252/embj.2019102003.Peer-Reviewed Original ResearchConceptsSmall ubiquitin-like modifierRNA polymerase IIC-terminal domainHistone sumoylationTranscription elongationActive genesSUMO proteaseRNAPII C-terminal domainChromatin regulatory mechanismsTranscriptional elongation defectsUbiquitin-like modifierCtk1 kinaseH2B ubiquitylationEukaryotic proteinsNucleosome associationElongation defectsPolySUMO chainsPolymerase IITranscript elongationCUP1 geneUlp2Saccharomyces cerevisiaeRegulatory mechanismsImpaired associationSerine 2Brd4 and P300 Confer Transcriptional Competency during Zygotic Genome Activation
Chan SH, Tang Y, Miao L, Darwich-Codore H, Vejnar CE, Beaudoin JD, Musaev D, Fernandez JP, Benitez MDJ, Bazzini AA, Moreno-Mateos MA, Giraldez AJ. Brd4 and P300 Confer Transcriptional Competency during Zygotic Genome Activation. Developmental Cell 2019, 49: 867-881.e8. PMID: 31211993, PMCID: PMC7201981, DOI: 10.1016/j.devcel.2019.05.037.Peer-Reviewed Original ResearchConceptsGenome activationTranscriptional competencyHistone acetylationP300-dependent histone acetylationZygotic genome activationFirst zygotic genesMaternal mRNA translationZygotic genesAnimal developmentZygotic developmentDevelopmental reprogrammingMRNA translationLive imagingCell cycleSilent genomeBRD4ZebrafishGenomeTranscriptionAcetylationActivationP300FertilizationReprogrammingGenes
2018
An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer
Lu X, Pan X, Wu C, Zhao D, Feng S, Zang Y, Lee R, Khadka S, Amin S, Jin E, Shang X, Deng P, Luo Y, Morgenlander W, Weinrich J, Lu X, Jiang S, Chang Q, Navone N, Troncoso P, DePinho R, Wang Y. An in vivo screen identifies PYGO2 as a driver for metastatic prostate cancer. Cancer Research 2018, 78: canres.3564.2017. PMID: 29769196, PMCID: PMC6381393, DOI: 10.1158/0008-5472.can-17-3564.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiomarkers, TumorCarcinogenesisCell Line, TumorDisease ProgressionGene Expression Regulation, NeoplasticHEK293 CellsHumansIntracellular Signaling Peptides and ProteinsLymph NodesMaleMiceMice, NudeNeoplasm GradingOncogenesPC-3 CellsProstatic NeoplasmsTranscriptional ActivationUp-RegulationWnt Signaling PathwayConceptsProstate cancer progressionDepth functional analysisCancer progressionWnt/β-catenin signalingCancer cell invasionΒ-catenin signalingFunctional genomicsProstate cancerTranscriptional activationCopy number aberrationsTranscriptomic datasetsFinger 2New oncogenePygo2's functionFunctional driversFunctional analysisLymph nodesImpairs tumor progressionChromosomal instabilityPutative oncogeneCell invasionNumber aberrationsPositive hitsAmplification/overexpressionOncogeneDigoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Stärkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metabolism 2018, 27: 339-350.e3. PMID: 29414684, PMCID: PMC5806149, DOI: 10.1016/j.cmet.2018.01.007.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell NucleusChromatinDigoxinDisease Models, AnimalEndotoxinsHistonesHumansHypoxia-Inducible Factor 1, alpha SubunitInflammationLiverNon-alcoholic Fatty Liver DiseaseOxidation-ReductionProtein BindingPyruvate KinaseTHP-1 CellsTranscription, GeneticTranscriptional ActivationConceptsHIF-1α transactivationSterile inflammationHIF-1α pathway activationNon-alcoholic steatohepatitisKinase M2Major clinical consequencesAbility of digoxinLiver inflammationLiver diseasePyruvate kinase M2Clinical consequencesTherapeutic targetInflammationTissue damageHIF-1αPathway activationDigoxinOxidative stressCardiac glycosidesSteatohepatitisDigoxin bindsNovel roleLiverUbiquitous responseActivationNF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise
Wong VC, Bass VL, Bullock ME, Chavali AK, Lee REC, Mothes W, Gaudet S, Miller-Jensen K. NF-κB-Chromatin Interactions Drive Diverse Phenotypes by Modulating Transcriptional Noise. Cell Reports 2018, 22: 585-599. PMID: 29346759, PMCID: PMC5812697, DOI: 10.1016/j.celrep.2017.12.080.Peer-Reviewed Original ResearchConceptsTranscriptional noiseIntegration sitesDiverse phenotypesRNA polymerase II regulationNoisy gene expressionGenomic integration sitesLive-cell imagingNF-κB activationChromatin environmentChromatin stateViral activationChromatin interactionsTranscript abundanceTranscription factor nuclear factor κBDivergent phenotypesGene expressionNoisy expressionNF-κBTranscript numbersNuclear factor κBPhenotypeTumor necrosis factorFactor κBActivationExpression
2017
Understanding Tissue-Specific Gene Regulation
Sonawane A, Platig J, Fagny M, Chen C, Paulson J, Lopes-Ramos C, DeMeo D, Quackenbush J, Glass K, Kuijjer M. Understanding Tissue-Specific Gene Regulation. Cell Reports 2017, 21: 1077-1088. PMID: 29069589, PMCID: PMC5828531, DOI: 10.1016/j.celrep.2017.10.001.Peer-Reviewed Original ResearchMeSH KeywordsGene Regulatory NetworksGenome, HumanHumansOrgan SpecificityProtein Interaction MapsTranscription FactorsTranscriptional ActivationTranscriptomeConceptsTissue specificityTissue-specific gene regulationGenotype-Tissue Expression projectControl tissue specificityTissue-specific genesTranscription factor targetsTissue-specific functionsGene expression patternsGene set enrichment analysisTissue-specific mannerTissue-specific processesInvestigate gene expressionGene regulationRegulatory interactionsTranscriptional controlTranscription factor expressionTranscription factorsExpression projectEnrichment analysisGene expressionExpression patternsGenesRegulation nodeFactor targetsTranscriptionMUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs
Pyzer AR, Stroopinsky D, Rosenblatt J, Anastasiadou E, Rajabi H, Washington A, Tagde A, Chu JH, Coll M, Jiao AL, Tsai LT, Tenen DE, Cole L, Palmer K, Ephraim A, Leaf RK, Nahas M, Apel A, Bar-Natan M, Jain S, McMasters M, Mendez L, Arnason J, Raby BA, Slack F, Kufe D, Avigan D. MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs. Leukemia 2017, 31: 2780-2790. PMID: 28555079, PMCID: PMC5791150, DOI: 10.1038/leu.2017.163.Peer-Reviewed Original ResearchConceptsPD-L1 expressionAcute myeloid leukemiaAML cellsMiR-200cPD-L1/PDT cell-mediated lysisPD-L1 mRNA levelsLeukemia-specific T cellsPD-L1 levelsAnti-tumor immunityImmunosuppressive tumor microenvironmentMurine AML modelHuman AML cellsAML cell linesPotential therapeutic targetMicroRNA miR-200cMiR-34a levelsNanostring arraysMyeloid leukemiaT cellsTherapeutic targetMUC1 inhibitionTumor microenvironmentAML modelUpregulation of miRNAsPurification of Zygotically Transcribed RNA through Metabolic Labeling of Early Zebrafish Embryos
Heyn P, Neugebauer KM. Purification of Zygotically Transcribed RNA through Metabolic Labeling of Early Zebrafish Embryos. Methods In Molecular Biology 2017, 1605: 121-131. PMID: 28456961, DOI: 10.1007/978-1-4939-6988-3_8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEmbryonic DevelopmentGene Expression Regulation, DevelopmentalRNA, MessengerTranscriptional ActivationUridine TriphosphateZebrafishZebrafish ProteinsWhole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development
Ferre-Fernández JJ, Aroca-Aguilar JD, Medina-Trillo C, Bonet-Fernández JM, Méndez-Hernández CD, Morales-Fernández L, Corton M, Cabañero-Valera MJ, Gut M, Tonda R, Ayuso C, Coca-Prados M, García-Feijoo J, Escribano J. Whole-Exome Sequencing of Congenital Glaucoma Patients Reveals Hypermorphic Variants in GPATCH3, a New Gene Involved in Ocular and Craniofacial Development. Scientific Reports 2017, 7: 46175. PMID: 28397860, PMCID: PMC5387416, DOI: 10.1038/srep46175.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsChromosome SegregationEmbryo, NonmammalianExome SequencingEyeFaceFamilyFemaleGene Expression Regulation, DevelopmentalGene Knockdown TechniquesGlaucomaHumansMaleMiddle AgedMutationOrgan SpecificityPedigreePhenotypePromoter Regions, GeneticReceptors, CXCR4SkullSubcellular FractionsTranscriptional ActivationZebrafishConceptsNew genesZebrafish embryosCraniofacial developmentEarly zebrafish embryosNeural crest cell migrationCrest cell migrationNew disease genesMesenchymal-like cellsHigh genetic heterogeneityUnidentified functionTransient overexpressionProximal promoterDisease genesGene Pitx2Whole-exome sequencingGenesCell migrationGenetic heterogeneityExome sequencingSkeletal muscleRare variantsCraniofacial abnormalitiesEmbryosSequencingProtein
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