2024
X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes
Hasenbein T, Hoelzl S, Smith Z, Gerhardinger C, Gonner M, Aguilar-Pimentel A, Amarie O, Becker L, Calzada-Wack J, Dragano N, da Silva-Buttkus P, Garrett L, Hölter S, Kraiger M, Östereicher M, Rathkolb B, Sanz-Moreno A, Spielmann N, Wurst W, Gailus-Durner V, Fuchs H, Hrabě de Angelis M, Meissner A, Engelhardt S, Rinn J, Andergassen D. X-linked deletion of Crossfirre, Firre, and Dxz4 in vivo uncovers diverse phenotypes and combinatorial effects on autosomes. Nature Communications 2024, 15: 10631. PMID: 39638999, PMCID: PMC11621363, DOI: 10.1038/s41467-024-54673-5.Peer-Reviewed Original ResearchConceptsAutosomal gene regulationRegions genome-wideAllele-specific analysisSex-specific lociLoci in vivoX-linked genesRandom X-chromosome inactivationX-chromosome inactivationSex-specific phenotypesFirre locusGenome-wideIn vivo roleChromatin structureGene regulationX chromosomeEpigenetic featuresDXZ4Epigenetic profilesKnockout studiesLociDiverse phenotypesLncRNA FIRREFunctional roleCombinatorial effectsFIRREAutonomous transposons tune their sequences to ensure somatic suppression
Ilık İ, Glažar P, Tse K, Brändl B, Meierhofer D, Müller F, Smith Z, Aktaş T. Autonomous transposons tune their sequences to ensure somatic suppression. Nature 2024, 626: 1116-1124. PMID: 38355802, PMCID: PMC10901741, DOI: 10.1038/s41586-024-07081-0.Peer-Reviewed Original ResearchConceptsTransposable elementsSAFB proteinsPiwi-interacting RNA pathwayRNA-basedIntronic transposed elementsRNA processing signalsPre-mRNA processingIntronic spaceNested genesPostmeiotic spermatidsAutonomous transposonsDNA transposonsRNA pathwaysCassette exonsSplicing codeSplicing eventsGenome integrityTE exonizationHuman genesL1 elementsRNA synthesisHost genesTissue-specificSAFBSomatic cells
2022
Hijacking of transcriptional condensates by endogenous retroviruses
Asimi V, Sampath Kumar A, Niskanen H, Riemenschneider C, Hetzel S, Naderi J, Fasching N, Popitsch N, Du M, Kretzmer H, Smith ZD, Weigert R, Walther M, Mamde S, Meierhofer D, Wittler L, Buschow R, Timmermann B, Cisse II, Ameres SL, Meissner A, Hnisz D. Hijacking of transcriptional condensates by endogenous retroviruses. Nature Genetics 2022, 54: 1238-1247. PMID: 35864192, PMCID: PMC9355880, DOI: 10.1038/s41588-022-01132-w.Peer-Reviewed Original ResearchConceptsTranscriptional condensatesEndogenous retrovirusesMurine embryonic stem cellsSingle-cell RNA-seq analysisKnockout mouse embryosRNA-seq analysisEmbryonic stem cellsMost endogenous retrovirusesERV RNAsPhase-separated dropletsNascent RNAPluripotency genesPluripotent lineageRNA polymeraseTranscription factorsReconstitution systemTriggers dissociationERV lociMouse embryosMediator coactivatorSelective degradationDisease contextsStem cellsRNASpecific depletion
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
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
2019
In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation
Andergassen D, Smith ZD, Lewandowski JP, Gerhardinger C, Meissner A, Rinn JL. In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation. ELife 2019, 8: e47214. PMID: 31738164, PMCID: PMC6860989, DOI: 10.7554/elife.47214.Peer-Reviewed Original ResearchConceptsX-chromosome inactivationAutosomal gene regulationGene regulationDouble deletionOrgan-specific mannerChromosome inactivationGene setsX chromosomeTranscriptional effectsExpression signaturesLociCell linesDeletionGenesRegulationVivo contributionRecent evidenceMegadomainsAutosomesFIRREMutantsChromosomesMain driversBiologySuperloopsDifferential regulation of OCT4 targets facilitates reacquisition of pluripotency
Thakurela S, Sindhu C, Yurkovsky E, Riemenschneider C, Smith ZD, Nachman I, Meissner A. Differential regulation of OCT4 targets facilitates reacquisition of pluripotency. Nature Communications 2019, 10: 4444. PMID: 31570708, PMCID: PMC6768871, DOI: 10.1038/s41467-019-11741-5.Peer-Reviewed Original ResearchConceptsEctopic transcription factorsReacquisition of pluripotencySomatic cell reprogrammingCis-regulatory elementsTranscription factor expressionExact molecular mechanismsOCT4 targetsPluripotent stem cellsPluripotency inductionCell reprogrammingTranscription factorsSomatic cellsMolecular mechanismsDifferential regulationPluripotencyStem cellsVivo differentiationPrimary targetCellsFactor expressionFinal stepExperimental systemReprogrammingTargetDifferentiationMolecular recording of mammalian embryogenesis
Chan MM, Smith ZD, Grosswendt S, Kretzmer H, Norman TM, Adamson B, Jost M, Quinn JJ, Yang D, Jones MG, Khodaverdian A, Yosef N, Meissner A, Weissman JS. Molecular recording of mammalian embryogenesis. Nature 2019, 570: 77-82. PMID: 31086336, PMCID: PMC7229772, DOI: 10.1038/s41586-019-1184-5.Peer-Reviewed Original ResearchConceptsCell fate mapsComplex multicellular organismsSingle totipotent cellSingle-cell readoutsSingle-cell RNA sequencing profilesEmbryonic progenitor cellsMulticellular organismsMammalian embryogenesisTranscriptional convergenceRNA sequencing profilesTotipotent cellsInternal gestationMammalian systemsAsymmetric partitioningMolecular recordersEndodermal cellsLineage tracerDevelopmental processesLineage informationMolecular recordingSequencing profilesEmbryonic originDifferent tissue typesProgenitor cellsTissue types
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 role
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 ResearchConceptsKrüppel-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
Epigenetic 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
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 modelEmbryosRegulationExpressionIn Vivo and In Vitro Dynamics of Undifferentiated Embryonic Cell Transcription Factor 1
Galonska C, Smith ZD, Meissner A. In Vivo and In Vitro Dynamics of Undifferentiated Embryonic Cell Transcription Factor 1. Stem Cell Reports 2014, 2: 245-252. PMID: 24672748, PMCID: PMC3964277, DOI: 10.1016/j.stemcr.2014.01.007.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiomarkersCell DifferentiationCell LineCellular ReprogrammingChromosomal Proteins, Non-HistoneDNAEmbryo, MammalianEmbryonic Stem CellsGene ExpressionGene Expression Regulation, DevelopmentalGene OrderGenes, ReporterGenetic VectorsMicePluripotent Stem CellsProtein BindingTrans-ActivatorsTranscription FactorsConceptsEmbryonic cell transcription factor 1Transcription factor 1Reporter linesDiverse rolesUndifferentiated embryonic cell transcription factor 1Factor 1Stem cell conditionsPluripotent stem cellsTargeted locusTranscription factorsDynamic regulationGerm layersBiotinylation systemUTF1Stem cellsCell conditionsPluripotencyGermlineLociRegulatorReporterBetter understandingRegulationLinesMajor interest
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 Research