2025
p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells
Miller K, Li B, Pierce-Hoffman H, Patel S, Lei X, Rajesh A, Teneche M, Havas A, Gandhi A, Macip C, Lyu J, Victorelli S, Woo S, Lagnado A, LaPorta M, Liu T, Dasgupta N, Li S, Davis A, Korotkov A, Hultenius E, Gao Z, Altman Y, Porritt R, Garcia G, Mogler C, Seluanov A, Gorbunova V, Kaech S, Tian X, Dou Z, Chen C, Passos J, Adams P. p53 enhances DNA repair and suppresses cytoplasmic chromatin fragments and inflammation in senescent cells. Nature Communications 2025, 16: 2229. PMID: 40044657, PMCID: PMC11882782, DOI: 10.1038/s41467-025-57229-3.Peer-Reviewed Original ResearchConceptsCytoplasmic chromatin fragmentsDNA repairGenome integrityChromatin fragmentsNuclear DNA damage signalsGenomic instabilitySenescent cellsActivation of p53Controlling DNA repairATM-dependent mannerDNA damage signalingSignatures of agingAge-associated accumulationActivate p53P53 activationHallmarks of agingDamage signalingAge-associated diseasesSignaling circuitsP53Molecular circuitsEnhanced DNA repairGenomePharmacological inhibitionAge-associated inflammation
2024
Development of a High-Throughput Platform for Quantitation of Histone Modifications on a New QTOF Instrument
Zahn E, Xie Y, Liu X, Karki R, Searfoss R, de Luna Vitorino F, Lempiäinen J, Gongora J, Lin Z, Zhao C, Yuan Z, Garcia B. Development of a High-Throughput Platform for Quantitation of Histone Modifications on a New QTOF Instrument. Molecular & Cellular Proteomics 2024, 24: 100897. PMID: 39708910, PMCID: PMC11787651, DOI: 10.1016/j.mcpro.2024.100897.Peer-Reviewed Original ResearchConceptsData-independent acquisitionModified histone peptidesLC-MSMass spectrometry (MS)-based approachesMicroflow liquid chromatographyNanoflow LC-MSPost-translational modificationsIsobaric peptidesQTOF instrumentLC gradientSequential window acquisitionHistone post-translational modificationsMass spectrometerHistone peptidesTransforming growth factor beta 1Histone deacetylase inhibitorsHistone samplesWindow acquisitionOrbitrapLow stoichiometryLiquid chromatographyCharacterization of histone PTMsHigh-throughput methodDeacetylase inhibitorsInstrumentation timeImmune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function
Andrade A, Annett A, Karimi E, Topouza D, Rezanejad M, Liu Y, McNicholas M, Gonzalez Santiago E, Llivichuzhca-Loja D, Gehlhaar A, Jessa S, De Cola A, Chandarana B, Russo C, Faury D, Danieau G, Puligandla E, Wei Y, Zeinieh M, Wu Q, Hebert S, Juretic N, Nakada E, Krug B, Larouche V, Weil A, Dudley R, Karamchandani J, Agnihotri S, Quail D, Ellezam B, Konnikova L, Walsh L, Pathania M, Kleinman C, Jabado N. Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function. Nature Communications 2024, 15: 7769. PMID: 39237515, PMCID: PMC11377583, DOI: 10.1038/s41467-024-52096-w.Peer-Reviewed Original ResearchConceptsMyeloid populationsTumor microenvironmentExpression of immune checkpoint markersImmune checkpoint pathwaysImmune checkpoint markersSyngeneic mouse modelTumor-promoting functionsCheckpoint markersMyeloid infiltrationImmune landscapeImmune infiltrationImmune lineagesMyeloid cellsLymphoid cellsTumor cellsMouse modelTumor formationBenefit of patientsTherapeutic benefitBrain tumorsGliomaTumorDysregulated epigenomeDual inhibitionInfiltrationACLY 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 cellsTwo DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Frisbie V, Hashimoto H, Xie Y, De Luna Vitorino F, Baeza J, Nguyen T, Yuan Z, Kiselar J, Garcia B, Debler E. Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids. Nature Communications 2024, 15: 2467. PMID: 38503750, PMCID: PMC10951340, DOI: 10.1038/s41467-024-46637-6.Peer-Reviewed Original ResearchConceptsMotif VIDot1 enzymesMechanism of substrate recognitionH2B mono-ubiquitinationHistone H3 lysine 79Active-site loopH3 lysine 79Histone H3 lysineEnzyme-substrate complexMotif IVTri-methyltransferaseSubstrate recognitionMethylation kineticsMono-ubiquitinationLysine 79Substrate preferenceH3 lysineTri-methylationDOT1BAcid residuesDot1Ala residuesKinetoplastidsMotifBiochemical analysisONC201 (Dordaviprone) in Recurrent H3 K27M–Mutant Diffuse Midline Glioma
Arrillaga-Romany I, Gardner S, Odia Y, Aguilera D, Allen J, Batchelor T, Butowski N, Chen C, Cloughesy T, Cluster A, de Groot J, Dixit K, Graber J, Haggiagi A, Harrison R, Kheradpour A, Kilburn L, Kurz S, Lu G, MacDonald T, Mehta M, Melemed A, Nghiemphu P, Ramage S, Shonka N, Sumrall A, Tarapore R, Taylor L, Umemura Y, Wen P. ONC201 (Dordaviprone) in Recurrent H3 K27M–Mutant Diffuse Midline Glioma. Journal Of Clinical Oncology 2024, 42: 1542-1552. PMID: 38335473, PMCID: PMC11095894, DOI: 10.1200/jco.23.01134.Peer-Reviewed Original ResearchConceptsH3 K27M-mutant diffuse midline gliomaDiffuse midline gliomaDuration of responseTime to responseHigh-grade gliomasLow-grade gliomasMidline gliomaMedian duration of responseMedian time to responseTreatment-emergent adverse eventsEnd pointsBlinded independent central reviewCorticosteroid dose reductionIndependent central reviewSecondary end pointsClinically meaningful efficacyRadiographic end pointsSpinal tumorsDose reductionDismal prognosisCentral reviewPerformance scoresCorticosteroid responseResponse assessmentAdverse eventsSmall-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response
Jaschke N, Breining D, Hofmann M, Pählig S, Baschant U, Oertel R, Traikov S, Grinenko T, Saettini F, Biondi A, Stylianou M, Bringmann H, Zhang C, Yoshida T, Weidner H, Poller W, Swirski F, Göbel A, Hofbauer L, Rauner M, Scheiermann C, Wang A, Rachner T. Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response. Immunity 2024, 57: 364-378.e9. PMID: 38301651, PMCID: PMC10923082, DOI: 10.1016/j.immuni.2024.01.005.Peer-Reviewed Original ResearchMeSH KeywordsBone MarrowHistone AcetyltransferasesHistonesHumansHypothalamo-Hypophyseal SystemNeutrophilsConceptsCorticotropin-releasing hormone receptor 1Hypothalamus-pituitary-adrenal glandAdrenocorticotropic hormoneBone marrowGranulocyte colony-stimulating factorAugmented host defenseMobilization of leukocytesColony-stimulating factorHistone acetyltransferase inhibitionHormone receptor 1Leukemic transformationG-CSFNeutrophil mobilizationReceptor 1Leukocyte mobilizationLeukocyte distributionHistone acetyltransferaseLeukocyte compartmentNeuroendocrine loopHost defenseEndocrine stress responseLeukocytesMarrowBloodReversible inhibition
2023
The H2Bub1-deposition complex is required for human and mouse cardiogenesis
Barish S, Berg K, Drozd J, Berglund-Brown I, Khizir L, Wasson L, Seidman C, Seidman J, Chen S, Brueckner M. The H2Bub1-deposition complex is required for human and mouse cardiogenesis. Development 2023, 150: dev201899. PMID: 38038666, PMCID: PMC10730087, DOI: 10.1242/dev.201899.Peer-Reviewed Original ResearchH3.1K27me1 loss confers Arabidopsis resistance to Geminivirus by sequestering DNA repair proteins onto host genome
Wang Z, Castillo-González C, Zhao C, Tong C, Li C, Zhong S, Liu Z, Xie K, Zhu J, Wu Z, Peng X, Jacob Y, Michaels S, Jacobsen S, Zhang X. H3.1K27me1 loss confers Arabidopsis resistance to Geminivirus by sequestering DNA repair proteins onto host genome. Nature Communications 2023, 14: 7484. PMID: 37980416, PMCID: PMC10657422, DOI: 10.1038/s41467-023-43311-1.Peer-Reviewed Original ResearchConceptsDNA repair proteinsDNA repair pathwaysRepair pathwaysRepair proteinsWild-type plantsDefense-related genesArabidopsis resistanceHeterochromatin amplificationHeterochromatic regionsRAD51 recruitmentRep proteinGenomic instabilityHealthy plantsUnstable genomeHost genomeATXR6GeminivirusesRobust resistanceProteinViral amplificationGenomeMutantsViral DNATransposonPlantsLysine Demethylation in Pathogenesis
Cao J, Yan Q. Lysine Demethylation in Pathogenesis. Advances In Experimental Medicine And Biology 2023, 1433: 1-14. PMID: 37751133, DOI: 10.1007/978-3-031-38176-8_1.ChaptersConceptsLysine demethylasesLSD1/KDM1AHistone lysine methylationHistone lysine methyltransferasesMajor epigenetic mechanismsNormal developmentNon-histone substratesSpecific small molecule inhibitorsSmall molecule inhibitorsLysine methylationLysine methyltransferasesHistone methylationHistone lysineLysine demethylationEpigenetic mechanismsDNA repairArginine residuesHuman diseasesMore subfamiliesMolecule inhibitorsLysine modificationDemethylasesMethylationTreatment of cancerEnzymeManipulating mitochondrial electron flow enhances tumor immunogenicity
Mangalhara K, Varanasi S, Johnson M, Burns M, Rojas G, Esparza Moltó P, Sainz A, Tadepalle N, Abbott K, Mendiratta G, Chen D, Farsakoglu Y, Kunchok T, Hoffmann F, Parisi B, Rincon M, Vander Heiden M, Bosenberg M, Hargreaves D, Kaech S, Shadel G. Manipulating mitochondrial electron flow enhances tumor immunogenicity. Science 2023, 381: 1316-1323. PMID: 37733872, PMCID: PMC11034774, DOI: 10.1126/science.abq1053.Peer-Reviewed Original ResearchConceptsElectron transport chainMethylation-controlled J proteinMitochondrial electron transport chainElectron flowMitochondrial electron flowJ-proteinsEpigenetic activationTransport chainMitochondrial respirationTumor growthPresentation genesElectron entryNoncancer cellsMelanoma tumor growthCommon mechanismTherapeutic potentialGenesRelative contributionProteinGrowthKnockoutAntigen presentationRespirationT cell-mediated killingExpressionAcetyl-methyllysine marks chromatin at active transcription start sites
Lu-Culligan W, Connor L, Xie Y, Ekundayo B, Rose B, Machyna M, Pintado-Urbanc A, Zimmer J, Vock I, Bhanu N, King M, Garcia B, Bleichert F, Simon M. Acetyl-methyllysine marks chromatin at active transcription start sites. Nature 2023, 622: 173-179. PMID: 37731000, PMCID: PMC10845139, DOI: 10.1038/s41586-023-06565-9.Peer-Reviewed Original ResearchConceptsPost-translational modificationsLysine residuesActive transcription start sitesTranscription start siteRange of speciesChromatin biologyChromatin proteinsLysine methylationActive chromatinProteins BRD2Transcriptional initiationLysine acetylationHistone H4Start siteMammalian tissuesHuman diseasesSame residuesMethylationAcetylationChromatinResiduesProteinBiological signalsHistonesBRD2TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes
Boutagy N, Fowler J, Grabinska K, Cardone R, Sun Q, Vazquez K, Whalen M, Zhu X, Chakraborty R, Martin K, Simons M, Romanoski C, Kibbey R, Sessa W. TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2218150120. PMID: 37695914, PMCID: PMC10515159, DOI: 10.1073/pnas.2218150120.Peer-Reviewed Original ResearchConceptsPyruvate dehydrogenase kinase 4Dehydrogenase kinase 4Lon proteasePyruvate dehydrogenase activityHistone acetylationMitochondrial metabolismKinase 4Specific gene lociPDH fluxEndothelial cellsSiRNA-mediated knockdownAcetyl-CoA generationLysine 27Gene transcriptionTCA fluxRNA sequencingHuman umbilical vein endothelial cellsProtein degradationHistone 3Gene locusUmbilical vein endothelial cellsNF-κB-dependent mechanismTricarboxylic acid cycle fluxVein endothelial cellsActive subunitMettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue
López A, Ko E, Huang S, Pacella G, Kuprasertkul N, D’souza C, Hueros R, Shen H, Stoute J, Elashal H, Sinkfield M, Anderson A, Prouty S, Li H, Seykora J, Liu K, Capell B. Mettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue. Science Advances 2023, 9: eadg5234. PMID: 37656787, PMCID: PMC10854438, DOI: 10.1126/sciadv.adg5234.Peer-Reviewed Original ResearchConceptsSomatic tissuesMessenger RNALayer of gene regulationHistone modifying enzymesImpaired cell adhesionChromatin modifiersGene regulationAbundant modificationGene expression abnormalitiesHistone modifiersSelf-renewalMethyltransferase-like protein 3Gross phenotypic abnormalitiesModifying enzymesN6</i>-methyladenosineEpithelial developmentCell adhesionPhenotypic abnormalitiesHair follicle morphogenesisProgenitors in vivoProtein 3Expression abnormalitiesOral ulcersEpithelial tissuesFollicle morphogenesisCatalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1
Abini-Agbomson S, Gretarsson K, Shih R, Hsieh L, Lou T, De Ioannes P, Vasilyev N, Lee R, Wang M, Simon M, Armache J, Nudler E, Narlikar G, Liu S, Lu C, Armache K. Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1. Molecular Cell 2023, 83: 2872-2883.e7. PMID: 37595555, DOI: 10.1016/j.molcel.2023.07.020.Peer-Reviewed Original ResearchConceptsNon-catalytic activitiesNon-catalytic mechanismHistone H4 lysine 20Histone variant H2A.ZH4 lysine 20Large macromolecular complexesCatalytic activityHeterochromatin formationHeterochromatin functionVariant H2A.ZLysine 20Nucleosome substratesGenomic stabilityDNA replicationNucleosomal DNAHistone methyltransferaseChromatin condensationSUV420H1Histone octamerMacromolecular complexesCryoelectron microscopyCellular analysisEssential roleDistinct phenotypesCrucial roleTranscriptomic identification of genes expressed in invasive S. aureus diabetic foot ulcer infection
Agidigbi T, Kwon H, Knight J, Zhao D, Lee F, Oh I. Transcriptomic identification of genes expressed in invasive S. aureus diabetic foot ulcer infection. Frontiers In Cellular And Infection Microbiology 2023, 13: 1198115. PMID: 37434783, PMCID: PMC10332306, DOI: 10.3389/fcimb.2023.1198115.Peer-Reviewed Original ResearchConceptsDiabetic foot ulcersPeripheral blood mononuclear cellsHost immune responseActive infectionImmune responseDiabetic foot ulcer infectionsInfected diabetic foot ulcersFoot ulcer infectionsPatients 8 weeksIntravenous antibiotic therapyBlood mononuclear cellsWound healing statusDFU infectionsPBMC expressionSalvage therapyUlcer infectionDifferent time pointsAntibiotic therapyMajor complicationsSurgical treatmentFoot ulcersMononuclear cellsPotential intervention optionsSpecies-specific infectionTreatment responseDOT1L bridges transcription and heterochromatin formation at mammalian pericentromeres
Malla A, Yu H, Farris D, Kadimi S, Lam T, Cox A, Smith Z, Lesch B. DOT1L bridges transcription and heterochromatin formation at mammalian pericentromeres. EMBO Reports 2023, 24: embr202256492. PMID: 37317657, PMCID: PMC10398668, DOI: 10.15252/embr.202256492.Peer-Reviewed Original ResearchConceptsMouse embryonic stem cellsBurst of transcriptionMajor satellite repeatsLong-term silencingRepetitive DNA elementsEmbryonic stem cellsSatellite transcriptionHeterochromatin stabilityHeterochromatin formationHeterochromatin structureChromatin stateSatellite repeatsGenome stabilityGenome integrityPericentromeric repeatsPericentromeric heterochromatinGenome featuresDNA elementsHistone H3Transcriptional activationHistone methyltransferaseRepetitive elementsDOT1L lossRepeat elementsTranscript productionEpigenetic markers and therapeutic targets for metastasis
Kravitz C, Yan Q, Nguyen D. Epigenetic markers and therapeutic targets for metastasis. Cancer And Metastasis Reviews 2023, 42: 427-443. PMID: 37286865, PMCID: PMC10595046, DOI: 10.1007/s10555-023-10109-y.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsEpigenomic alterationsLineage integrityTherapeutic targetEpigenetic markersCancer cellsGenetic aberrationsCurrent knowledgeHuman tumorsMalignant cell cloneTumor progressionDNANumber of discoveriesCell clonesDisseminated diseaseCertain organsPrimary tumorTherapeutic responseMetastatic cancerEpigenomeChromatinHistonesLiquid biopsyAlterationsClonesTargetATR protects centromere identity by promoting DAXX association with PML nuclear bodies
Trier I, Black E, Joo Y, Kabeche L. ATR protects centromere identity by promoting DAXX association with PML nuclear bodies. Cell Reports 2023, 42: 112495. PMID: 37163376, DOI: 10.1016/j.celrep.2023.112495.Peer-Reviewed Original ResearchConceptsCentromere identityInterphase centromeresNuclear bodiesDNA damage-independent mannerPromyelocytic leukemia nuclear bodiesMitotic chromosome segregationCentromere protein AATR inhibitionDNA damage responsePML nuclear bodiesATR-dependent phosphorylationAcute ATR inhibitionChaperone DAXXGenome stabilityChromosome segregationPML-NBsDamage responseUnperturbed cellsMaster regulatorAtaxia telangiectasiaC-terminusFormation defectsCentromeresCENPAberrant increaseDOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacement
Malla A, Rainsford S, Smith Z, Lesch B. DOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacement. Development 2023, 150 PMID: 37082969, PMCID: PMC10259660, DOI: 10.1242/dev.201497.Peer-Reviewed Original ResearchConceptsHistone replacementMale sterilityProtamine exchangeSpermatid differentiationHistone H3 lysine 79Chromatin remodeling factorsRNA polymerase IIH3 lysine 79Expression of genesMature sperm headSperm headPostmeiotic germ cellsHistone methyltransferase DOT1LPolymerase IILysine 79Embryonic lethalityRemodeling factorsProtamine transitionProtamine replacementTranscriptional dysregulationMethyltransferase DOT1LIndispensable regulatorDOT1LHistonesGerm cells
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