2025
Modeling SMAD2 Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis.
Ward T, Morton S, Venturini G, Tai W, Jang M, Gorham J, Delaughter D, Wasson L, Khazal Z, Homsy J, Gelb B, Chung W, Bruneau B, Brueckner M, Tristani-Firouzi M, DePalma S, Seidman C, Seidman J. Modeling SMAD2 Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis. Journal Of The American Heart Association 2025, 14: e036860. PMID: 40028843, DOI: 10.1161/jaha.124.036860.Peer-Reviewed Original ResearchConceptsLoss-of-functionCongenital heart diseaseChromatin accessibilityMissense variantsCHD probandsPluripotent stem cellsHomozygous loss-of-functionCHD-associated genesHeterozygous loss-of-functionTranscription factor bindingMutant induced pluripotent stem cellsChromatin immunoprecipitation dataChromatin peaksStem cellsChromatin interactionsInduced pluripotent stem cellsFactor bindingTranscription factor NanogExome sequencingImmunoprecipitation dataTranscription factorsRNA sequencingChromatinMissenseMolecular consequences
2024
Single-nucleus multi-omics analyses reveal cellular and molecular innovations in the anterior cingulate cortex during primate evolution
Yuan J, Dong K, Wu H, Zeng X, Liu X, Liu Y, Dai J, Yin J, Chen Y, Guo Y, Luo W, Liu N, Sun Y, Zhang S, Su B. Single-nucleus multi-omics analyses reveal cellular and molecular innovations in the anterior cingulate cortex during primate evolution. Cell Genomics 2024, 4: 100703. PMID: 39631404, PMCID: PMC11701334, DOI: 10.1016/j.xgen.2024.100703.Peer-Reviewed Original ResearchConceptsChromatin accessibilitySingle-nucleusGene expressionTranscription factor bindingPatterns of gene expressionSingle-nucleus resolutionCell lineage originACC gene expressionPrimate evolutionMulti-omics analysisAnterior cingulate cortexFactor bindingEvolutionary roleFunctional innovationSequence changesMolecular innovationsVon Economo neuronsMolecular regulationMarker genesPublished mouse dataCell typesChromatinMolecular identityHuman originCingulate cortexPP7.7 – 00092 Single-Nucleus Multiomic Sequencing Uncovers Differential Chromatin Accessibility and Gene Regulation in Cerebrospinal Fluid Cells of PWH
Lu C, Orlinick B, Das B, Filippidis P, Mehta S, Spudich S, Pang A, Kluger Y, Corley M, Farhadian S. PP7.7 – 00092 Single-Nucleus Multiomic Sequencing Uncovers Differential Chromatin Accessibility and Gene Regulation in Cerebrospinal Fluid Cells of PWH. Journal Of Virus Eradication 2024, 10: 87-88. DOI: 10.1016/j.jve.2024.100530.Peer-Reviewed Original ResearchMetastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties.
Shin J, Park J, Lim J, Jeong J, Dinesh R, Maher S, Kim J, Park S, Hong J, Wysolmerski J, Choi J, Bothwell A. Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties. ELife 2024, 13 PMID: 39535280, PMCID: PMC11560131, DOI: 10.7554/elife.97279.Peer-Reviewed Original ResearchConceptsCancer cellsDickkopf-2Analysis of transcriptomeGeneration of cancer cellsPositive cancer cellsStem cell niche factorsColon cancer cellsPaneth cell differentiationHepatocyte nuclear factor 4 alphaLysozyme positive cellsChromatin accessibilityHNF4A proteinSingle-cell RNA sequencing analysisCell propertiesPaneth cell markersSequence analysisChromatin immunoprecipitationPromoter regionTranscription factorsTranscriptome analysisColon cancerColon cancer metastasisReduction of liver metastasisDownstream targetsCell differentiationMetastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties
Shin J, Park J, Lim J, Jeong J, Dinesh R, Maher S, Kim J, Park S, Hong J, Wysolmerski J, Choi J, Bothwell A. Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties. ELife 2024, 13 DOI: 10.7554/elife.97279.3.Peer-Reviewed Original ResearchCancer cellsDickkopf-2Promoter region of Sox9Analysis of transcriptomeGeneration of cancer cellsPositive cancer cellsStem cell niche factorsColon cancer cellsPaneth cell differentiationHepatocyte nuclear factor 4 alphaLysozyme positive cellsChromatin accessibilityHNF4A proteinSingle-cell RNA sequencing analysisCell propertiesPaneth cell markersSequence analysisChromatin immunoprecipitationPromoter regionTranscription factorsTranscriptome analysisColon cancerColon cancer metastasisReduction of liver metastasisDownstream targetsComparative single-cell multiome identifies evolutionary changes in neural progenitor cells during primate brain development
Liu Y, Luo X, Sun Y, Chen K, Hu T, You B, Xu J, Zhang F, Cheng Q, Meng X, Yan T, Li X, Qi X, He X, Guo X, Li C, Su B. Comparative single-cell multiome identifies evolutionary changes in neural progenitor cells during primate brain development. Developmental Cell 2024, 60: 414-428.e8. PMID: 39481377, DOI: 10.1016/j.devcel.2024.10.005.Peer-Reviewed Original ResearchEvolutionary changesDistal regulatory elementsGene regulatory mechanismsExtracellular matrixSingle-cell multiomicsProgenitor cellsTranscriptional divergenceEvolutionary divergenceChromatin regionsChromatin accessibilityNeural progenitorsRegulatory elementsSequence changesTranscriptional rewiringGenetic mechanismsMouse prefrontal cortexRegulatory mechanismsPrefrontal cortexHuman neural progenitorsHuman-specific featuresUpper-layer neuronsNeural progenitor cellsChromatinCellular propertiesProgenitor proliferationDetection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders
Zhou B, Arthur J, Guo H, Kim T, Huang Y, Pattni R, Wang T, Kundu S, Luo J, Lee H, Nachun D, Purmann C, Monte E, Weimer A, Qu P, Shi M, Jiang L, Yang X, Fullard J, Bendl J, Girdhar K, Kim M, Chen X, Consortium P, Greenleaf W, Duncan L, Ji H, Zhu X, Song G, Montgomery S, Palejev D, Dohna H, Roussos P, Kundaje A, Hallmayer J, Snyder M, Wong H, Urban A. Detection and analysis of complex structural variation in human genomes across populations and in brains of donors with psychiatric disorders. Cell 2024, 187: 6687-6706.e25. PMID: 39353437, PMCID: PMC11608572, DOI: 10.1016/j.cell.2024.09.014.Peer-Reviewed Original ResearchComplex structural variationsNatural human genetic variationHuman genetic variationCell type-specific expressionHuman-specific evolutionDifferential gene expressionStructural variationsContinental populationsChromatin accessibilityHuman genomeGenetic variationNeural genesGenomeGene expressionRisk allelesMolecular etiologyCell typesGenesPostmortem brainsChromatinLociAllelesMachine-learning-based methodsMultiomicsBrain regionsA cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders
Lee A, Ayers L, Kosicki M, Chan W, Fozo L, Pratt B, Collins T, Zhao B, Rose M, Sanchis-Juan A, Fu J, Wong I, Zhao X, Tenney A, Lee C, Laricchia K, Barry B, Bradford V, Jurgens J, England E, Lek M, MacArthur D, Lee E, Talkowski M, Brand H, Pennacchio L, Engle E. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders. Nature Communications 2024, 15: 8268. PMID: 39333082, PMCID: PMC11436875, DOI: 10.1038/s41467-024-52463-7.Peer-Reviewed Original ResearchConceptsNon-coding variantsCranial motor neuronsMendelian disordersIn vivo transgenic assayPredictor of enhancer activityCis-regulatory elementsMulti-omic frameworkWhole-genome sequencingEnhanced activityVariant discoveryGenome sequenceChromatin accessibilityPutative enhancersHistone modificationsRegulatory elementsGene expression assaysGene predictionTransgenic assaysEpigenomic profilingMendelian casesExpression assaysMutational enhancementCongenital cranial dysinnervation disordersCell typesFunctional impactAcute and persistent responses after H5N1 vaccination in humans
Apps R, Biancotto A, Candia J, Kotliarov Y, Perl S, Cheung F, Farmer R, Mulè M, Rachmaninoff N, Chen J, Martins A, Shi R, Zhou H, Bansal N, Schum P, Olnes M, Milanez-Almeida P, Han K, Sellers B, Cortese M, Hagan T, Rouphael N, Pulendran B, King L, Manischewitz J, Khurana S, Golding H, van der Most R, Dickler H, Germain R, Schwartzberg P, Tsang J. Acute and persistent responses after H5N1 vaccination in humans. Cell Reports 2024, 43: 114706. PMID: 39235945, PMCID: PMC11949244, DOI: 10.1016/j.celrep.2024.114706.Peer-Reviewed Original ResearchH5N1 influenza vaccineImpact vaccine responsesTime pointsAdjuvant AS03H5N1 vaccineInfluenza vaccineT cellsVaccine responseVaccinated cohortHigh antibody respondersImmune stateVaccine antigensMultiple time pointsSingle-cell profilingInitial vaccinationSystems immunologyVaccinePersistent responseSurface proteinsCell type-specific signaturesChromatin accessibilityTranscription factorsH5N1DaysAS03ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses
Kaymak I, Watson M, Oswald B, Ma S, Johnson B, DeCamp L, Mabvakure B, Luda K, H. E, Lau K, Fu Z, Muhire B, Kitchen-Goosen S, Vander Ark A, Dahabieh M, Samborska B, Vos M, Shen H, Fan Z, Roddy T, Kingsbury G, Sousa C, Krawczyk C, Williams K, Sheldon R, Kaech S, Roy D, Jones R. ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. Journal Of Experimental Medicine 2024, 221: e20231820. PMID: 39150482, PMCID: PMC11329787, DOI: 10.1084/jem.20231820.Peer-Reviewed Original ResearchConceptsAcyl-CoA synthetase short-chain family member 2Acetyl-CoA productionATP citrate lyaseChromatin accessibilityAcetyl-CoAEnzyme ATP citrate lyaseFamily member 2Function in vivoCoordination of cellular metabolismTCA cycleMetabolic nodesGene locusCitrate lyaseT cell effector responsesHistone acetylationCellular metabolismEffector functionsCD8 T cellsResponse to infectionMember 2ChromatinEffector responsesMetabolic substratesT cell response to infectionT cellsSpatially resolved epigenome sequencing via Tn5 transposition and deterministic DNA barcoding in tissue
Farzad N, Enninful A, Bao S, Zhang D, Deng Y, Fan R. Spatially resolved epigenome sequencing via Tn5 transposition and deterministic DNA barcoding in tissue. Nature Protocols 2024, 19: 3389-3425. PMID: 38943021, DOI: 10.1038/s41596-024-01013-y.Peer-Reviewed Original ResearchTn5 transpositionDeterministic barcodingGenome-wide profiling of histone modificationsProfiling of histone modificationsTransposase-accessible chromatin sequencingEpigenomic profiling methodsGenome-wide profilingSingle-base resolutionGene regulation programsGenomic DNA locusNext-generation sequencingDNA lociBioinformatics skillsLibrary preparationDNA barcodingChromatin accessibilityChromatin sequencingHistone modificationsEpigenome sequencingEpigenetic landscapeEpigenetic mapsCellular functionsEpigenetic markersCustom pipelineBarcodingDetecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling
Zarif T, Meador C, Qiu X, Seo J, Davidsohn M, Savignano H, Lakshminarayanan G, McClure H, Canniff J, Fortunato B, Li R, Banwait M, Semaan K, Eid M, Long H, Hung Y, Mahadevan N, Barbie D, Oser M, Piotrowska Z, Choueiri T, Baca S, Hata A, Freedman M, Berchuck J. Detecting small cell transformation in patients with advanced EGFR mutant lung adenocarcinoma through epigenomic cfDNA profiling. Clinical Cancer Research 2024, 30: 3798-3811. PMID: 38912901, PMCID: PMC11369616, DOI: 10.1158/1078-0432.ccr-24-0466.Peer-Reviewed Original ResearchConceptsEGFR mutant lung adenocarcinomaSmall cell lung cancerSmall cell transformationLung cancer patient-derived xenograftPatient-derived xenograftsLung adenocarcinomaEGFR mutantsChIP-seqEpigenomic featuresMeDIP-seqImmunoprecipitation sequencingCell transformationHistological transformation to small cell lung cancerTransformation to small cell lung cancerMethylated DNA immunoprecipitation sequencingTransposase-accessible chromatin sequencingH3K27ac ChIP-seqMechanisms of treatment resistanceChromatin immunoprecipitation sequencingHistone modification H3K27acMutant lung adenocarcinomaCell lung cancerChromatin accessibilityChromatin sequencingEpigenomic landscapeTranscription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape
Boddu P, Gupta A, Roy R, De La Peña Avalos B, Olazabal-Herrero A, Neuenkirchen N, Zimmer J, Chandhok N, King D, Nannya Y, Ogawa S, Lin H, Simon M, Dray E, Kupfer G, Verma A, Neugebauer K, Pillai M. Transcription elongation defects link oncogenic SF3B1 mutations to targetable alterations in chromatin landscape. Molecular Cell 2024, 84: 1475-1495.e18. PMID: 38521065, PMCID: PMC11061666, DOI: 10.1016/j.molcel.2024.02.032.Peer-Reviewed Original ResearchRate of RNA polymerase IIChromatin landscapeElongation defectsElongation rate of RNA polymerase IIImpaired protein-protein interactionsSplicing of pre-messenger RNATranscription elongation defectsRNA polymerase IIProtein-protein interactionsPre-messenger RNACancer-associated mutationsIsogenic cell linesSin3/HDAC complexGene bodiesPolymerase IIChromatin accessibilityH3K4me3 markChromatin changesMutant SF3B1ChromatinMutant mouse modelsEpigenetic disordersEpigenetic factorsHuman diseasesMutant stateMechanosensing regulates tissue repair program in macrophages
Meizlish M, Kimura Y, Pope S, Matta R, Kim C, Philip N, Meyaard L, Gonzalez A, Medzhitov R. Mechanosensing regulates tissue repair program in macrophages. Science Advances 2024, 10: eadk6906. PMID: 38478620, PMCID: PMC10936955, DOI: 10.1126/sciadv.adk6906.Peer-Reviewed Original ResearchConceptsExtracellular matrixRegulate chromatin accessibilityTissue repair programGene expression programsCytoskeletal dynamicsChromatin accessibilityAmoeboid migrationCytoskeletal remodelingBiochemical signalsTissue homeostasisExpression programsColony-stimulating factor-1Tissue-resident macrophagesFactor 1MechanosensingRegulating tissue repairTissue integrityMacrophagesTissueThree-dimensional environmentRepair programHomeostasisAn epigenetic timer regulates the transition from cell division to cell expansion during Arabidopsis petal organogenesis
Huang R, Irish V. An epigenetic timer regulates the transition from cell division to cell expansion during Arabidopsis petal organogenesis. PLOS Genetics 2024, 20: e1011203. PMID: 38442104, PMCID: PMC10942257, DOI: 10.1371/journal.pgen.1011203.Peer-Reviewed Original ResearchConceptsCell division to cell expansionCell divisionCell expansionRemodeling of chromatin accessibilityResponse to environmental changesRNA polymerase activityPlant developmental timingRegulate developmental eventsMultiple cell divisionsDownstream direct targetsCorepressor TOPLESSArabidopsis petalsChromatin accessibilityHistone modificationsPetal developmentEpigenetic stateTranscriptional repressorPetal organogenesisPolymerase activityEpigenetic memoryPetal primordiaPlant organogenesisCell cycleEpigenetic factorsControl organogenesisThe IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer
Amara C, Kami Reddy K, Yuntao Y, Chan Y, Piyarathna D, Dobrolecki L, Shih D, Shi Z, Xu J, Huang S, Ellis M, Apolo A, Ballester L, Gao J, Hansel D, Lotan Y, Hodges H, Lerner S, Creighton C, Sreekumar A, Zheng W, Msaouel P, Kavuri S, Putluri N. The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer. Nature Communications 2024, 15: 1373. PMID: 38355560, PMCID: PMC10867091, DOI: 10.1038/s41467-024-45132-2.Peer-Reviewed Original ResearchConceptsSignaling axisSMARCB1-deficient tumorsSMARCB1 deficiencyBladder cancerChromatin accessibilitySTAT3 inhibitorTumor growthSMARCB1 lossPatient-derived xenograft modelsCell line-derived xenograftsTherapeutic vulnerabilitiesTarget pathwaysReduced tumor growthIncreased tumor growthCell linesIn vivo modelsSTAT3Gene signatureSMARCB1TTI-101Solid tumorsXenograft modelClinical evaluationDisease progressionTumorChapter 2 The Mechanism, Regulation and Evolution of V(D)J Recombination
Schatz D, Zhang Y, Xiao J, Zha S, Zhang Y, Alt F. Chapter 2 The Mechanism, Regulation and Evolution of V(D)J Recombination. 2024, 13-57. DOI: 10.1016/b978-0-323-95895-0.00004-0.Peer-Reviewed Original ResearchAntigen receptor lociNon-homologous end joiningChromatin loop extrusionRecombination-activating geneLoop extrusionV(D)J recombinationRecombination-activating gene proteinV(D)J recombination reactionReceptor locusEnd joiningDouble-strand (ds) DNA breaksLoop extrusion mechanismRegulation of recombinationRepertoire of antigen receptorsLymphocyte developmentOncogenic chromosomal translocationsVariable region gene segmentsDNA repair proteinsDNA repair pathwaysChromatin accessibilityDNA segmentsV(D)J recombinase activitySubstrate DNALoop domainV(D)J junctions
2023
Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53
Lee J, Menasche B, Mavrikaki M, Uyemura M, Hong S, Kozlova N, Wei J, Alfajaro M, Filler R, Müller A, Saxena T, Posey R, Cheung P, Muranen T, Heng Y, Paulo J, Wilen C, Slack F. Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53. Cell Reports 2023, 42: 113478. PMID: 37991919, PMCID: PMC10785701, DOI: 10.1016/j.celrep.2023.113478.Peer-Reviewed Original ResearchConceptsChromatin accessibilityProteomic compositionCellular senescenceTP53 stabilizationSARS-CoV-2 spikeCell-cell fusionPathogenic coronavirusesSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variantsSenescence-associated inflammationSARS-CoV-2 infectionMiddle East respiratory syndromeAccessibility stateInflammatory cytokine releaseSevere respiratory infectionsSARS-CoV-2 variantsSignificant public health threatCoronavirus disease 2019SARS-CoV-2Public health threatBreakthrough infectionsRespiratory infectionsCytokine releaseSenescenceDisease 2019Respiratory syndromeMulti-omic profiling of the developing human cerebral cortex at the single-cell level
Zhu K, Bendl J, Rahman S, Vicari J, Coleman C, Clarence T, Latouche O, Tsankova N, Li A, Brennand K, Lee D, Yuan G, Fullard J, Roussos P. Multi-omic profiling of the developing human cerebral cortex at the single-cell level. Science Advances 2023, 9: eadg3754. PMID: 37824614, PMCID: PMC10569714, DOI: 10.1126/sciadv.adg3754.Peer-Reviewed Original ResearchConceptsCis-regulatory elementsChromatin accessibilityGene expressionPseudotime trajectory analysisNeuronal lineage commitmentMulti-omics profilingSingle-cell levelSpecific genetic lociDevelopmental time pointsChromatin structureType-specific domainsLineage determinationCellular complexityLineage commitmentNeuropsychiatric traitsComplex regulationGenetic lociSpatiotemporal activityDynamic changesCritical roleExpressionSpatiotemporal alterationsCell compositionCritical stageNeuropsychiatric diseasesMammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
de Miguel F, Gentile C, Feng W, Silva S, Sankar A, Exposito F, Cai W, Melnick M, Robles-Oteiza C, Hinkley M, Tsai J, Hartley A, Wei J, Wurtz A, Li F, Toki M, Rimm D, Homer R, Wilen C, Xiao A, Qi J, Yan Q, Nguyen D, Jänne P, Kadoch C, Politi K. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell 2023, 41: 1516-1534.e9. PMID: 37541244, PMCID: PMC10957226, DOI: 10.1016/j.ccell.2023.07.005.Peer-Reviewed Original ResearchConceptsMammalian SWI/SNF chromatinSWI/SNF chromatinMSWI/SNF complexesGenome-wide localizationGene regulatory signaturesNon-genetic mechanismsEpithelial cell differentiationEGFR-mutant cellsChromatin accessibilitySNF complexCellular programsRegulatory signaturesTKI-resistant lung cancerGene targetsKinase inhibitor resistanceCell differentiationMesenchymal transitionTKI resistancePharmacologic disruptionTyrosine kinase inhibitor resistanceCell proliferationChromatinInhibitor resistanceEGFR-mutant lungKinase inhibitors
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