Featured Publications
Acetyl-methyllysine marks chromatin at active transcription start sites
Lu-Culligan W, Connor L, Xie Y, Ekundayo B, Rose B, Machyna M, Pintado-Urbanc A, Zimmer J, Vock I, Bhanu N, King M, Garcia B, Bleichert F, Simon M. Acetyl-methyllysine marks chromatin at active transcription start sites. Nature 2023, 622: 173-179. PMID: 37731000, PMCID: PMC10845139, DOI: 10.1038/s41586-023-06565-9.Peer-Reviewed Original ResearchConceptsPost-translational modificationsLysine residuesActive transcription start sitesTranscription start siteRange of speciesChromatin biologyChromatin proteinsLysine methylationActive chromatinProteins BRD2Transcriptional initiationLysine acetylationHistone H4Start siteMammalian tissuesHuman diseasesSame residuesMethylationAcetylationChromatinResiduesProteinBiological signalsHistonesBRD2TimeLapse-seq: adding a temporal dimension to RNA sequencing through nucleoside recoding
Schofield JA, Duffy EE, Kiefer L, Sullivan MC, Simon MD. TimeLapse-seq: adding a temporal dimension to RNA sequencing through nucleoside recoding. Nature Methods 2018, 15: 221-225. PMID: 29355846, PMCID: PMC5831505, DOI: 10.1038/nmeth.4582.Peer-Reviewed Original Research
2023
ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control
Gao Y, Zimmer J, Vasic R, Liu C, Gbyli R, Zheng S, Patel A, Liu W, Qi Z, Li Y, Nelakanti R, Song Y, Biancon G, Xiao A, Slavoff S, Kibbey R, Flavell R, Simon M, Tebaldi T, Li H, Halene S. ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control. Cell Reports 2023, 42: 113163. PMID: 37742191, PMCID: PMC10636609, DOI: 10.1016/j.celrep.2023.113163.Peer-Reviewed Original ResearchConceptsAlkB homolog 5Post-transcriptional regulatory mechanismsHematopoietic stemNumerous cellular processesProgenitor cell fitnessEnergy metabolismMitochondrial ATP productionMethyladenosine (m<sup>6</sup>A) RNA modificationTricarboxylic acid cycleCell energy metabolismHuman hematopoietic cellsMitochondrial energy productionCell fitnessCellular processesRNA modificationsRNA methylationRegulatory mechanismsEnzyme transcriptsATP productionHomolog 5Acid cycleΑ-ketoglutarateHematopoietic cellsMessenger RNAΑ-KGCatalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1
Abini-Agbomson S, Gretarsson K, Shih R, Hsieh L, Lou T, De Ioannes P, Vasilyev N, Lee R, Wang M, Simon M, Armache J, Nudler E, Narlikar G, Liu S, Lu C, Armache K. Catalytic and non-catalytic mechanisms of histone H4 lysine 20 methyltransferase SUV420H1. Molecular Cell 2023, 83: 2872-2883.e7. PMID: 37595555, DOI: 10.1016/j.molcel.2023.07.020.Peer-Reviewed Original ResearchConceptsNon-catalytic activitiesNon-catalytic mechanismHistone H4 lysine 20Histone variant H2A.ZH4 lysine 20Large macromolecular complexesCatalytic activityHeterochromatin formationHeterochromatin functionVariant H2A.ZLysine 20Nucleosome substratesGenomic stabilityDNA replicationNucleosomal DNAHistone methyltransferaseChromatin condensationSUV420H1Histone octamerMacromolecular complexesCryoelectron microscopyCellular analysisEssential roleDistinct phenotypesCrucial role
2022
Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC
Swartzel JC, Bond MJ, Pintado-Urbanc AP, Daftary M, Krone MW, Douglas T, Carder EJ, Zimmer JT, Maeda T, Simon MD, Crews CM. Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC. ACS Chemical Biology 2022, 17: 1789-1798. PMID: 35749470, PMCID: PMC10367122, DOI: 10.1021/acschembio.2c00145.Peer-Reviewed Original ResearchPrecision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies
Biancon G, Joshi P, Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES, Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen N, Lin H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T, Halene S. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Molecular Cell 2022, 82: 1107-1122.e7. PMID: 35303483, PMCID: PMC8988922, DOI: 10.1016/j.molcel.2022.02.025.Peer-Reviewed Original Research
2021
Noncoding RNAs: biology and applications—a Keystone Symposia report
Cable J, Heard E, Hirose T, Prasanth KV, Chen L, Henninger JE, Quinodoz SA, Spector DL, Diermeier SD, Porman AM, Kumar D, Feinberg MW, Shen X, Unfried JP, Johnson R, Chen C, Wilusz JE, Lempradl A, McGeary SE, Wahba L, Pyle AM, Hargrove AE, Simon MD, Marcia M, Przanowska RK, Chang HY, Jaffrey SR, Contreras LM, Chen Q, Shi J, Mendell JT, He L, Song E, Rinn JL, Lalwani MK, Kalem MC, Chuong EB, Maquat LE, Liu X. Noncoding RNAs: biology and applications—a Keystone Symposia report. Annals Of The New York Academy Of Sciences 2021, 1506: 118-141. PMID: 34791665, PMCID: PMC9808899, DOI: 10.1111/nyas.14713.Peer-Reviewed Original ResearchConceptsPIWI-interacting RNAsKeystone Symposia reportPotential drug targetsRNA biologyHuman transcriptomeEpigenetic modificationsKeystone eSymposiumNoncoding RNAsCell signalingBasic biologyDrug targetsRNABiologyDisease mechanismsNucleotidesSpeciesTranscriptomeImportant roleRNAsTranscriptionSymposium reportSignalingTranslationRoleTargetHyperosmotic stress alters the RNA polymerase II interactome and induces readthrough transcription despite widespread transcriptional repression
Rosa-Mercado NA, Zimmer JT, Apostolidi M, Rinehart J, Simon MD, Steitz JA. Hyperosmotic stress alters the RNA polymerase II interactome and induces readthrough transcription despite widespread transcriptional repression. Molecular Cell 2021, 81: 502-513.e4. PMID: 33400923, PMCID: PMC7867636, DOI: 10.1016/j.molcel.2020.12.002.Peer-Reviewed Original ResearchConceptsWidespread transcriptional repressionTranscriptional repressionPol IIIntegrator complex subunitsRNA polymerase IIGenome-wide lossStress-induced redistributionParental genesTranscriptional outputDoG inductionPolymerase IIChIP sequencingHuman cell linesUpstream geneComplex subunitsPolyadenylation factorsTranscription profilesReadthrough transcriptsCatalytic subunitIntegrator activityCellular stressHyperosmotic stressTranscriptional levelTranscription resultsGenes
2020
Discovery of cellular substrates of human RNA-decapping enzyme DCP2 using a stapled bicyclic peptide inhibitor
Luo Y, Schofield JA, Na Z, Hann T, Simon MD, Slavoff SA. Discovery of cellular substrates of human RNA-decapping enzyme DCP2 using a stapled bicyclic peptide inhibitor. Cell Chemical Biology 2020, 28: 463-474.e7. PMID: 33357462, PMCID: PMC8052284, DOI: 10.1016/j.chembiol.2020.12.003.Peer-Reviewed Original ResearchConceptsRNA decayEnzyme DCP2P-bodiesDCP2Genetic approachesRNA substratesBicyclic peptide inhibitorsHuman RNAExpression changesCellular substratesPhage display selectionSelective chemical inhibitorsChemical inhibitorsHuman cellsGenetic ablationBicyclic peptide ligandsPeptide inhibitorCP21Display selectionPeptide ligandsHigh affinityRegulomeTranscriptionInhibitorsPowerful toolGenome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection
Wei J, Alfajaro MM, DeWeirdt PC, Hanna RE, Lu-Culligan WJ, Cai WL, Strine MS, Zhang SM, Graziano VR, Schmitz CO, Chen JS, Mankowski MC, Filler RB, Ravindra NG, Gasque V, de Miguel FJ, Patil A, Chen H, Oguntuyo KY, Abriola L, Surovtseva YV, Orchard RC, Lee B, Lindenbach BD, Politi K, van Dijk D, Kadoch C, Simon MD, Yan Q, Doench JG, Wilen CB. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection. Cell 2020, 184: 76-91.e13. PMID: 33147444, PMCID: PMC7574718, DOI: 10.1016/j.cell.2020.10.028.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme 2AnimalsCell LineChlorocebus aethiopsClustered Regularly Interspaced Short Palindromic RepeatsCoronavirusCoronavirus InfectionsCOVID-19Gene Knockout TechniquesGene Regulatory NetworksGenome-Wide Association StudyHEK293 CellsHMGB1 ProteinHost-Pathogen InteractionsHumansSARS-CoV-2Vero CellsVirus InternalizationConceptsSARS-CoV-2 infectionSARS-CoV-2Vesicular stomatitis virusGenome-wide CRISPR screenSWI/SNF chromatinSARS-CoV-2 host factorsAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionTherapeutic targetHost factorsCoronavirus disease 2019 (COVID-19) pathogenesisSyndrome coronavirus 2 infectionCRISPR screensHost genesGene productsMiddle East respiratory syndrome CoVCoronavirus 2 infectionGenetic hitsHuman cellsSARS-CoV-2 spikeNovel therapeutic targetPotential therapeutic targetVero E6 cellsSARS-CoV-1Small molecule antagonists
2019
Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice
Canzio D, Nwakeze CL, Horta A, Rajkumar SM, Coffey EL, Duffy EE, Duffié R, Monahan K, O'Keeffe S, Simon MD, Lomvardas S, Maniatis T. Antisense lncRNA Transcription Mediates DNA Demethylation to Drive Stochastic Protocadherin α Promoter Choice. Cell 2019, 177: 639-653.e15. PMID: 30955885, PMCID: PMC6823843, DOI: 10.1016/j.cell.2019.03.008.Peer-Reviewed Original ResearchConceptsDNA demethylationAntisense promoterPromoter choiceHS5-1 enhancerCTCF binding siteNeural circuit assemblyMouse olfactory neuronsPcdhα genesDemethylation functionLncRNA transcriptionSense promoterAntisense transcriptionProtocadherin (Pcdh) αTET3 overexpressionTranscriptional statesAlternate genesPromoter DNAGene choiceDistal enhancerFirst exonPromoterTranscriptionΓ geneGenesOlfactory neurons
2018
Gaining insight into transcriptome‐wide RNA population dynamics through the chemistry of 4‐thiouridine
Duffy EE, Schofield JA, Simon MD. Gaining insight into transcriptome‐wide RNA population dynamics through the chemistry of 4‐thiouridine. Wiley Interdisciplinary Reviews - RNA 2018, 10: e1513. PMID: 30370679, PMCID: PMC6768404, DOI: 10.1002/wrna.1513.Peer-Reviewed Original ResearchConceptsDifferent RNA populationsRNA populationsNumerous experimental strategiesCellular RNA levelsMetabolic labeling experimentsRNA levelsRNA metabolismRNA turnoverRNA stabilityRNA transcriptionRNA sequencingMetabolic labelingPopulation dynamicsMetabolic labelTargeted incorporationRNA analysisRNA methodWhole cellsC mutationLabeling experimentsExperimental strategiesSequencingAvailable poolGenomeCellsSolid phase chemistry to covalently and reversibly capture thiolated RNA
Duffy EE, Canzio D, Maniatis T, Simon MD. Solid phase chemistry to covalently and reversibly capture thiolated RNA. Nucleic Acids Research 2018, 46: gky556-. PMID: 29986098, PMCID: PMC6101502, DOI: 10.1093/nar/gky556.Peer-Reviewed Original Research
2017
Catching RNAs on chromatin using hybridization capture methods
Machyna M, Simon MD. Catching RNAs on chromatin using hybridization capture methods. Briefings In Functional Genomics 2017, 17: 96-103. PMID: 29126220, PMCID: PMC5888980, DOI: 10.1093/bfgp/elx038.Peer-Reviewed Original ResearchConceptsRNA affinity purificationHybridization capture methodsCross-linked chromatin extractsGenome-wide scaleEnrichment of RNAInteraction of lncRNAsLncRNA localizationChromatin isolationChromatin extractsSite of interactionCapture methodAffinity purificationBiological roleRNA targetsHybridization analysisRNARNA purificationChromatinLncRNAsOligonucleotide hybridizationPurificationDevelopment of methodsProteinCapture experimentsHybridization
2015
Probing Xist RNA Structure in Cells Using Targeted Structure-Seq
Fang R, Moss WN, Rutenberg-Schoenberg M, Simon MD. Probing Xist RNA Structure in Cells Using Targeted Structure-Seq. PLOS Genetics 2015, 11: e1005668. PMID: 26646615, PMCID: PMC4672913, DOI: 10.1371/journal.pgen.1005668.Peer-Reviewed Original ResearchConceptsStructure-seqRNA structureRNA conformationNon-coding RNA XISTLong non-coding RNA XISTX-chromosome inactivationSecondary structure mappingRNA of interestXist lncRNAMolecular evolutionC-repeatLncRNA functionsHigher-order structureXist functionRNA functionMammalian cellsMaster regulatorXISTSequencing readsChemical probingParallel sequencingTarget RNARNA XISTRNA basesRNATracking Distinct RNA Populations Using Efficient and Reversible Covalent Chemistry
Duffy EE, Rutenberg-Schoenberg M, Stark CD, Kitchen RR, Gerstein MB, Simon MD. Tracking Distinct RNA Populations Using Efficient and Reversible Covalent Chemistry. Molecular Cell 2015, 59: 858-866. PMID: 26340425, PMCID: PMC4560836, DOI: 10.1016/j.molcel.2015.07.023.Peer-Reviewed Original ResearchConceptsDynamic transcriptome analysisReversible covalent chemistryGlobal miRNA levelsMiRNA processing machineryTissue-specific transcriptionCovalent chemistryCultured human cellsChemical methodsImproved chemistryRNA turnoverRNA populationsTranscriptome analysisMethanethiosulfonate reagentsProcessing machineryHuman cellsHPDP-biotinHigh yieldsDisulfide bondsChemistryMiRNA levelsRNADifferent populationsTurnoverBondsReagents