2024
Two 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 analysis
2023
MGMT promoter methylation in 1p19q-intact gliomas
Kinslow C, Siegelin M, Iwamoto F, Gallitto M, Neugut A, Yu J, Cheng S, Wang T. MGMT promoter methylation in 1p19q-intact gliomas. Journal Of Neuro-Oncology 2023, 166: 73-78. PMID: 38114801, DOI: 10.1007/s11060-023-04515-z.Peer-Reviewed Original ResearchConceptsNational Cancer DatabaseMGMT promoter methylationOverall survivalIDH-wildtypeMGMT statusAdjuvant temozolomideAnaplastic gliomasPromoter methylationAssociated with poor survivalAssociation of MGMTClinical efficacy of temozolomideIDH-mutant astrocytomasCox proportional hazards regression modelsIDH-wildtype gliomasKaplan-Meier methodWell-powered prospective studiesMGMT promoter statusEfficacy of temozolomideProportional hazards regression modelsInternational randomized phaseStandard-of-careHazards regression modelsCATNON trialAnaplastic astrocytomaCancer DatabaseManipulating 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 signalsHistonesBRD2MGMT Promoter Methylation Predicts Overall Survival after Chemotherapy for 1p/19q-Codeleted Gliomas.
Kinslow C, Rae A, Taparra K, Kumar P, Siegelin M, Grinband J, Gill B, McKhann G, Sisti M, Bruce J, Canoll P, Iwamoto F, Horowitz D, Kachnic L, Neugut A, Yu J, Cheng S, Wang T. MGMT Promoter Methylation Predicts Overall Survival after Chemotherapy for 1p/19q-Codeleted Gliomas. Clinical Cancer Research 2023, 29: 4399-4407. PMID: 37611077, PMCID: PMC10872921, DOI: 10.1158/1078-0432.ccr-23-1295.Peer-Reviewed Original ResearchConceptsAssociated with worse survivalOverall survivalMGMT promoter statusUnmethylated MGMTWorse survivalPrognostic of progression-free survivalPromoter statusMultivariate Cox proportional hazards regression modelsWorld Health Organization gradeProgression-free survivalNational Cancer DatabaseCox proportional hazards regression modelsMGMT promoter methylationProportional hazards regression modelsGuiding treatment decisionsHazards regression modelsCourse of treatmentPredictive of responseMultiagent chemotherapyMGMT promoterCancer DatabaseMMGMTAlkylating chemotherapyChemotherapyEligible patientsAssociation of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy
Kinslow C, Mercurio A, Kumar P, Rae A, Siegelin M, Grinband J, Taparra K, Upadhyayula P, McKhann G, Sisti M, Bruce J, Canoll P, Iwamoto F, Kachnic L, Yu J, Cheng S, Wang T. Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy. JAMA Oncology 2023, 9: 919-927. PMID: 37200021, PMCID: PMC10196932, DOI: 10.1001/jamaoncol.2023.0990.Peer-Reviewed Original ResearchConceptsProgression-free survivalResponse to alkylating chemotherapyMGMT promoter methylationMGMT promoter statusOverall survivalAnaplastic gliomasIDH-mutantAlkylating chemotherapyLow-gradePromoter methylationChemotherapy responseAssociated with progression-free survivalCohort studyPromoter statusAssociated with chemotherapy responseMultivariate Cox proportional hazards regression modelsClinical trials of patientsO6-methylguanine-DNA methyltransferaseCox proportional hazards regression modelsIDH wild-typeTrial of patientsIDH wild-type gliomasProportional hazards regression modelsO6-methylguanine-DNAProspective cohort studyMETTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells
Xiao Z, Wang S, Tian Y, Lv W, Sheng H, Zhan M, Huang Q, Zhang Z, Zhu L, Zhu C, Zhong H, Wen Q, Liu Z, Tan J, Xu Y, Yang M, Liu Y, Flavell R, Yang Q, Cao G, Yin Z. METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells. Cell Reports 2023, 42: 112684. PMID: 37355989, DOI: 10.1016/j.celrep.2023.112684.Peer-Reviewed Original ResearchConceptsM6A methylationMRNA stabilityΓδ T17 cellsEndogenous double-stranded RNADouble-stranded RNAActivation of STAT1MRNA metabolismMRNA turnoverGene expressionKey enzymeDsRNA contentT17 cellsMethylationFunctional specializationRNA contentΓδ TCritical roleMETTL3Numerous aspectsCellsT17Distinct subsetsM6ATranscriptsRNA7SK methylation by METTL3 promotes transcriptional activity
Perez-Pepe M, Desotell A, Li H, Li W, Han B, Lin Q, Klein D, Liu Y, Goodarzi H, Alarcón C. 7SK methylation by METTL3 promotes transcriptional activity. Science Advances 2023, 9: eade7500. PMID: 37163588, PMCID: PMC10171809, DOI: 10.1126/sciadv.ade7500.Peer-Reviewed Original ResearchConceptsTranscriptional elongationTranscriptional responseAdaptive transcriptional responseHeterogeneous nuclear ribonucleoproteinsElongation factor complexPositive transcription elongation factor complexGrowth factorExtracellular signalsRNA modificationsRNA 7SKEpidermal growth factorCell signalingInduces phosphorylationMethyltransferase 3Nuclear ribonucleoproteinFactor complexTranscriptional activityUnknown functionMethylationMETTL3RibonucleoproteinPhosphorylationTEFbElongationSignaling
2022
Histone H3 proline 16 hydroxylation regulates mammalian gene expression
Liu X, Wang J, Boyer J, Gong W, Zhao S, Xie L, Wu Q, Zhang C, Jain K, Guo Y, Rodriguez J, Li M, Uryu H, Liao C, Hu L, Zhou J, Shi X, Tsai Y, Yan Q, Luo W, Chen X, Strahl B, von Kriegsheim A, Zhang Q, Wang G, Baldwin A, Zhang Q. Histone H3 proline 16 hydroxylation regulates mammalian gene expression. Nature Genetics 2022, 54: 1721-1735. PMID: 36347944, PMCID: PMC9674084, DOI: 10.1038/s41588-022-01212-x.Peer-Reviewed Original ResearchConceptsPost-translational modificationsHistone post-translational modificationsMammalian gene expressionGene expressionHistone H3Mammalian cellsDNA-templated processesTranscriptome-wide analysisTarget gene expressionHydroxylation of prolineWnt/β-cateninChromatin recruitmentHistone codeTarget genesRegulatory marksLysine residuesDirect bindingTriple-negative breast cancerΒ-cateninResidues 16H3ExpressionH3K4me3TrimethylationGenomeRNA methylation in immune cells
Chen Y, Oh M, Flavell R, Li H. RNA methylation in immune cells. Advances In Immunology 2022, 155: 39-94. PMID: 36357012, DOI: 10.1016/bs.ai.2022.08.002.Peer-Reviewed Original ResearchMethylation of microribonucleic acid Let-7b regulatory regions in endometriosis
Meixell DA, Mamillapalli R, Taylor HS. Methylation of microribonucleic acid Let-7b regulatory regions in endometriosis. F&S Science 2022, 3: 197-203. PMID: 35560017, DOI: 10.1016/j.xfss.2022.03.001.Peer-Reviewed Original ResearchThe histone H3.1 variant regulates TONSOKU-mediated DNA repair during replication
Davarinejad H, Huang YC, Mermaz B, LeBlanc C, Poulet A, Thomson G, Joly V, Muñoz M, Arvanitis-Vigneault A, Valsakumar D, Villarino G, Ross A, Rotstein BH, Alarcon EI, Brunzelle JS, Voigt P, Dong J, Couture JF, Jacob Y. The histone H3.1 variant regulates TONSOKU-mediated DNA repair during replication. Science 2022, 375: 1281-1286. PMID: 35298257, PMCID: PMC9153895, DOI: 10.1126/science.abm5320.Peer-Reviewed Original ResearchConceptsTetratricopeptide repeat domainDNA polymerase thetaMulticellular eukaryotesHistone H3.1Replication forksChromatin maturationRepeat domainDNA repairGenomic instabilityPolymerase thetaPosition 31Amino acidsH3.1PlantsReplicationEukaryotesH3.3HistonesMonomethylationVariantsCommon strategyForkResiduesMaturationFunction
2021
METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells
Song H, Song J, Cheng M, Zheng M, Wang T, Tian S, Flavell RA, Zhu S, Li HB, Ding C, Wei H, Sun R, Peng H, Tian Z. METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells. Nature Communications 2021, 12: 5522. PMID: 34535671, PMCID: PMC8448775, DOI: 10.1038/s41467-021-25803-0.Peer-Reviewed Original ResearchMeSH KeywordsAdenosineAnimalsCarcinogenesisCell Line, TumorGene DeletionHomeostasisInterleukin-15Killer Cells, NaturalLymphocytes, Tumor-InfiltratingMethylationMethyltransferasesMice, Inbred C57BLMice, KnockoutNeoplasmsProtein Tyrosine Phosphatase, Non-Receptor Type 11Proto-Oncogene Proteins c-aktRNASignal TransductionTumor MicroenvironmentConceptsAnti-tumor immunityNK cellsTumor-infiltrating NK cellsNK cell infiltrationNatural killer cellsAccelerated tumor developmentExert critical rolesImmunosurveillance functionKiller cellsIL-15Cell infiltrationTumor microenvironmentTumor developmentProtein expressionSuppressed activationM6A RNA methylationEffector moleculesExpression levelsMETTL3Cells altersImmunityM6A methylationCellsPositive correlationHomeostasisUHRF1 regulates alternative splicing by interacting with splicing factors and U snRNAs in a H3R2me involved manner
Xu P, Zhang L, Xiao Y, Li W, Hu Z, Zhang R, Li J, Wu F, Xi Y, Zou Q, Wang Z, Guo R, Ma H, Dong S, Xiao M, Yang Z, Ren X, Wei C, Yu W. UHRF1 regulates alternative splicing by interacting with splicing factors and U snRNAs in a H3R2me involved manner. Human Molecular Genetics 2021, 30: 2110-2122. PMID: 34196368, DOI: 10.1093/hmg/ddab178.Peer-Reviewed Original ResearchConceptsU snRNAsSplicing factorsDNA methylation maintenanceAlternative splicing eventsFunctions of UHRF1RNA splicing regulationAlternative RNA splicingDNA damage repairU2 snRNAMethylation maintenanceProtein interactomeRNA metabolismSplicing regulationRNA splicingSplicing eventsSpliceosome componentsAlternative splicingRNA interactomeUHRF1Chromatin configurationBinding preferencesCell cycleMolecular basisBiological processesMethylation statusMethylation of dual-specificity phosphatase 4 controls cell differentiation
Su H, Jiang M, Senevirathne C, Aluri S, Zhang T, Guo H, Xavier-Ferrucio J, Jin S, Tran NT, Liu SM, Sun CW, Zhu Y, Zhao Q, Chen Y, Cable L, Shen Y, Liu J, Qu CK, Han X, Klug CA, Bhatia R, Chen Y, Nimer SD, Zheng YG, Iancu-Rubin C, Jin J, Deng H, Krause DS, Xiang J, Verma A, Luo M, Zhao X. Methylation of dual-specificity phosphatase 4 controls cell differentiation. Cell Reports 2021, 36: 109421. PMID: 34320342, PMCID: PMC9110119, DOI: 10.1016/j.celrep.2021.109421.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsArginineCell DifferentiationCell LineChildDual-Specificity PhosphatasesEnzyme StabilityFemaleHEK293 CellsHumansMaleMAP Kinase Signaling SystemMegakaryocytesMethylationMice, Inbred C57BLMiddle AgedMitogen-Activated Protein Kinase PhosphatasesMyelodysplastic Syndromesp38 Mitogen-Activated Protein KinasesPolyubiquitinProtein-Arginine N-MethyltransferasesProteolysisRepressor ProteinsUbiquitinationYoung AdultConceptsDual-specificity phosphataseCell differentiationSingle-cell transcriptional analysisP38 MAPKControls cell differentiationE3 ligase HUWE1Knockdown screeningMK differentiationTranscriptional analysisMegakaryocyte differentiationProtein kinaseP38 axisP38 activationPRMT1Transcriptional signatureContext of thrombocytopeniaMK cellsMechanistic insightsPharmacological inhibitionDifferentiationMethylationMAPKPhosphataseUbiquitinylationActivationDMA-tudor interaction modules control the specificity of in vivo condensates
Courchaine EM, Barentine AES, Straube K, Lee DR, Bewersdorf J, Neugebauer KM. DMA-tudor interaction modules control the specificity of in vivo condensates. Cell 2021, 184: 3612-3625.e17. PMID: 34115980, PMCID: PMC8402948, DOI: 10.1016/j.cell.2021.05.008.Peer-Reviewed Original ResearchMultiple Functions of RNA Methylation in T Cells: A Review
Chao Y, Li H, Zhou J. Multiple Functions of RNA Methylation in T Cells: A Review. Frontiers In Immunology 2021, 12: 627455. PMID: 33912158, PMCID: PMC8071866, DOI: 10.3389/fimmu.2021.627455.Peer-Reviewed Original ResearchConceptsRNA methylationRNA modificationsMessenger RNAFate determinationEpigenetic regulationEpigenetic modificationsNoncoding RNAsCell homeostasisUbiquitous mechanismMethylationBiological significanceT cell homeostasisMultiple functionsCell proliferationEssential rolePotential therapeutic strategyRecent findingsRNAImmune responseBiological activityPathological statesT cellsCellsTherapeutic strategiesViral infectionH3.1K27me1 maintains transcriptional silencing and genome stability by preventing GCN5-mediated histone acetylation
Dong J, LeBlanc C, Poulet A, Mermaz B, Villarino G, Webb KM, Joly V, Mendez J, Voigt P, Jacob Y. H3.1K27me1 maintains transcriptional silencing and genome stability by preventing GCN5-mediated histone acetylation. The Plant Cell 2021, 33: 961-979. PMID: 33793815, PMCID: PMC8226292, DOI: 10.1093/plcell/koaa027.Peer-Reviewed Original ResearchConceptsGenome stabilityGenomic instabilityHistone acetylationSAGA-like complexesMultiple lysine residuesArabidopsis GCN5ARABIDOPSIS TRITHORAXArabidopsis thalianaTranscriptional silencingHeterochromatin defectsDouble mutantDNA replicationEpigenetic mechanismsGCN5Molecular roleEssential functionsDiverse rolesMolecular mechanismsLysine residuesProtein 5AcetylationMutantsPlantsADA2bATXR6
2020
Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation
Ryu HY, Zhao D, Li J, Su D, Hochstrasser M. Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation. Nucleic Acids Research 2020, 48: gkaa1093-. PMID: 33231641, PMCID: PMC7708062, DOI: 10.1093/nar/gkaa1093.Peer-Reviewed Original ResearchConceptsHistone deacetylase complexSet3 histone deacetylase complexHistone sumoylationTrans-tail regulationGenome-wide analysisSUMO-interacting motifSUMO conjugation pathwayAltered gene expression profilesDeacetylation of histonesGene expression profilesSet3 complexH2B ubiquitylationDeacetylase complexSpurious transcriptionRNA genesTranscriptional regulationActive genesTranscriptional fidelityTranscription initiationSUMOylationMRNA genesExpression profilesCrosstalk pathwaysHistone deacetylaseGenesOncometabolites suppress DNA repair by disrupting local chromatin signalling
Sulkowski PL, Oeck S, Dow J, Economos NG, Mirfakhraie L, Liu Y, Noronha K, Bao X, Li J, Shuch BM, King MC, Bindra RS, Glazer PM. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 2020, 582: 586-591. PMID: 32494005, PMCID: PMC7319896, DOI: 10.1038/s41586-020-2363-0.Peer-Reviewed Original ResearchConceptsDNA repairDNA breaksFumarate hydrataseDownstream repair factorsHistone 3 lysine 9Homology-dependent repairPoly (ADP-ribose) polymeraseRecruitment of TIP60Deregulation of metabolismChromatin signalingSuccinate dehydrogenase genesGenome integrityLysine 9Repair factorsDehydrogenase geneEnd resectionIsocitrate dehydrogenase 1Aberrant hypermethylationMechanistic basisSomatic mutationsDehydrogenase 1GenesHuman malignanciesProper executionMutations
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