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 ResearchConceptsX-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
TETs 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
2019
Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression
Tsankov AM, Wadsworth MH, Akopian V, Charlton J, Allon SJ, Arczewska A, Mead BE, Drake RS, Smith ZD, Mikkelsen TS, Shalek AK, Meissner A. Loss of DNA methyltransferase activity in primed human ES cells triggers increased cell-cell variability and transcriptional repression. Development 2019, 146: dev174722. PMID: 31515224, PMCID: PMC6803377, DOI: 10.1242/dev.174722.Peer-Reviewed Original ResearchMeSH KeywordsCell CycleCell DifferentiationDNA (Cytosine-5-)-Methyltransferase 1DNA (Cytosine-5-)-MethyltransferasesDNA MethylationDNA Methyltransferase 3AEnhancer Elements, GeneticEntropyGene Expression Regulation, DevelopmentalHuman Embryonic Stem CellsHumansMaleRepressor ProteinsRNA, MessengerTranscription, GeneticConceptsGlobal methylation levelsTranscriptional repressionSingle-cell RNA-sequencing dataMethylation levelsNew cell fatesMaintenance of pluripotencyHuman embryonic stem cellsMethylation of cytosineRNA-sequencing dataCell-cell variabilityStem cellsEmbryonic stem cellsHuman pluripotent stem cellsDNA methyltransferase activityMRNA expression dataPluripotent stem cellsTranscriptional variabilityMethyltransferases Dnmt3aCell fateEpigenetic regulatorsMethyltransferase DNMT3AExtrinsic signalsHigh-resolution viewMethyltransferase activityProper differentiation
2018
Targets and genomic constraints of ectopic Dnmt3b expression
Zhang Y, Charlton J, Karnik R, Beerman I, Smith ZD, Gu H, Boyle P, Mi X, Clement K, Pop R, Gnirke A, Rossi DJ, Meissner A. Targets and genomic constraints of ectopic Dnmt3b expression. ELife 2018, 7: e40757. PMID: 30468428, PMCID: PMC6251628, DOI: 10.7554/elife.40757.Peer-Reviewed Original ResearchConceptsDNA methylationCpG islandsDe novo DNA methyltransferase DNMT3BCertain CpG islandsDNA methyltransferase DNMT3BGenome-wide dataCpG island hypermethylationDifferent cell typesMammalian genomesChromatin landscapeGenomic constraintsTranscriptional statesCancer methylomeMethyltransferase DNMT3BBisulfite sequencingGenomic targetsIsland hypermethylationResponsible enzymeDNMT3B expressionAberrant methylationDNMT3BMethylationCell typesH3K27me3Essential roleGlobal 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 reductionImmunoprecipitation
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
2014
DNA methylation dynamics of the human preimplantation embryo
Smith ZD, Chan MM, Humm KC, Karnik R, Mekhoubad S, Regev A, Eggan K, Meissner A. DNA methylation dynamics of the human preimplantation embryo. Nature 2014, 511: 611-615. PMID: 25079558, PMCID: PMC4178976, DOI: 10.1038/nature13581.Peer-Reviewed Original ResearchConceptsGenome-scale DNA methylationMaternal-specific methylationDNA methylation dynamicsTransposable element activityEmbryonic stem cell derivationStem cell derivationEarly human embryogenesisHuman preimplantation embryosMethylation dynamicsDNA methylationHuman embryogenesisElement activityPreimplantation embryosCell derivationUnique modeMethylationEmbryogenesisMouse modelEmbryosRegulationExpression
2013
Tet1 Regulates Adult Hippocampal Neurogenesis and Cognition
Zhang RR, Cui QY, Murai K, Lim YC, Smith ZD, Jin S, Ye P, Rosa L, Lee YK, Wu HP, Liu W, Xu ZM, Yang L, Ding YQ, Tang F, Meissner A, Ding C, Shi Y, Xu GL. Tet1 Regulates Adult Hippocampal Neurogenesis and Cognition. Cell Stem Cell 2013, 13: 237-245. PMID: 23770080, PMCID: PMC4474382, DOI: 10.1016/j.stem.2013.05.006.Peer-Reviewed Original ResearchConceptsNeural progenitor cell proliferationProgenitor cell proliferationCohort of genesEmbryonic stem cellsCell proliferationNeural progenitor cellsAdult neural progenitor cellsTET dioxygenasesEpigenetic regulationAdult mouse brainBiological functionsHippocampal neurogenesisProgenitor proliferationTET1DNA hydroxylationStem cellsProgenitor cellsAdult hippocampal neurogenesisAdult brainProliferationMouse brainNeurogenesisImportant roleCellsDioxygenasesProliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging
Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, Rossi DJ. Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging. Cell Stem Cell 2013, 12: 413-425. PMID: 23415915, DOI: 10.1016/j.stem.2013.01.017.Peer-Reviewed Original ResearchConceptsDNA methylationHSC declineHematopoietic stem cell agingPolycomb repressive complex 2DNA methylation landscapeStem cell agingStem cell declineRepressive complex 2Global DNA methylationSite-specific alterationsHematopoietic lineage potentialMethylation landscapeDNA methylomeGenomic regionsLineage potentialEpigenomic alterationsDNA hypermethylationReplicative limitCell agingDownstream progenitorsFunctional analysisFunctional potentialMethylationProliferation of HSCsGenesDNA 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 specificationThe simplest explanation: passive DNA demethylation in PGCs
Smith ZD, Meissner A. The simplest explanation: passive DNA demethylation in PGCs. The EMBO Journal 2013, 32: 318-321. PMID: 23299938, PMCID: PMC3567498, DOI: 10.1038/emboj.2012.349.Peer-Reviewed Original Research
2012
Mouse ooplasm confers context-specific reprogramming capacity
Chan MM, Smith ZD, Egli D, Regev A, Meissner A. Mouse ooplasm confers context-specific reprogramming capacity. Nature Genetics 2012, 44: 978-980. PMID: 22902786, PMCID: PMC3432711, DOI: 10.1038/ng.2382.Peer-Reviewed Original ResearchDNA Methylation Dynamics during In Vivo Differentiation of Blood and Skin Stem Cells
Bock C, Beerman I, Lien WH, Smith ZD, Gu H, Boyle P, Gnirke A, Fuchs E, Rossi DJ, Meissner A. DNA Methylation Dynamics during In Vivo Differentiation of Blood and Skin Stem Cells. Molecular Cell 2012, 47: 633-647. PMID: 22841485, PMCID: PMC3428428, DOI: 10.1016/j.molcel.2012.06.019.Peer-Reviewed Original ResearchConceptsDNA methylationHigh-resolution DNA methylation mapsVivo differentiationLineage-associated transcription factorsAdult stem cell differentiationDNA methylation mapsDNA methylation dynamicsGenome-scale dataCellular differentiation hierarchiesDNA methylation changesStem cellsStem cell differentiationAdult stem cellsTranscription factor activationSkin stem cellsMethylation mapsGenomic distributionMethylation dynamicsDifferentiation hierarchyEpigenetic regulationBlood lineagesTranscription factorsTissue homeostasisMethylation changesGene expressionA unique regulatory phase of DNA methylation in the early mammalian embryo
Smith ZD, Chan MM, Mikkelsen TS, Gu H, Gnirke A, Regev A, Meissner A. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature 2012, 484: 339-344. PMID: 22456710, PMCID: PMC3331945, DOI: 10.1038/nature10960.Peer-Reviewed Original ResearchConceptsDNA methylationGenome-scale DNA methylation mapsLong terminal repeat (LTR) retroelementsDNA methylation mapsBase-resolution mapsEarly mammalian embryoCpG island promotersBlastocyst stageMammalian embryogenesisMethylation mapsPaternal genomeMammalian embryosEpigenetic modificationsEarly embryosSomatic cellsGlobal hypomethylationSomatic patternMouse gametesElement 1MethylationEmbryosMethylation valuesRegulatory phaseGametesZygotesEpigenomics 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 ResearchGel-free multiplexed reduced representation bisulfite sequencing for large-scale DNA methylation profiling
Boyle P, Clement K, Gu H, Smith ZD, Ziller M, Fostel JL, Holmes L, Meldrim J, Kelley F, Gnirke A, Meissner A. Gel-free multiplexed reduced representation bisulfite sequencing for large-scale DNA methylation profiling. Genome Biology 2012, 13: r92. PMID: 23034176, PMCID: PMC3491420, DOI: 10.1186/gb-2012-13-10-r92.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCpG IslandsDNA MethylationGenomeHumansMiceMolecular Sequence DataNIH 3T3 CellsSequence Analysis, DNASulfites
2011
Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling
Gu H, Smith ZD, Bock C, Boyle P, Gnirke A, Meissner A. Preparation of reduced representation bisulfite sequencing libraries for genome-scale DNA methylation profiling. Nature Protocols 2011, 6: 468-481. PMID: 21412275, DOI: 10.1038/nprot.2010.190.Peer-Reviewed Original ResearchMeSH KeywordsCpG IslandsDNA MethylationGene LibraryGenomicsPolymerase Chain ReactionSequence Analysis, DNASulfitesConceptsSingle-nucleotide resolutionGenome-scale DNA methylation profilingCpG-rich DNA fragmentsGenome-wide mappingGenome-wide scaleStandard molecular biology laboratoryMajority of promotersRelevant genomic regionsIllumina Genome AnalyzerNext-generation sequencing approachDNA methylation profilingDNA methylation measurementsRestriction enzyme MspIReduced representationMolecular biology laboratoryGenomic regionsRRBS librariesGenome AnalyzerSequencing librariesMethylation profilingSequencing approachEnzyme MspIAmount of sequencingLow input requirementsGenomic DNAReference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines
Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, Ziller M, Croft GF, Amoroso MW, Oakley DH, Gnirke A, Eggan K, Meissner A. Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines. Cell 2011, 144: 439-452. PMID: 21295703, PMCID: PMC3063454, DOI: 10.1016/j.cell.2010.12.032.Peer-Reviewed Original ResearchMeSH KeywordsCell DifferentiationCell LineDNA MethylationEmbryonic Stem CellsGene Expression ProfilingHumansInduced Pluripotent Stem CellsConceptsPluripotent cell linesEmbryonic stemPluripotent stem cellsCell linesDisease-relevant cell typesHuman iPS cell linesStem cellsReference mapHuman pluripotent stem cellsHuman embryonic stemIPS cell linesDifferentiation propensityDNA methylationIndividual cell linesHigh-throughput characterizationTranscriptional similarityGene expressionIPS cellsCell typesDifferentiation efficiencyDevelopmental potentialBiomedical researchComprehensive characterizationSpecific differencesCells
2010
Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution
Gu H, Bock C, Mikkelsen TS, Jäger N, Smith ZD, Tomazou E, Gnirke A, Lander ES, Meissner A. Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution. Nature Methods 2010, 7: 133-136. PMID: 20062050, PMCID: PMC2860480, DOI: 10.1038/nmeth.1414.Peer-Reviewed Original Research
2009
High-throughput bisulfite sequencing in mammalian genomes
Smith ZD, Gu H, Bock C, Gnirke A, Meissner A. High-throughput bisulfite sequencing in mammalian genomes. Methods 2009, 48: 226-232. PMID: 19442738, PMCID: PMC2864123, DOI: 10.1016/j.ymeth.2009.05.003.Peer-Reviewed Original ResearchConceptsDNA methylationHigh-throughput bisulfite sequencingCritical epigenetic markCpG-dense regionsGenome-wide distributionArray-based technologiesMammalian genomesEpigenetic marksMammalian developmentGenomic regionsRRBS librariesBisulfite sequencingMethylome profilingSequencing librariesRRBS librarySequence analysisMethylationRestriction digestionSequencingGenomeLibraryRelative coverageMspIProfilingSample throughput