2021
Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages
Andergassen D, Smith ZD, Kretzmer H, Rinn JL, Meissner A. Diverse epigenetic mechanisms maintain parental imprints within the embryonic and extraembryonic lineages. Developmental Cell 2021, 56: 2995-3005.e4. PMID: 34752748, PMCID: PMC9463566, DOI: 10.1016/j.devcel.2021.10.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineageDNA MethylationEctodermEpigenesis, GeneticFemaleGenomic ImprintingHistonesMicePlacentaPregnancyRNA, Long NoncodingConceptsX-chromosome inactivationGenomic imprintingEpigenetic mechanismsEpigenetic pathwaysIndependent gene clustersPolycomb group repressorsDiverse epigenetic mechanismsDistinct gene setsAllele-specific expressionH3K9 methyltransferase G9aAutosomal imprintingChromosomal scaleExtraembryonic lineagesParental imprintsPlacental lineagesGene clusterChromosome inactivationEutherian mammalsMethyltransferase G9aDNA methylationExtraembryonic ectodermGene setsSingle locusX chromosomeDistinct domains
2020
Epigenetic regulator function through mouse gastrulation
Grosswendt S, Kretzmer H, Smith ZD, Kumar AS, Hetzel S, Wittler L, Klages S, Timmermann B, Mukherji S, Meissner A. Epigenetic regulator function through mouse gastrulation. Nature 2020, 584: 102-108. PMID: 32728215, PMCID: PMC7415732, DOI: 10.1038/s41586-020-2552-x.Peer-Reviewed Original ResearchConceptsMutant phenotypePolycomb Repressive Complex 1Single-cell RNA sequencingComplex mutant phenotypesSingle totipotent cellRepressive Complex 1Mutant mouse embryosSpecific transcription factorsMouse gastrulationTranscriptional informationEpigenetic machineryHistone residuesMolecular functionsCellular diversityTotipotent cellsTranscriptional changesTranscription factorsEssential regulatorRNA sequencingDevelopmental roleMouse embryosGenetic templatesRegulator functionSubstantial cooperativityGastrulationTETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers
Charlton J, Jung EJ, Mattei AL, Bailly N, Liao J, Martin EJ, Giesselmann P, Brändl B, Stamenova EK, Müller FJ, Kiskinis E, Gnirke A, Smith ZD, Meissner A. TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers. Nature Genetics 2020, 52: 819-827. PMID: 32514123, PMCID: PMC7415576, DOI: 10.1038/s41588-020-0639-9.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell LineDNA (Cytosine-5-)-MethyltransferasesDNA MethylationDNA Methyltransferase 3AEmbryonic Stem CellsEnhancer Elements, GeneticEpigenesis, GeneticGene Expression Regulation, DevelopmentalGerm LayersHumansMiceMice, KnockoutMixed Function OxygenasesPluripotent Stem CellsProto-Oncogene ProteinsConceptsPluripotent cellsHuman embryonic stem cell linesEmbryonic stem cell linesDNA methylation landscapeEpiblast stem cellsStem cell linesGlobal methylation levelsMethylation landscapeMouse ESCsMammalian cellsRegulatory sequencesDNA methylationSomatic tissuesNegative regulatorTET expressionMethylation levelsDynamic locusStem cellsCell linesLociDemethylationRegulatorEnhancerCellsTet
2018
Global delay in nascent strand DNA methylation
Charlton J, Downing TL, Smith ZD, Gu H, Clement K, Pop R, Akopian V, Klages S, Santos DP, Tsankov AM, Timmermann B, Ziller MJ, Kiskinis E, Gnirke A, Meissner A. Global delay in nascent strand DNA methylation. Nature Structural & Molecular Biology 2018, 25: 327-332. PMID: 29531288, PMCID: PMC5889353, DOI: 10.1038/s41594-018-0046-4.Peer-Reviewed Original ResearchMeSH KeywordsCell CycleCell ProliferationCpG IslandsCytosineDNADNA (Cytosine-5-)-MethyltransferasesDNA MethylationDNA Methyltransferase 3ADNA ReplicationEmbryonic Stem CellsEpigenesis, GeneticGene Expression RegulationGenome, HumanHCT116 CellsHumansMaleMethylationMitosisMotor NeuronsNeoplasmsSequence Analysis, RNATranscription FactorsConceptsCytosine methylationCpG methylationGenome-wide bisulfite sequencingCis-regulatory elementsEmbryonic stem cellsCancer cell line HCT116Cell cycle arrestEpigenetic informationMammalian developmentGene regulationMitotic transmissionEpigenetic heterogeneityEpigenetic roleBisulfite sequencingCell line HCT116DNA methylationHuman cellsMethylationHeterogeneous methylationStem cellsCellsBrdU labelingPronounced lagGlobal reductionImmunoprecipitationGenetic determinants and epigenetic effects of pioneer-factor occupancy
Donaghey J, Thakurela S, Charlton J, Chen JS, Smith ZD, Gu H, Pop R, Clement K, Stamenova EK, Karnik R, Kelley DR, Gifford CA, Cacchiarelli D, Rinn JL, Gnirke A, Ziller MJ, Meissner A. Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nature Genetics 2018, 50: 250-258. PMID: 29358654, PMCID: PMC6517675, DOI: 10.1038/s41588-017-0034-3.Peer-Reviewed Original ResearchMeSH KeywordsA549 CellsBinding SitesCell LineageCells, CulturedComputational BiologyDNAEpigenesis, GeneticEpistasis, GeneticGATA4 Transcription FactorGene Expression RegulationGene Regulatory NetworksGenes, SwitchHEK293 CellsHep G2 CellsHepatocyte Nuclear Factor 3-betaHumansOctamer Transcription Factor-3Protein BindingTranscription FactorsConceptsCell typesAlternative cell typesGenomic occupancyDNA accessibilityPioneer factorsDNA replicationDNA methylationDNA sequencesEpigenetic effectsGene expressionDevelopmental transitionsMolecular componentsGenetic determinantsFOXA2TF activityGATA4Specific bindingExpressionSubsequent lossOccupancyEnrichmentMethylationLociLow enrichmentBinding
2017
Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer
Smith ZD, Shi J, Gu H, Donaghey J, Clement K, Cacchiarelli D, Gnirke A, Michor F, Meissner A. Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature 2017, 549: 543-547. PMID: 28959968, PMCID: PMC5789792, DOI: 10.1038/nature23891.Peer-Reviewed Original Research
2016
Molecular features of cellular reprogramming and development
Smith ZD, Sindhu C, Meissner A. Molecular features of cellular reprogramming and development. Nature Reviews Molecular Cell Biology 2016, 17: 139-154. PMID: 26883001, DOI: 10.1038/nrm.2016.6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCellular ReprogrammingEctopic Gene ExpressionEpigenesis, GeneticHumansNuclear Transfer TechniquesPluripotent Stem CellsConceptsKrüppel-like factor 4Pluripotent stateSRY-box 2Somatic cellsDirect reprogrammingInduced pluripotent stem cell generationDifferentiated cellsPluripotent stem cell generationCis-regulatory elementsStem cell generationAdditional molecular featuresMolecular featuresPluripotent stem cellsChromatin remodellersBivalent chromatinEpigenetic barriersDevelopmental genesCellular identityCellular reprogrammingGenetic modulesEpigenetic regulationCompact chromatinTranscriptional inductionEpigenetic repressorEpigenetic modifiers
2015
Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency
Cacchiarelli D, Trapnell C, Ziller MJ, Soumillon M, Cesana M, Karnik R, Donaghey J, Smith ZD, Ratanasirintrawoot S, Zhang X, Sui S, Wu Z, Akopian V, Gifford CA, Doench J, Rinn JL, Daley GQ, Meissner A, Lander ES, Mikkelsen TS. Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency. Cell 2015, 162: 412-424. PMID: 26186193, PMCID: PMC4511597, DOI: 10.1016/j.cell.2015.06.016.Peer-Reviewed Original ResearchConceptsInduced pluripotencyHuman cellsEmbryonic patterning genesComplementary functional analysesPre-implantation stagesPatterning genesDevelopmental regulatorsEpigenomic analysisMolecular principlesNovel regulatorFunctional analysisIntegrative analysisIntercellular heterogeneityMolecular underpinningsPluripotencyDisease modelingCell platformRegulatorCellsDistinct wavesDonor variabilityGenesEpigenetic predisposition to reprogramming fates in somatic cells
Pour M, Pilzer I, Rosner R, Smith ZD, Meissner A, Nachman I. Epigenetic predisposition to reprogramming fates in somatic cells. EMBO Reports 2015, 16: 370-378. PMID: 25600117, PMCID: PMC4364876, DOI: 10.15252/embr.201439264.Peer-Reviewed Original ResearchConceptsSomatic cellsFactor inductionLive-cell imagingPluripotent stem cellsEpigenetic stateCell identitySuccessful reprogrammingEpigenetic heterogeneityDaughter cellsSister cellsCell lineagesCellular responsesLineagesEZH2 inhibitorsLow-efficiency processColony formationStem cellsEpigenetic predispositionReprogramPopulation levelCellsNovel statistical approachSomatic populationInductionFate
2013
DNA methylation: roles in mammalian development
Smith ZD, Meissner A. DNA methylation: roles in mammalian development. Nature Reviews Genetics 2013, 14: 204-220. PMID: 23400093, DOI: 10.1038/nrg3354.Peer-Reviewed Original ResearchConceptsEmbryonic stem cellsDNA methylationMammalian developmentPaternal genomeEmbryonic lineagesEpigenetic mechanismsPrimordial germ cell specificationDNA methylation erasureDNA methylation functionsKey PointsDNA methylationGerm cell specificationGermline-specific genesGlobal nuclear organizationSimilar epigenetic mechanismsTranscription factor bindingStem cellsPre-implantation stagesAdult stem cellsCpG island methylationMethylation erasureHeritable memoryMethylation functionsCell specificationCpG densityLineage specification
2012
Epigenomics and chromatin dynamics
Akopian V, Chan MM, Clement K, Galonska C, Gifford CA, Lehtola E, Liao J, Samavarchi-Tehrani P, Sindhu C, Smith ZD, Tsankov AM, Webster J, Zhang Y, Ziller MJ, Meissner A. Epigenomics and chromatin dynamics. Genome Biology 2012, 13: 313. PMID: 22364154, PMCID: PMC3334565, DOI: 10.1186/gb-2012-13-2-313.Peer-Reviewed Original Research
2011
Reprogramming Factor Expression Initiates Widespread Targeted Chromatin Remodeling
Koche RP, Smith ZD, Adli M, Gu H, Ku M, Gnirke A, Bernstein BE, Meissner A. Reprogramming Factor Expression Initiates Widespread Targeted Chromatin Remodeling. Cell Stem Cell 2011, 8: 96-105. PMID: 21211784, PMCID: PMC3220622, DOI: 10.1016/j.stem.2010.12.001.Peer-Reviewed Original ResearchConceptsPluripotent stem cell stateEuchromatic histone modificationsRepressive H3K27me3 modificationGenome-wide changesStem cell stateChromatin remodelingH3K4 methylationHistone modificationsH3K27me3 modificationEpigenetic responsesTranscriptional changesSomatic cellsRegulatory eventsGene promoterEpigenetic changesCell statesCorresponding lociSomatic identityMechanistic questionsFactor inductionEarly eventsLociH3K4me2ReprogrammingRapid progress