2023
DOT1L 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 productionDOT1L 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
2021
Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions
Chandrasekaran S, Espeso-Gil S, Loh YE, Javidfar B, Kassim B, Zhu Y, Zhang Y, Dong Y, Bicks LK, Li H, Rajarajan P, Peter CJ, Sun D, Agullo-Pascual E, Iskhakova M, Estill M, Lesch BJ, Shen L, Jiang Y, Akbarian S. Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions. Nature Communications 2021, 12: 7243. PMID: 34903713, PMCID: PMC8669064, DOI: 10.1038/s41467-021-26862-z.Peer-Reviewed Original ResearchConceptsCellular stress response genesOpen chromatin domainsChromatin domain organizationRepeat-rich sequencesStress response genesRetrotransposon expansionsSPRET/EiJChromatin domainsChromosomal architectureChromosomal conformationDomain organizationAdult mouse cerebral cortexMurine germlineTranscriptional dysregulationResponse genesRegulatory mechanismsMus musculusMature neuronsNeuronal ablationStrong enrichmentMouse cerebral cortexSequenceSETDB1Single moleculesGermline
2019
A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of a sox-2-activating factor
Alqadah A, Hsieh YW, Xiong R, Lesch BJ, Chang C, Chuang CF. A universal transportin protein drives stochastic choice of olfactory neurons via specific nuclear import of a sox-2-activating factor. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 25137-25146. PMID: 31767767, PMCID: PMC6911211, DOI: 10.1073/pnas.1908168116.Peer-Reviewed Original ResearchConceptsBK potassium channelsNuclear importUnbiased forward genetic screenSpecific nuclear importForward genetic screenCell fate choiceTranscription factor SOX-2Notch-independent mechanismStructure-function insightsPotassium channelsHigh mobility groupProtein kinase pathwayAmino acid residuesAWC asymmetryGenetic screenFunction mutantsHuman neurological disordersAWC neuronsFate choiceKinase pathwayBiological processesAcid residuesMobility groupCalcium signalingSox-2Intergenerational epigenetic inheritance of cancer susceptibility in mammals
Lesch BJ, Tothova Z, Morgan EA, Liao Z, Bronson RT, Ebert BL, Page DC. Intergenerational epigenetic inheritance of cancer susceptibility in mammals. ELife 2019, 8: e39380. PMID: 30963999, PMCID: PMC6456297, DOI: 10.7554/elife.39380.Peer-Reviewed Original ResearchConceptsGerm lineEpigenetic changesParental germ lineIntergenerational epigenetic inheritanceRegulation of genesPaternal germ lineCancer susceptibilityChromatin regulatorsEpigenetic inheritanceH3K27me3 marksHypermethylated regionsDNA methylationSomatic tissuesMale gametesElevated tumor incidenceCancer initiationGenetic variantsGermline deletionMutantsHeritabilityDeletionSuccessive generationsSpermOffspringWild-type mice
2016
Parallel evolution of male germline epigenetic poising and somatic development in animals
Lesch BJ, Silber SJ, McCarrey JR, Page DC. Parallel evolution of male germline epigenetic poising and somatic development in animals. Nature Genetics 2016, 48: 888-894. PMID: 27294618, DOI: 10.1038/ng.3591.Peer-Reviewed Original Research
2014
Poised chromatin in the mammalian germ line
Lesch BJ, Page DC. Poised chromatin in the mammalian germ line. Development 2014, 141: 3619-3626. PMID: 25249456, PMCID: PMC4197577, DOI: 10.1242/dev.113027.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMammalian germ lineGerm cell identityCell identityGerm lineMammalian germ cellsEmbryonic stem cellsChromatin stateEpigenetic inheritanceHistone modificationsRegulatory genesGene activationDNA methylationEpigenetic featuresChromatinGerm cellsStem cellsSomatic developmentGenesPromoterFetal stageTotipotencyCellsMeiosisGametogenesisRepressionA Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response
Alpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, Stützer A, Armache KJ, Simon MD, Xu C, Ali M, Murn J, Prisic S, Kutateladze TG, Vakoc CR, Min J, Kingston RE, Fischle W, Warren ST, Page DC, Shi Y. A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response. Cell 2014, 157: 869-881. PMID: 24813610, PMCID: PMC4038154, DOI: 10.1016/j.cell.2014.03.040.Peer-Reviewed Original ResearchConceptsDNA damage responseMental retardation protein FMRPProtein FMRPFragile X syndromeDDR machineryDamage responseChromatin-binding proteinsTandem Tudor domainTranslation of proteinsX syndromeChromatin interfaceFMRP bindsTudor domainMeiotic chromosomesGenomic stabilityFMRPDevelopmental processesMouse spermatogenesisGametogenesisDependent mannerSynaptic functionMachineryProteinChromatinImportant role
2013
A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis
Lesch BJ, Dokshin GA, Young RA, McCarrey JR, Page DC. A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 16061-16066. PMID: 24043772, PMCID: PMC3791702, DOI: 10.1073/pnas.1315204110.Peer-Reviewed Original ResearchConceptsSet of genesGerm cellsPostmeiotic male germ cellsGerm line nucleiSexual differentiationRNA-seq analysisFemale germ cellsSubset of genesEmbryonic stem cellsMale germ cellsRegulators of differentiationEnd of meiosisCompletion of meiosisMouse germ cellsTotipotent zygoteDifferentiated gametesMulticellular organismsGamete precursorsDevelopmental genesChIP-seqGerm lineGamete unionExtraembryonic tissuesMeiotic initiationPostmeiotic cellsThe Ligand Binding Domain of GCNF Is Not Required for Repression of Pluripotency Genes in Mouse Fetal Ovarian Germ Cells
Okumura LM, Lesch BJ, Page DC. The Ligand Binding Domain of GCNF Is Not Required for Repression of Pluripotency Genes in Mouse Fetal Ovarian Germ Cells. PLOS ONE 2013, 8: e66062. PMID: 23762465, PMCID: PMC3676325, DOI: 10.1371/journal.pone.0066062.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDown-RegulationExonsFemaleFetusGene Expression Regulation, DevelopmentalGene TargetingGerm CellsHomeodomain ProteinsLigandsMeiosisMiceMice, Inbred C57BLMice, Mutant StrainsMutationNanog Homeobox ProteinNuclear Receptor Subfamily 6, Group A, Member 1Octamer Transcription Factor-3OogenesisOvaryPhenotypePluripotent Stem CellsProtein BindingProtein Structure, TertiarySequence DeletionStructure-Activity RelationshipConceptsFetal ovarian germ cellsOvarian germ cellsPluripotency genesSomatic cellsGerm cellsSilencing of Oct4Initiation of meiosisEmbryonic stem cellsLigand binding domainsGCNF geneEmbryonic day 14.5Tamoxifen-inducible CreDifferent developmental timepointsBinding domainsDifferentiated stateGCNFDevelopmental timepointsNanogGenesConditional ablationStem cellsDay 14.5CellsExpressionE8.0
2012
Genetics of germ cell development
Lesch BJ, Page DC. Genetics of germ cell development. Nature Reviews Genetics 2012, 13: 781-794. PMID: 23044825, DOI: 10.1038/nrg3294.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsGerm cell developmentGerm cellsHaploid genomeMultiple speciesCell developmentPluripotent stem cell systemsRepressive chromatin configurationGerm cell identityRNA polymerase IIGerm cell biologyStem cell systemEarly germ cellsPolymerase IICell identityDiploid genomeChromatin configurationIndividual organismsCell biologyMitotic proliferationGenomeSame speciesDifferent speciesGermline precursorsLater stepsMeiosis