2025
S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity
Zhang X, Vlkolinsky R, Wu C, Dolatabadi N, Scott H, Prikhodko O, Zhang A, Blanco M, Lang N, Piña-Crespo J, Nakamura T, Roberto M, Lipton S. S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418179122. PMID: 40014571, PMCID: PMC11892585, DOI: 10.1073/pnas.2418179122.Peer-Reviewed Original ResearchConceptsActivity-dependent gene expressionGene expressionAlzheimer's diseaseCREB-dependent gene expressionS-nitrosylationNitric oxide (NO)-related speciesTargets of S-nitrosylationNeuronal activity-dependent gene expressionPathogenesis of ADDecreased neurite lengthIncreased neuronal cell deathNeuronal cell deathSynaptic plasticityTranscriptional pathwaysCell deathCRISPR/Cas9 techniqueTranscription coactivator 1AD modelLong-term memory formationIncreased S-nitrosylationLong-term potentiationTherapeutic targetExpressionNeurite lengthCerebrocortical neuronsKLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection
Fagerberg E, Attanasio J, Dien C, Singh J, Kessler E, Abdullah L, Shen J, Hunt B, Connolly K, De Brouwer E, He J, Iyer N, Buck J, Borr E, Damo M, Foster G, Giles J, Huang Y, Tsang J, Krishnaswamy S, Cui W, Joshi N. KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection. Science 2025, 387: eadn2337. PMID: 39946463, DOI: 10.1126/science.adn2337.Peer-Reviewed Original ResearchConceptsCD8 T cellsT cellsCD8 T cell exhaustionNaive CD8 T cellsAcute LCMV infectionT cell exhaustionT cell fate decisionsLineage fidelityLCMV infectionEffector differentiationAcute infectionExhaustion programTranscription factorsImmune responseEpigenetic modulationSuppress differentiationProgenitor stateKLF2InfectionFunctional stateFate decisionsCD8A neoantigen vaccine generates antitumour immunity in renal cell carcinoma
Braun D, Moranzoni G, Chea V, McGregor B, Blass E, Tu C, Vanasse A, Forman C, Forman J, Afeyan A, Schindler N, Liu Y, Li S, Southard J, Chang S, Hirsch M, LeBoeuf N, Olive O, Mehndiratta A, Greenslade H, Shetty K, Klaeger S, Sarkizova S, Pedersen C, Mossanen M, Carulli I, Tarren A, Duke-Cohan J, Howard A, Iorgulescu J, Shim B, Simon J, Signoretti S, Aster J, Elagina L, Carr S, Leshchiner I, Getz G, Gabriel S, Hacohen N, Olsen L, Oliveira G, Neuberg D, Livak K, Shukla S, Fritsch E, Wu C, Keskin D, Ott P, Choueiri T. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature 2025, 639: 474-482. PMID: 39910301, PMCID: PMC11903305, DOI: 10.1038/s41586-024-08507-5.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntigens, NeoplasmCancer VaccinesCarcinoma, Renal CellClass I Phosphatidylinositol 3-KinasesDNA-Binding ProteinsFemaleHumansIpilimumabKidney NeoplasmsMaleMiddle AgedMutationPrecision MedicineT-LymphocytesTranscription FactorsTumor Suppressor ProteinsUbiquitin ThiolesteraseVon Hippel-Lindau Tumor Suppressor ProteinConceptsPersonalized cancer vaccinesRenal cell carcinomaDriver mutationsAntitumour immunityCell carcinomaI trialResected clear cell renal cell carcinomaImmune responseT cell immune responsesClear cell renal cell carcinomaHigh-risk RCCDose-limiting toxicityLow mutational burdenCell renal cell carcinomaEffective adjuvant therapyPhase I trialT cell reactivityAbsence of recurrenceCirculating immune responsesCell immune responseAutologous tumorNeoantigen vaccinesCancer vaccinesAdjuvant therapyMutational burden
2024
TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling
Lu W, Zalmas L, Bailey C, Black J, Martinez-Ruiz C, Pich O, Gimeno-Valiente F, Usaite I, Magness A, Thol K, Webber T, Jiang M, Saunders R, Liu Y, Biswas D, Ige E, Aerne B, Grönroos E, Venkatesan S, Stavrou G, Karasaki T, Al Bakir M, Renshaw M, Xu H, Schneider-Luftman D, Sharma N, Tovini L, Jamal-Hanjani M, McClelland S, Litchfield K, Birkbak N, Howell M, Tapon N, Fugger K, McGranahan N, Bartek J, Kanu N, Swanton C. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling. Nature Cell Biology 2024, 27: 154-168. PMID: 39738653, PMCID: PMC11735399, DOI: 10.1038/s41556-024-01558-w.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCadherinsCarcinoma, Non-Small-Cell LungCell Line, TumorChromosomal InstabilityGene Expression Regulation, NeoplasticHippo Signaling PathwayHumansLung NeoplasmsMiceMitosisProtein Serine-Threonine KinasesSignal TransductionTranscription FactorsYAP-Signaling ProteinsConceptsWhole-genome doublingStructural chromosome instabilityChromosomal instabilityHomologous recombinationNumerical chromosome instabilityNon-small-cell lung cancerHR deficiencyPersistent replication stressGenome doublingRadial chromosomesHippo signalingReplication stressChromosomal translocationsEvolutionary adaptationDriver eventsGenetic alterationsFAT1Increased tumor heterogeneityChromosomeCO depletionYAP1Downstream mechanismsRepair deficiencyIntratumour heterogeneityExperimental approachParalog Co-Targeting Identifies Selective Genetic Redundancies across Cancer Types.
Gauthier-Coles G, Sheltzer J. Paralog Co-Targeting Identifies Selective Genetic Redundancies across Cancer Types. Cancer Discovery 2024, 14: 2312-2314. PMID: 39618283, DOI: 10.1158/2159-8290.cd-24-1349.Peer-Reviewed Original ResearchSomatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Maury E, Jones A, Seplyarskiy V, Nguyen T, Rosenbluh C, Bae T, Wang Y, Abyzov A, Khoshkhoo S, Chahine Y, Zhao S, Venkatesh S, Root E, Voloudakis G, Roussos P, Network B, Park P, Akbarian S, Brennand K, Reilly S, Lee E, Sunyaev S, Walsh C, Chess A. Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes. Science 2024, 386: 217-224. PMID: 39388546, PMCID: PMC11490355, DOI: 10.1126/science.adq1456.Peer-Reviewed Original ResearchConceptsTranscription factor binding sitesWhole-genome sequencingOpen chromatinMutational processesSomatic mutationsFactor binding sitesSchizophrenia casesSchizophrenia risk genesSomatic mosaicismSomatic variantsRisk genesG mutationGene expressionGermline mutationsBinding sitesGenesMutationsIncreased somatic mutationsChromatinMosaic somatic mutationsPrenatal neurogenesisContext of schizophreniaBrain neuronsSchizophrenia brainVariantsAn RNA-centric view of transcription and genome organization
Henninger J, Young R. An RNA-centric view of transcription and genome organization. Molecular Cell 2024, 84: 3627-3643. PMID: 39366351, PMCID: PMC11495847, DOI: 10.1016/j.molcel.2024.08.021.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChromatinDNADNA-Directed RNA PolymerasesGene Expression RegulationGenomeHumansRNATranscription FactorsTranscription, GeneticConceptsGene regulationGenome architectureTranscriptional regulationModel of transcriptional regulationAssembly of protein complexesAssembly of transcription complexesLocal genome architectureSilencing of genesGenomic compartmentsGenome organizationGenomic structureRNA polymeraseChromatin regulationTranscription complexActive genesProtein complexesRNA moleculesTranscription factorsGenomeProtein kinaseSpecific genesGenesFeedback regulationRNASpatial compartmentsSWI/SNF Complex-Deficient Undifferentiated Carcinoma of the Pancreas: Clinicopathologic and Genomic Analysis
Yavas A, Ozcan K, Adsay N, Balci S, Tarcan Z, Hechtman J, Luchini C, Scarpa A, Lawlor R, Mafficini A, Reid M, Xue Y, Yang Z, Haye K, Bellizzi A, Vanoli A, Benhamida J, Balachandran V, Jarnagin W, Park W, O'Reilly E, Klimstra D, Basturk O. SWI/SNF Complex-Deficient Undifferentiated Carcinoma of the Pancreas: Clinicopathologic and Genomic Analysis. Modern Pathology 2024, 37: 100585. PMID: 39094734, PMCID: PMC11585460, DOI: 10.1016/j.modpat.2024.100585.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaUndifferentiated carcinomaConventional pancreatic ductal adenocarcinomaSMARCB1 protein expressionPancreatic undifferentiated carcinomaProtein expressionPD-L1SMARCB1 deletionRhabdoid morphologyPD-L1 protein expressionCase of undifferentiated carcinomaNext-generation sequencingCombined positive scoreLoss of SMARCB1 protein expressionKRAS wild typeNegative prognostic impactChromatin remodeling complex subunitMultiple tumor typesPrognostic impactTumor characteristicsOverall survivalSWI/SNF deficiencyTumor groupGene alterationsInactivating alterationsUsing a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements
Pratt H, Andrews G, Shedd N, Phalke N, Li T, Pampari A, Jensen M, Wen C, Consortium P, Gandal M, Geschwind D, Gerstein M, Moore J, Kundaje A, Colubri A, Weng Z. Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements. Science Advances 2024, 10: eadj4452. PMID: 38781344, PMCID: PMC11114231, DOI: 10.1126/sciadv.adj4452.Peer-Reviewed Original ResearchConceptsEpigenetic dataCell-type-specific gene regulationCis-regulatory elementsComprehensive atlasGenetic variants associated with psychiatric disordersLineage-specific transcription factorsBrain cell typesMammalian elementsPsychENCODE ConsortiumNoncoding regionsEvolutionary historyGene regulationRegulatory elementsSequence mutationsTranscription factorsSequence syntaxRegulatory informationPrimate-specific sequencesBinding sitesHuman traitsCell typesFunctional implicationsPsychiatric disordersSequenceFetal brain developmentAbnormalities in pharyngeal arch‐derived structures in SATB2‐associated syndrome
Zarate Y, Bosanko K, Derar N, Fish J. Abnormalities in pharyngeal arch‐derived structures in SATB2‐associated syndrome. Clinical Genetics 2024, 106: 209-213. PMID: 38693682, PMCID: PMC11216868, DOI: 10.1111/cge.14540.Peer-Reviewed Original ResearchConceptsSATB2-associated syndromeMutant miceAutosomal dominant disorderAnalyzed mutant miceEmbryonic mouse developmentDental anomaliesCraniofacial abnormalitiesMandibular distractionTrigeminal gangliaCraniofacial phenotypeClinical phenotypeDominant disorderCraniofacial developmentMouse developmentMicePhenotypic aspectsPatient dataThyroidSyndromeAbnormalitiesLower jawPharyngeal arch-derived structuresSATB2Mandibular morphologyPhenotypeNKX2-2 based nuclei sorting on frozen human archival pancreas enables the enrichment of islet endocrine populations for single-nucleus RNA sequencing
Xie G, Toledo M, Hu X, Yong H, Sanchez P, Liu C, Naji A, Irianto J, Wang Y. NKX2-2 based nuclei sorting on frozen human archival pancreas enables the enrichment of islet endocrine populations for single-nucleus RNA sequencing. BMC Genomics 2024, 25: 427. PMID: 38689254, PMCID: PMC11059690, DOI: 10.1186/s12864-024-10335-w.Peer-Reviewed Original ResearchConceptsSingle-nucleus RNA sequencingRNA sequencingNuclei sortingSnRNA-seqGene expressionEndocrine populationsFluorescence-activated nuclei sortingHuman isletsGene expression librariesNuclei isolation protocolSingle-cell RNA sequencingFrozen archival tissuesIsolated human isletsHuman pancreatic endocrine cellsSingle-cell transcriptomicsTranscriptomic studiesCytoplasmic contaminationTranscriptome profilingConclusionsOur workNKX2-2Isolated nucleiRNA integrityLiving cellsIsolation protocolPancreatic endocrine cellsA mammalian tripartite enhancer cluster controls hypothalamic Pomc expression, food intake, and body weight
Rojo D, Hael C, Soria A, de Souza F, Low M, Franchini L, Rubinstein M. A mammalian tripartite enhancer cluster controls hypothalamic Pomc expression, food intake, and body weight. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2322692121. PMID: 38652744, PMCID: PMC11067048, DOI: 10.1073/pnas.2322692121.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBody WeightEatingEnhancer Elements, GeneticFemaleHumansHypothalamusMaleMammalsMiceMice, TransgenicPro-OpiomelanocortinTranscription FactorsZebrafishConceptsFood intakeControl of food intakeHypothalamic POMC expressionBody weight homeostasisHypothalamic arcuate neuronsConvergent evolutionary processesReporter gene expressionPurifying selectionArcuate neuronsDeletion eventsMouse genomeMolecular evolutionWeight homeostasisFemale miceAdult micePOMC expressionTranscriptional enhancersMutant miceEnhancer mutantsTranscription factorsPlacental mammalsMammalian ordersGene expressionMiceEvolutionary processTemporal coordination of the transcription factor response to H2O2 stress
Jose E, March-Steinman W, Wilson B, Shanks L, Parkinson C, Alvarado-Cruz I, Sweasy J, Paek A. Temporal coordination of the transcription factor response to H2O2 stress. Nature Communications 2024, 15: 3440. PMID: 38653977, PMCID: PMC11039679, DOI: 10.1038/s41467-024-47837-w.Peer-Reviewed Original ResearchConceptsGroup of transcription factorsTranscription factorsResponse to H2O2 stressTranscription factor activityCell cycle arrestDose-dependent outcomeRepair oxidative damageOxidative stressDose-dependent activationTime-lapse imagingH2O2 stressCell deathRestoring redox balanceDose-dependentlyTranscriptionRedox balanceGlucose oxidase enzymeNF-kBFactor activityVascular mimicry as a facilitator of melanoma brain metastasis
Provance O, Oria V, Tran T, Caulfield J, Zito C, Aguirre-Ducler A, Schalper K, Kluger H, Jilaveanu L. Vascular mimicry as a facilitator of melanoma brain metastasis. Cellular And Molecular Life Sciences 2024, 81: 188. PMID: 38635031, PMCID: PMC11026261, DOI: 10.1007/s00018-024-05217-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainBrain NeoplasmsCell LineHumansMelanomaMiceNeovascularization, PathologicTranscription FactorsConceptsVascular mimicryBrain metastasesMouse model of metastatic melanomaIncreased risk of metastasisAssociated with tumor volumeMelanoma brain metastasesRisk of metastasisSurvival of miceFuture treatment regimensCell line modelsTumor suppressor pathwayMetastatic melanomaTumor volumeSolid tumorsTreatment regimensTumor typesPoor prognosisHippo tumor suppressor pathwayIncreased riskMouse modelDownstream targets YAPMelanomaMetastasisSuppressor pathwayTumorRORγt up-regulates RAG gene expression in DP thymocytes to expand the Tcra repertoire
Naik A, Dauphars D, Corbett E, Simpson L, Schatz D, Krangel M. RORγt up-regulates RAG gene expression in DP thymocytes to expand the Tcra repertoire. Science Immunology 2024, 9: eadh5318. PMID: 38489350, PMCID: PMC11005092, DOI: 10.1126/sciimmunol.adh5318.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGene ExpressionMiceNuclear Receptor Subfamily 1, Group F, Member 3Receptors, Antigen, T-Cell, alpha-betaThymocytesTranscription FactorsConceptsRecombination activating geneDP thymocytesUp-regulatedAntigen receptor lociDouble-positive (DP) stageRAG expressionTranscriptional up-regulationDouble-negative (DNRAG gene expressionActive genesTcra repertoireReceptor locusDN thymocytesGene expressionThymocyte transitionLymphocyte developmentThymocyte proliferationPhysiological importanceMultiple pathwaysRORgtThymocytesExpressionRepertoireRecombinationAntisilencingARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis
Barisic D, Chin C, Meydan C, Teater M, Tsialta I, Mlynarczyk C, Chadburn A, Wang X, Sarkozy M, Xia M, Carson S, Raggiri S, Debek S, Pelzer B, Durmaz C, Deng Q, Lakra P, Rivas M, Steidl C, Scott D, Weng A, Mason C, Green M, Melnick A. ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis. Cancer Cell 2024, 42: 583-604.e11. PMID: 38458187, PMCID: PMC11407687, DOI: 10.1016/j.ccell.2024.02.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDNA-Binding ProteinsHumansLymphomaMemory B CellsMiceMutationNuclear ProteinsTranscription FactorsConceptsFollicular lymphomaGerminal centersB cell fateAggressive follicular lymphomasMemory B cellsHigh-risk patientsSequential bindingNucleosome remodeling complexAggressive diseaseARID1A mutationsBinding of PUClonal precursorsBCL2 oncogeneB cellsPrecision therapyARID1ACD40 signalingLymphomaARID1A inactivationNF-kBRemodeling complexCell fateTranscription factorsPatientsMutationsAn 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 ResearchMeSH KeywordsArabidopsisArabidopsis ProteinsCell DivisionEpigenesis, GeneticFlowersGene Expression Regulation, PlantTranscription FactorsConceptsCell 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 organogenesisGenomic transcription factor binding site selection is edited by the chromatin remodeling factor CHD4
Saotome M, Poduval D, Grimm S, Nagornyuk A, Gunarathna S, Shimbo T, Wade P, Takaku M. Genomic transcription factor binding site selection is edited by the chromatin remodeling factor CHD4. Nucleic Acids Research 2024, 52: 3607-3622. PMID: 38281186, PMCID: PMC11039999, DOI: 10.1093/nar/gkae025.Peer-Reviewed Original ResearchConceptsTranscription factorsBreast cancer cellsBinding motifTranscription factor binding motifsTranscription factor-DNA interactionsLineage-determining transcription factorsCellular reprogrammingProof-reading enzymeBasal breast cancer cellsChromatin-binding activityCancer cellsBinding site selectionEukaryotic genomesNucleosome positioningChromatin accessibilityChromatin openingGene activationCHD4Gene expressionChromatinTranscriptionBinding activityFrequent mutationsUnoccupied sitesExquisite specificity“Deficiency in ELF4, X-Linked”: a Monogenic Disease Entity Resembling Behçet’s Syndrome and Inflammatory Bowel Disease
Olyha S, O’Connor S, Kribis M, Bucklin M, Uthaya Kumar D, Tyler P, Alam F, Jones K, Sheikha H, Konnikova L, Lakhani S, Montgomery R, Catanzaro J, Du H, DiGiacomo D, Rothermel H, Moran C, Fiedler K, Warner N, Hoppenreijs E, van der Made C, Hoischen A, Olbrich P, Neth O, Rodríguez-Martínez A, Lucena Soto J, van Rossum A, Dalm V, Muise A, Lucas C. “Deficiency in ELF4, X-Linked”: a Monogenic Disease Entity Resembling Behçet’s Syndrome and Inflammatory Bowel Disease. Journal Of Clinical Immunology 2024, 44: 44. PMID: 38231408, PMCID: PMC10929603, DOI: 10.1007/s10875-023-01610-8.Peer-Reviewed Original ResearchMeSH KeywordsArthralgiaArthritisBehcet SyndromeBiological ProductsDNA-Binding ProteinsHumansInflammatory Bowel DiseasesMaleTranscription FactorsConceptsDEX patientsClass-switched memory B cellsInborn errors of immunityTreated with anti-inflammatory agentsLow natural killerX-linkedMemory B cellsErrors of immunityCohort of patientsIncreased inflammatory cytokinesLoss-of-function variantsHeterogeneous clinical phenotypesInflammatory bowel diseaseTargeted therapeutic interventionsNatural killerAnti-inflammatory agentsAphthous ulcersTherapeutic responseAutoinflammatory syndromeInflammatory markersClinical manifestationsB cellsBehcet's syndromeGastrointestinal symptomsMechanisms of diseaseSkeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α
Liu B, Xie D, Huang X, Jin S, Dai Y, Sun X, Li D, Bennett A, Diano S, Huang Y. Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α. Diabetologia 2024, 67: 724-737. PMID: 38216792, PMCID: PMC10904493, DOI: 10.1007/s00125-023-06073-5.Peer-Reviewed Original ResearchConceptsTen-eleven translocationMuscle insulin sensitivityRNA-seqPGC-1aRegulation of muscle insulin sensitivityType 2 diabetesAnalysis of RNA-seqResponse to environmental cuesGenome-wide expression profilingWild-typeHFD-fedHFD-induced insulin resistanceHigh-fat diet (HFD)-inducedExpression levelsMaintenance of glucoseSkeletal muscle insulin sensitivityAccession numbersSkeletal muscleEnhanced glucose toleranceFamily dioxygenasesMitochondrial respirationSkeletal muscle of humansEnvironmental cuesMitochondrial functionBiological processes
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