2023
HEXIM1 is an essential transcription regulator during human erythropoiesis
Lv X, Murphy K, Murphy Z, Getman M, Rahman N, Nakamura Y, Blanc L, Gallagher P, Palis J, Mohandas N, Steiner L. HEXIM1 is an essential transcription regulator during human erythropoiesis. Blood 2023, 142: 2198-2215. PMID: 37738561, PMCID: PMC10733840, DOI: 10.1182/blood.2022019495.Peer-Reviewed Original ResearchConceptsFetal globin expressionGene expressionGlobin expressionCycle progressionErythroid gene expressionBeta-globinBeta-globin locusGenome-wide profilingRNA polymerase II activityLong non-coding RNANon-coding RNAErythroid proliferationPolymerase II activityCell cycle progressionEssential transcription regulatorRNAPII activityRNAPII occupancyGlobin locusTranscription machineryTranscription regulatorsFetal globinRNAPIIFetal gene expressionHEXIM1Human erythropoiesisIdentification of a Novel Gene Regulatory Element in Human Erythroid Progenitor Cells
Schulz V, Lezon-Geyda K, Shan P, Papoin J, Narla M, Steiner L, Blanc L, Palis J, Gallagher P. Identification of a Novel Gene Regulatory Element in Human Erythroid Progenitor Cells. Blood 2023, 142: 9. DOI: 10.1182/blood-2023-186046.Peer-Reviewed Original ResearchErythroid progenitor cellsActive enhancersEarly erythropoiesisChIP-seqRegulatory elementsGene expressionATAC-seqRUNX motifsGATA motifSingle nucleotide polymorphismsProgenitor cellsGATA1 bindingDisease genesEnhancer regionErythroid lineageTissue-specific transcription factorsNovel gene regulatory elementsNovel enhancer regionErythrocyte traitsGenome-wide association studiesDirect tissue-specific expressionNovel regulatory elementGene regulatory elementsHuman erythroid progenitor cellsTerminal erythroid differentiation
2021
Regulation of RNA polymerase II activity is essential for terminal erythroid maturation
Murphy ZC, Murphy K, Myers J, Getman M, Couch T, Schulz VP, Lezon-Geyda K, Palumbo C, Yan H, Mohandas N, Gallagher PG, Steiner LA. Regulation of RNA polymerase II activity is essential for terminal erythroid maturation. Blood 2021, 138: 1740-1756. PMID: 34075391, PMCID: PMC8569412, DOI: 10.1182/blood.2020009903.Peer-Reviewed Original ResearchConceptsRNA polymerase IIRNA polymerase II activityTerminal erythroid maturationPolymerase II activityPolymerase IIErythroid maturationHuman erythroblastsGene expressionTerminal maturationII activityStage-specific regulationHistone posttranslational modificationsTransposase-accessible chromatinErythroid-specific genesAccumulation of heterochromatinHigh-throughput sequencingLevel of transcriptionLate-stage erythroblastsEssential biologic processesAccessible chromatinHistone marksTranscription elongationChromatin structureTranscriptional repressionChromatin immunoprecipitationImpairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency
Wang Y, Li W, Schulz VP, Zhao H, Qu X, Qi Q, Cheng Y, Guo X, Zhang S, Wei X, Liu D, Yazdanbakhsh K, Hillyer CD, Mohandas N, Chen L, Gallagher PG, An X. Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency. Blood 2021, 138: 1615-1627. PMID: 34036344, PMCID: PMC8554652, DOI: 10.1182/blood.2020007401.Peer-Reviewed Original ResearchConceptsTerminal erythroid differentiationChromatin condensationErythroid differentiationHuman erythroid cellsAcetylation of H4RNA sequencing analysisEnucleation of erythroblastsGroup of enzymesLate-stage erythroblastsErythroid cell culturesHDAC family membersActivation of p53Short hairpin RNAChromatin accessibilityATAC-seqMammalian erythropoiesisH4 deacetylationNonhistone proteinsH4 acetylationDiverse functionsHDAC inhibitor treatmentHuman erythropoiesisKnockdown of HDAC5Erythroid cellsGene expression
2019
Terminal Erythroid Maturation Is Associated with Dynamic Changes in the Abundance of Histone Marks Associated with Active Transcription Elongation and RNA Polymerase II Pausing
Murphy Z, Couch T, Lillis J, Getman M, Lezon-Geyda K, Schulz V, Narla M, Gallagher P, Steiner L. Terminal Erythroid Maturation Is Associated with Dynamic Changes in the Abundance of Histone Marks Associated with Active Transcription Elongation and RNA Polymerase II Pausing. Blood 2019, 134: 154. DOI: 10.1182/blood-2019-129561.Peer-Reviewed Original ResearchRNA polymerase II pausingTerminal erythroid maturationPol IIC-terminal domainErythroid maturationGene expressionTranscription elongationPosttranslational modificationsSpecific histone posttranslational modificationsPol II C-terminal domainRNA polymerase II pause releaseKey regulatorHistone H4 lysine 16 acetylationHistone H4 lysine 20Histone post-translational modificationsH4 lysine 16 acetylationHistone H3 lysine 79H4 lysine 20Histone posttranslational modificationsRNA Pol IIH3 lysine 79Multiple histone marksPost-translational modificationsTranscription start siteChIP-seq dataA Unique Epigenomic Landscape Defines Human Erythropoiesis
Schulz VP, Yan H, Lezon-Geyda K, An X, Hale J, Hillyer CD, Mohandas N, Gallagher PG. A Unique Epigenomic Landscape Defines Human Erythropoiesis. Cell Reports 2019, 28: 2996-3009.e7. PMID: 31509757, PMCID: PMC6863094, DOI: 10.1016/j.celrep.2019.08.020.Peer-Reviewed Original ResearchMeSH KeywordsChromatinChromatin Assembly and DisassemblyDNA MethylationEpigenesis, GeneticErythroid CellsErythropoiesisGene Expression ProfilingGene Expression RegulationHematologic DiseasesHematopoietic Stem CellsHumansMultigene FamilyPolymorphism, Single NucleotideRegulatory Sequences, Nucleic AcidTranscriptomeConceptsChromatin accessibilityDNA methylationHuman erythropoiesisStage-specific gene regulationErythroid cellsPrimary human erythroid cellsChromatin state dynamicsCell typesCis-regulatory elementsGenome-wide studiesSpecialized cell typesHuman erythroid cellsCell phenotypic variationNonhematopoietic cell typesChromatin primingErythroid genesEpigenomic landscapeGene regulationMammalian erythropoiesisPhenotypic variationTranscriptome dataOrganismal needsRegulation of erythropoiesisNonpromoter sitesGene expression
2016
CTCF and CohesinSA-1 Mark Active Promoters and Boundaries of Repressive Chromatin Domains in Primary Human Erythroid Cells
Steiner LA, Schulz V, Makismova Y, Lezon-Geyda K, Gallagher PG. CTCF and CohesinSA-1 Mark Active Promoters and Boundaries of Repressive Chromatin Domains in Primary Human Erythroid Cells. PLOS ONE 2016, 11: e0155378. PMID: 27219007, PMCID: PMC4878738, DOI: 10.1371/journal.pone.0155378.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCCCTC-Binding FactorCells, CulturedChromatinChromatin ImmunoprecipitationErythroid CellsErythropoiesisGene Expression ProfilingHematopoietic Stem CellsHigh-Throughput Nucleotide SequencingHumansK562 CellsNuclear ProteinsPromoter Regions, GeneticProtein BindingProtein Interaction MapsRepressor ProteinsSequence Analysis, RNAConceptsPrimary human erythroid cellsRepressive chromatin domainsHuman erythroid cellsChromatin domainsErythroid cellsChromatin architectureGene promoterGene expressionPrimary human hematopoietic stemCell type-specific mannerCritical cellular processesSites of CTCFGenome-wide dataHigh-throughput sequencingMRNA transcriptome analysisHuman hematopoietic stemRepressive chromatinCohesin sitesProtein occupancyInsulator functionRepressive domainsTranscriptional regulationCTCF sitesDomain architectureRelated gene expression
2014
Assessment of HbF QTLs Affecting Disease Severity and Genetic Analysis in Patients Homozygous for Codon 8 (–AA) β0-Thalassemia Mutation
Jiang Z, Huang S, Luo H, Akar N, Basak A, Al-Allawi N, Unal S, Gumruk F, Davis L, Morrison T, Campbell A, Gallagher P, Forget B, Steinberg M, Chui D. Assessment of HbF QTLs Affecting Disease Severity and Genetic Analysis in Patients Homozygous for Codon 8 (–AA) β0-Thalassemia Mutation. Blood 2014, 124: 2690. DOI: 10.1182/blood.v124.21.2690.2690.Peer-Reviewed Original ResearchQuantitative trait lociGene clusterIntergenic regionHbF quantitative trait lociΓ-globin gene expressionKb intergenic regionSevere phenotypeMild phenotypeHBS1L-MYB intergenic regionΒ-globin gene clusterGenome-wide SNP arraysMild disease phenotypeDisease phenotypeMinor alleleWhole-genome sequencingTrait lociHPFH mutationNovel SNPsGenetic analysisSNP arrayGene expressionΒ-hemoglobinopathiesGenome sequencingQTL genotypesWhole-exome sequencingGlobal transcriptome analyses of human and murine terminal erythroid differentiation
An X, Schulz VP, Li J, Wu K, Liu J, Xue F, Hu J, Mohandas N, Gallagher PG. Global transcriptome analyses of human and murine terminal erythroid differentiation. Blood 2014, 123: 3466-3477. PMID: 24637361, PMCID: PMC4041167, DOI: 10.1182/blood-2014-01-548305.Peer-Reviewed Original ResearchConceptsTerminal erythroid differentiationErythroid differentiationGene expressionMurine terminal erythroid differentiationStage-specific transcriptomesDifferentiation stageGlobal transcriptome analysisStage-specific patternsRNA sequencing analysisGene expression profilesDistinct developmental stagesMurine transcriptomesFluorescence-activated cell sortingTranscriptional spaceErythroid developmentMurine erythroblastsTranscriptome analysisUnique transcriptomeBioinformatics analysisPerturbed erythropoiesisTranscriptomeExpression profilesErythroid disordersDevelopmental stagesSequencing analysisLong noncoding RNAs in erythropoiesis
Gallagher PG. Long noncoding RNAs in erythropoiesis. Blood 2014, 123: 465-466. PMID: 24458276, DOI: 10.1182/blood-2013-12-538306.Peer-Reviewed Original Research
2013
Enhancers and Super Enhancers Are Associated With Genes That Control Phenotypic Traits In Primary Human Erythroid Cells
Schulz V, Lezon-Geyda K, Maksimova Y, Gallagher P. Enhancers and Super Enhancers Are Associated With Genes That Control Phenotypic Traits In Primary Human Erythroid Cells. Blood 2013, 122: 1200. DOI: 10.1182/blood.v122.21.1200.1200.Peer-Reviewed Original ResearchTranscriptional start siteRegulation of programsSuper enhancersErythroid cellsGene expressionErythroid enhancerTF motifsTranscription factorsHistone H3 lysine 4 monomethylationSpecific enhancersH3K27ac modificationGWAS catalogGene locusHistone H3 lysine 27 acetylationCell type-specific enhancersPrimary human erythroid cellsH3 lysine 27 acetylationAlpha-globin gene clusterDisease-associated genetic variantsGenome-wide mapsNHGRI GWAS catalogSubset of enhancersHundreds of kilobasesLysine 27 acetylationSpecialized cell types
2012
Identification of Biologicaly Relevant Enhancers in Human Erythroid Cells
Su M, Steiner L, Bogardus H, Schulz V, Hardison R, Gallagher P. Identification of Biologicaly Relevant Enhancers in Human Erythroid Cells. Blood 2012, 120: 368. DOI: 10.1182/blood.v120.21.368.368.Peer-Reviewed Original ResearchTranscriptional start siteHuman erythroid cellsCell type-specific enhancersErythroid transcription factorsErythroid-specific genesTranscription factorsErythroid cellsCandidate enhancersSpecific enhancersSignificant enrichmentGene expressionPrimary human erythroid cellsRegulation of programsDisease-associated genetic variantsGenome-wide mapsHundreds of kilobasesSpecialized cell typesTranscription factor sitesKb of genesGene expression analysisParallel gene expression analysisGenomic vicinityGenomic methodologiesEvolutionary analysisHigh conservationMKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation
Smith EC, Thon JN, Devine MT, Lin S, Schulz VP, Guo Y, Massaro SA, Halene S, Gallagher P, Italiano JE, Krause DS. MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation. Blood 2012, 120: 2317-2329. PMID: 22806889, PMCID: PMC3447785, DOI: 10.1182/blood-2012-04-420828.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine DiphosphateAnimalsBleeding TimeBlood PlateletsBone Marrow CellsCells, CulturedCrosses, GeneticCytoplasmCytoskeletonGene Expression ProfilingHematopoiesisMegakaryocytesMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisPlatelet ActivationThrombocytopeniaTrans-ActivatorsTranscription FactorsConceptsMegakaryocyte maturationPlatelet formationSerum response factorSerum response factor expressionMembrane organizationGene expressionMKL1MKL2Response factorDKO miceKO backgroundMegakaryocyte compartmentMegakaryocytesCritical roleMegakaryocyte ploidyExpressionMaturationKnockout miceFactor expressionCrucial roleHomologuesGenesMiceProlonged bleeding timeRole
2011
Patterns of Histone H3 Lysine 27 Monomethylation and Erythroid Cell Type-specific Gene Expression*
Steiner LA, Schulz VP, Maksimova Y, Wong C, Gallagher PG. Patterns of Histone H3 Lysine 27 Monomethylation and Erythroid Cell Type-specific Gene Expression*. Journal Of Biological Chemistry 2011, 286: 39457-39465. PMID: 21937433, PMCID: PMC3234769, DOI: 10.1074/jbc.m111.243006.Peer-Reviewed Original ResearchConceptsTranscription start siteCell type-specific gene expressionGene expressionHistone modificationsType-specific gene expressionPost-translational histone modificationsHistone H3 lysine 27Numerous cellular processesH3 lysine 27Gene-specific patternsSpecific gene expressionContext-dependent mannerExpression array analysisChromatin signaturesGene bodiesH3K27 monomethylationActive genesActive transcriptionCellular processesChromatin immunoprecipitationIndividual genesLysine 27Start siteChip microarrayErythroid cells
2010
Dynamic CO-Localization of GATA1, NFE2, and EKLF and Changes in Gene Expression During Hematopoiesis
Steiner L, Schulz V, Maksimova Y, Mahajan M, Bodine D, Gallagher P. Dynamic CO-Localization of GATA1, NFE2, and EKLF and Changes in Gene Expression During Hematopoiesis. Blood 2010, 116: 741. DOI: 10.1182/blood.v116.21.741.741.Peer-Reviewed Original ResearchErythroid cellsGene expressionTranscription factorsProximal promoterCell type-specific gene expressionHuman beta-globin gene locusBeta-globin gene locusErythrocyte membrane protein genesErythroid-expressed genesGenome-wide scaleGlobin gene locusDNA-protein interactionsHuman primary erythroid cellsNF-E2Primary erythroid cellsMembrane protein geneSpecific gene expressionCritical regulatory elementsPrimary hematopoietic stemCommon regulatory siteUltrahigh-throughput sequencingLineage choiceChromatin immunoprecipitationCoordinated bindingEKLF
2009
Patterns of Monomethylation of Histone H3 Lysine 27 Influence Gene Expression in a Cell-Type Specific Manner.
Steiner L, Schulz V, Maksimova Y, Wong C, Tuck D, Gallagher P. Patterns of Monomethylation of Histone H3 Lysine 27 Influence Gene Expression in a Cell-Type Specific Manner. Blood 2009, 114: 4585. DOI: 10.1182/blood.v114.22.4585.4585.Peer-Reviewed Original ResearchTranscription start siteNon-erythroid cellsPost-translational histone modificationsHistone H3 lysine 27Cell type-specific mannerH3 lysine 27Gene expressionGene repressionHistone modificationsActive transcriptionLysine 27Start siteHistone H3 lysine 4Expression arraysHistone H3 lysine 9Beta-globin locusH3 lysine 4Regions of heterochromatinH3 lysine 9Influence gene expressionMRNA transcript analysisType-specific mannerCell-type specificGene expression variesChromatin architectureA Modified ANK-1 Promoter Directs Uniform, Copy Number Dependent Gamma Globin Gene Expression at Therapeutic Levels of a in a Lentivirus Vector.
Harrow F, Cline A, Seidel N, Persons D, Gallagher P, Bodine D. A Modified ANK-1 Promoter Directs Uniform, Copy Number Dependent Gamma Globin Gene Expression at Therapeutic Levels of a in a Lentivirus Vector. Blood 2009, 114: 3565. DOI: 10.1182/blood.v114.22.3565.3565.Peer-Reviewed Original ResearchBeta-like globin genesMouse alpha-globinGamma-globin geneGamma-globin mRNAGlobin gene expressionLocus control regionGamma-globin expressionGlobin genesAlpha-globinHematopoietic stem cellsGene expressionEnhancer elementsMouse alpha-globin mRNAHuman gamma-globin geneBeta-globin locus control regionGamma-globin gene expressionSequence variantsTranscription initiation complexLCR elementsBeta-like globinCopy number-dependent expressionBinding of TFIIDAlpha-globin mRNACis-acting enhancer elementPromoter sequence variants
2008
An insulator with barrier-element activity promotes α-spectrin gene expression in erythroid cells
Gallagher PG, Nilson DG, Steiner LA, Maksimova YD, Lin JY, Bodine DM. An insulator with barrier-element activity promotes α-spectrin gene expression in erythroid cells. Blood 2008, 113: 1547-1554. PMID: 19008453, PMCID: PMC2644083, DOI: 10.1182/blood-2008-06-164954.Peer-Reviewed Original ResearchConceptsIntron 1Erythroid cellsErythrocyte membrane protein genesExon 1Chicken HS4 insulatorGamma-globin proteinChromatin immunoprecipitation assaysEarly erythroid developmentMembrane protein geneAlpha-spectrin geneTissue-specific expressionMembrane biogenesisErythroid developmentGlobin genesHS4 insulatorImmunoprecipitation assaysProtein geneReporter geneGene expressionDevelopmental stagesGenesPromoterAdult erythrocytesExpressionSpectrin
2005
Molecular mechanisms in the inherited red cell membrane disorders
Liem R, Gallagher P. Molecular mechanisms in the inherited red cell membrane disorders. Drug Discovery Today Disease Mechanisms 2005, 2: 539-545. DOI: 10.1016/j.ddmec.2005.11.004.Peer-Reviewed Original ResearchRed cell membrane disordersSingle molecular defectEpigenetic controlMRNA processingProtein functionGene expressionMolecular mechanismsMolecular defectsErythrocyte membrane structureRed cell membrane abnormalitiesMembrane structureMolecular medicineMutationsMembrane disordersDiverse groupCurrent knowledgeGenesRegion mutationsMolecular heterogeneityPromoter mutationsCell membrane abnormalitiesErythrocyte membranesInherited disorderMembrane abnormalitiesProteinGATA-1 and Oct-1 Are Required for Expression of the Human α-Hemoglobin-stabilizing Protein Gene*
Gallagher PG, Liem RI, Wong E, Weiss MJ, Bodine DM. GATA-1 and Oct-1 Are Required for Expression of the Human α-Hemoglobin-stabilizing Protein Gene*. Journal Of Biological Chemistry 2005, 280: 39016-39023. PMID: 16186125, DOI: 10.1074/jbc.m506062200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceBinding SitesBlood ProteinsCell LineCloning, MolecularDNA, ComplementaryErythropoiesisGATA1 Transcription FactorGene ExpressionGlobinsHeLa CellsHumansMiceMice, TransgenicMolecular ChaperonesMolecular Sequence DataMutationOctamer Transcription Factor-1Promoter Regions, GeneticRecombinant ProteinsRNA, MessengerConceptsAlpha-hemoglobin-stabilizing proteinGATA-1AHSP promoterAHSP genePromoter/reporter plasmidsGel mobility shift assaysAHSP gene expressionChromatin immunoprecipitation assaysErythroid-specific expressionMobility shift assaysFurther genetic studiesHuman tissue culture cell linesErythroid proteinTissue culture cell linesErythroid promoterNonerythroid tissuesProtein geneImmunoprecipitation assaysRegulatory elementsShift assaysGene promoterReporter geneCandidate genesDNase IGene expression