2024
Transcription 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 state
2023
Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E
Boddu P, Gupta A, Roy R, De La Pena Avalos B, Herrero A, Zimmer J, Simon M, Chandhok N, King D, Neuenkirchen N, Dray E, Lin H, Kupfer G, Verma A, Neugebauer K, Pillai M. Impaired Early Spliceosome Complex Assembly Underlies Gene Body Elongation Transcription Defect in SF3B1K700E. Blood 2023, 142: 714. DOI: 10.1182/blood-2023-187303.Peer-Reviewed Original ResearchSplicing factorsChIP-seqK562 cell lineKey regulatory genesCell linesSingle mutant alleleNon-denaturing gelsAlternative splicingTranscriptional kineticsRegulatory genesSpliceosome assemblySplicing efficiencyMRNA splicingCRISPR/Progenitor populationsNeomorphic functionsMolecular mechanismsMutant allelesIsoform changesGene editingNovel mechanismMutationsSF mutationsRecurrent mutationsAssembly kinetics
2022
Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus
Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ, Ma S, Spajic A, Dong W, Juusola J, Kiziltug E, Kundishora AJ, Koundal S, Pedram MZ, Torres-Fernández LA, Händler K, De Domenico E, Becker M, Ulas T, Juranek SA, Cuevas E, Hao LT, Jux B, Sousa AMM, Liu F, Kim SK, Li M, Yang Y, Takeo Y, Duque A, Nelson-Williams C, Ha Y, Selvaganesan K, Robert SM, Singh AK, Allington G, Furey CG, Timberlake AT, Reeves BC, Smith H, Dunbar A, DeSpenza T, Goto J, Marlier A, Moreno-De-Luca A, Yu X, Butler WE, Carter BS, Lake EMR, Constable RT, Rakic P, Lin H, Deniz E, Benveniste H, Malvankar NS, Estrada-Veras JI, Walsh CA, Alper SL, Schultze JL, Paeschke K, Doetzlhofer A, Wulczyn FG, Jin SC, Lifton RP, Sestan N, Kolanus W, Kahle KT. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nature Neuroscience 2022, 25: 458-473. PMID: 35379995, PMCID: PMC9664907, DOI: 10.1038/s41593-022-01043-3.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventricular dilatationPrimary defectNeuroepithelial cell differentiationRisk genesCerebrospinal fluid homeostasisWhole-exome sequencingNeuroepithelial stem cellsCortical hypoplasiaReduced neurogenesisVentricular dilatationVentricular enlargementCH mutationsPrenatal hydrocephalusDisease heterogeneityBrain surgeryCSF circulationHydrocephalusGenetic subtypesFluid homeostasisNeuroepithelial cellsNovo mutationsBrain transcriptomicsStem cellsCell differentiationPUMILIO proteins promote colorectal cancer growth via suppressing p21
Gong Y, Liu Z, Yuan Y, Yang Z, Zhang J, Lu Q, Wang W, Fang C, Lin H, Liu S. PUMILIO proteins promote colorectal cancer growth via suppressing p21. Nature Communications 2022, 13: 1627. PMID: 35338151, PMCID: PMC8956581, DOI: 10.1038/s41467-022-29309-1.Peer-Reviewed Original ResearchConceptsColorectal cancerAOM/DSS modelIntestine-specific knockoutColitis-associated cancerHuman CRC cellsOrthotopic colon cancer modelColorectal cancer growthG1/S transitionHuman colorectal cancerColorectal tumor growthColon cancer modelCancer cell growthCRC progressionCRC cellsIntravenous injectionTherapeutic targetCancer growthCancer modelTumor growthSignificant decreaseS transitionDirect targetP21 mRNACancerDSS modelPrecision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies
Biancon G, Joshi P, Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES, Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen N, Lin H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T, Halene S. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Molecular Cell 2022, 82: 1107-1122.e7. PMID: 35303483, PMCID: PMC8988922, DOI: 10.1016/j.molcel.2022.02.025.Peer-Reviewed Original Research
2021
20 years of Developmental Cell: Looking back.
Chory J, Olson EN, Solnica-Krezel L, Munro S, Fuchs E, St Johnston D, Lefebvre V, Coupland G, Millar SE, Lin H. 20 years of Developmental Cell: Looking back. Developmental Cell 2021, 56: 3181-3184. PMID: 34875223, DOI: 10.1016/j.devcel.2021.11.014.Peer-Reviewed Original ResearchMaternal Piwi regulates primordial germ cell development to ensure the fertility of female progeny in Drosophila
Gonzalez LE, Tang X, Lin H. Maternal Piwi regulates primordial germ cell development to ensure the fertility of female progeny in Drosophila. Genetics 2021, 219: iyab091. PMID: 34142134, PMCID: PMC8757300, DOI: 10.1093/genetics/iyab091.Peer-Reviewed Original ResearchConceptsPIWI-interacting RNAsGermline developmentPiwi knockdownPIWI proteinsEarly embryosPiwi/piRNA complexesPIWI/piRNA pathwayFemale progenyPrimordial germ cell developmentGermline sex determinationLoss of PiwiGermline stem cellsDrosophila early embryosGerm cell developmentGerm cell proliferationGonad coalescencePiRNA complexesPiRNA pathwayPiRNA poolTransposon suppressionZygotic genesEmbryonic germlineEmbryonic functionEarly embryogenesisPiwiCPA-seq reveals small ncRNAs with methylated nucleosides and diverse termini
Wang H, Huang R, Li L, Zhu J, Li Z, Peng C, Zhuang X, Lin H, Shi S, Huang P. CPA-seq reveals small ncRNAs with methylated nucleosides and diverse termini. Cell Discovery 2021, 7: 25. PMID: 33867522, PMCID: PMC8053708, DOI: 10.1038/s41421-021-00265-2.Peer-Reviewed Original ResearchSmall noncoding RNAsMethylated nucleosidesHepatic reprogrammingPolynucleotide kinaseHigh-throughput sequencingSRNA transcriptomeTissue-specific differencesSmall ncRNAsT4 polynucleotide kinaseNoncoding RNAsAdapter ligationMouse tissuesAcid pyrophosphataseReprogrammingComplex landscapeMethylationTerminusReverse transcriptionRNASequencingMentorship in Science: Response to AlShebli et al., Nature Communications 2020.
Mummery C, Little M, Lin H, Clark A, Zaret K, Srivastava D, Fuchs E, Watt F, Temple S. Mentorship in Science: Response to AlShebli et al., Nature Communications 2020. Stem Cell Reports 2021, 16: 1-2. PMID: 33440177, PMCID: PMC7815941, DOI: 10.1016/j.stemcr.2020.12.016.Peer-Reviewed Original ResearchRoles of piRNAs in transposon and pseudogene regulation of germline mRNAs and lncRNAs
Wang C, Lin H. Roles of piRNAs in transposon and pseudogene regulation of germline mRNAs and lncRNAs. Genome Biology 2021, 22: 27. PMID: 33419460, PMCID: PMC7792047, DOI: 10.1186/s13059-020-02221-x.Peer-Reviewed Original ResearchConceptsPIWI-interacting RNAsPIWI proteinsRole of piRNAsPIWI-piRNA pathwayRNA-binding proteinSmall noncoding RNAsGermline mRNAsGermline developmentNoncoding RNAsRegulatory relationshipsGerm cellsRNAProteinTransposonMajor classesRNA levelsRecent studiesExpressionGenomeSubfamiliesGermlineLncRNAsMajor constituentsMRNARegulationGenome-wide mapping of Piwi association with specific loci in Drosophila ovaries
Liu N, Neuenkirchen N, Zhong M, Lin H. Genome-wide mapping of Piwi association with specific loci in Drosophila ovaries. G3: Genes, Genomes, Genetics 2021, 11: jkaa059. PMID: 33609367, PMCID: PMC8022938, DOI: 10.1093/g3journal/jkaa059.Peer-Reviewed Original ResearchConceptsPIWI-interacting RNAsProtein-coding genesDrosophila ovaryGermline stem cell maintenanceRole of piRNAsTermination sitesGenome-wide mappingGenomic binding profileTranscriptional termination sitesSpecific genomic sitesStem cell maintenanceRNA pathwaysTransposon repressionTranscriptional startEuchromatic regionsGene regulationEpigenetic regulationGenomic sitesCell maintenancePiwiSpecific lociMethylation signalsDiverse mechanismsTarget siteBinding sitesThe Essential Function of SETDB1 in Homologous Chromosome Pairing and Synapsis during Meiosis
Cheng EC, Hsieh CL, Liu N, Wang J, Zhong M, Chen T, Li E, Lin H. The Essential Function of SETDB1 in Homologous Chromosome Pairing and Synapsis during Meiosis. Cell Reports 2021, 34: 108575. PMID: 33406415, PMCID: PMC8513770, DOI: 10.1016/j.celrep.2020.108575.Peer-Reviewed Original ResearchConceptsEarly meiosisEarly meiotic prophase IFunction of SETDB1Homologous chromosome pairingMeiotic prophase IHistone-lysine N-methyltransferaseMeiotic silencingSurvival of spermatocytesGermline developmentBouquet formationHomologous chromosomesLineage genesChromosome pairingBivalent formationPericentromeric regionProphase IApoptosis of spermatocytesSETDB1Essential functionsHomologous bivalentsH3K9me3Meiotic arrestMeiosisSpermatocytesN-methyltransferaseUltradeep sequencing differentiates patterns of skin clonal mutations associated with sun-exposure status and skin cancer burden
Wei L, Christensen SR, Fitzgerald ME, Graham J, Hutson ND, Zhang C, Huang Z, Hu Q, Zhan F, Xie J, Zhang J, Liu S, Remenyik E, Gellen E, Colegio OR, Bax M, Xu J, Lin H, Huss WJ, Foster BA, Paragh G. Ultradeep sequencing differentiates patterns of skin clonal mutations associated with sun-exposure status and skin cancer burden. Science Advances 2021, 7: eabd7703. PMID: 33523857, PMCID: PMC7775785, DOI: 10.1126/sciadv.abd7703.Peer-Reviewed Original ResearchConceptsSkin cancer riskCancer burdenCancer riskCutaneous squamous cell carcinomaNormal human skin samplesClonal mutationsCarcinogenic effectsSun-exposure statusSquamous cell carcinomaSkin cancer burdenCell carcinomaClonal cell growthNormal skinHuman skin samplesUV exposureUltradeep sequencingUV-induced mutationsSkin samplesCell growthSkinBurdenRiskMutationsExposureUV damage
2020
Piwi in the stem cell niche regulates nurse cell number and oocyte specification
Zhu G, Gonzalez LE, Lin H. Piwi in the stem cell niche regulates nurse cell number and oocyte specification. MicroPublication Biology 2020, 2020: 10.17912/micropub.biology.000327. PMID: 33274324, PMCID: PMC7704254, DOI: 10.17912/micropub.biology.000327.Peer-Reviewed Original ResearchOvarian somatic Piwi regulates nurse cell proliferation and oocyte specification in Drosophila
Gonzalez LE, Zhu G, Lin H. Ovarian somatic Piwi regulates nurse cell proliferation and oocyte specification in Drosophila. MicroPublication Biology 2020, 2020: 10.17912/micropub.biology.000324. PMID: 33274329, PMCID: PMC7704259, DOI: 10.17912/micropub.biology.000324.Peer-Reviewed Original ResearchPIWIL1 promotes gastric cancer via a piRNA-independent mechanism
Shi S, Yang ZZ, Liu S, Yang F, Lin H. PIWIL1 promotes gastric cancer via a piRNA-independent mechanism. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 22390-22401. PMID: 32848063, PMCID: PMC7486755, DOI: 10.1073/pnas.2008724117.Peer-Reviewed Original ResearchConceptsPIWI-interacting RNAsPIWI proteinsGastric cancer cellsNonsense-mediated mRNA decay mechanismPiRNA-independent mechanismDomain protein familyMRNA decay mechanismMammalian somatic tissuesRNA deep sequencingGastric cancer cell line SNU-1Cancer cellsGastric cancer cell proliferationRNA pathwaysPPD proteinsProtein familyPiwil1 geneSomatic tissuesSomatic cancersCancer cell proliferationDeep sequencingRegulatory mechanismsOncogenic functionPIWIL1Gastric cancer tissuesDetectable functionMIWI prevents aneuploidy during meiosis by cleaving excess satellite RNA
Hsieh C, Xia J, Lin H. MIWI prevents aneuploidy during meiosis by cleaving excess satellite RNA. The EMBO Journal 2020, 39: embj2019103614. PMID: 32677148, PMCID: PMC7429737, DOI: 10.15252/embj.2019103614.Peer-Reviewed Original ResearchConceptsChromosome misalignmentSatellite RNAKinetochore assemblySatellite repeatsWild-type spermatocytesPericentromeric satellite repeatsFaithful chromosome segregationProper kinetochore assemblyChromosome mis-segregationPost-transcriptional regulationPiRNA biogenesisMeiotic functionsPIWI proteinsChromosome segregationMis-segregationMurine memberElevated aneuploidyMale meiosisPrevents aneuploidyDicer cleavageMIWIMetaphase IRNA fragmentsMeiosisRNAPumilio proteins utilize distinct regulatory mechanisms to achieve complementary functions required for pluripotency and embryogenesis
Uyhazi KE, Yang Y, Liu N, Qi H, Huang XA, Mak W, Weatherbee SD, de Prisco N, Gennarino VA, Song X, Lin H. Pumilio proteins utilize distinct regulatory mechanisms to achieve complementary functions required for pluripotency and embryogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 7851-7862. PMID: 32198202, PMCID: PMC7148564, DOI: 10.1073/pnas.1916471117.Peer-Reviewed Original ResearchConceptsEmbryonic stem cellsTarget messenger RNAsPumilio proteinsPUM proteinsMessenger RNAEssential functionsStem cell maintenanceDistinct regulatory mechanismsEmbryonic day 8.5ESC pluripotencyTranslational regulatorPluripotency genesGene regulationEarly embryogenesisDifferentiation genesPosttranscriptional levelHigh homologyMRNA stabilityRegulatory mechanismsDouble mutant micePluripotencyDay 8.5Morula stagePluripotency markersEmbryogenesisDevelopment of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance
Sun N, Ren C, Kong Y, Zhong H, Chen J, Li Y, Zhang J, Zhou Y, Qiu X, Lin H, Song X, Yang X, Jiang B. Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance. European Journal Of Medicinal Chemistry 2020, 193: 112190. PMID: 32179332, DOI: 10.1016/j.ejmech.2020.112190.Peer-Reviewed Original ResearchMeSH KeywordsAnaplastic Lymphoma KinaseAntineoplastic AgentsCarcinoma, Non-Small-Cell LungCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug DevelopmentDrug Resistance, NeoplasmDrug Screening Assays, AntitumorHEK293 CellsHumansLung NeoplasmsMolecular Docking SimulationMolecular StructureProtein Kinase InhibitorsStructure-Activity RelationshipConceptsAnaplastic large cell lymphomaCell lung cancerLung cancerALK proteinNon-small cell lung cancerDrug resistanceSmall cell lung cancerLarge cell lymphomaPotential therapeutic strategyAnti-proliferation abilityCell linesNPM-ALK fusion proteinT cell linesCancer cell linesEML4-ALKCancer regressionTherapeutic strategiesPotential treatmentGrowth inhibition effectInhibitor drugsALK activityCancerCancer resistanceBrigatinibLymphomaPIWI–piRNA pathway-mediated transposable element repression in Hydra somatic stem cells
Teefy BB, Siebert S, Cazet JF, Lin H, Juliano CE. PIWI–piRNA pathway-mediated transposable element repression in Hydra somatic stem cells. RNA 2020, 26: 550-563. PMID: 32075940, PMCID: PMC7161359, DOI: 10.1261/rna.072835.119.Peer-Reviewed Original ResearchConceptsPIWI-piRNA pathwayTE expressionSomatic stem cellsTransposable elementsTE transcriptsStem cellsFreshwater cnidarianSmall RNA pathwaysTransposable element repressionSomatic cell lineagesGermline of animalsInterstitial stem cellsStem cell populationInterstitial lineageSomatic piRNAsDegradome sequencingEpithelial cellsAncestral functionRNA pathwaysGermline piRNAsPIWI proteinsTE repressionGermline competenceSequence signaturesRNA immunoprecipitation