Featured Publications
Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk
Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casiño C, Powell S, Yashaswini C, LaMarca EA, Kassim B, Javidfar B, Espeso-Gil S, Li A, Won H, Geschwind DH, Ho SM, MacDonald M, Hoffman GE, Roussos P, Zhang B, Hahn CG, Weng Z, Brennand KJ, Akbarian S. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 2018, 362 PMID: 30545851, PMCID: PMC6408958, DOI: 10.1126/science.aat4311.Peer-Reviewed Original ResearchMeSH KeywordsBrainCells, CulturedChromatinChromatin Assembly and DisassemblyChromosomes, HumanConnectomeEpigenesis, GeneticGene Expression Regulation, DevelopmentalGenetic Predisposition to DiseaseGenome, HumanGenome-Wide Association StudyHumansMaleNeural Stem CellsNeurogenesisNeurogliaNeuronsNucleic Acid ConformationProtein Interaction MapsProteomicsRiskSchizophreniaTranscription, GeneticTranscriptomeConceptsCoordinated transcriptional regulationThree-dimensional genomeSpatial genome organizationChromosomal contact mapsNeural progenitor cellsSchizophrenia risk variantsGenome organizationChromatin remodelingChromosomal conformationTranscriptional regulationProteomic interactionsDevelopmental remodelingHeritable riskGlial differentiationRisk variantsContact mapsProgenitor cellsVariant sequencesGenesConformation changeNeuronal connectivitySchizophrenia riskSequenceNeuropsychiatric diseasesDistal targets
2024
Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Maury E, Jones A, Seplyarskiy V, Nguyen T, Rosenbluh C, Bae T, Wang Y, Abyzov A, Khoshkhoo S, Chahine Y, Zhao S, Venkatesh S, Root E, Voloudakis G, Roussos P, Network B, Park P, Akbarian S, Brennand K, Reilly S, Lee E, Sunyaev S, Walsh C, Chess A. Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes. Science 2024, 386: 217-224. PMID: 39388546, PMCID: PMC11490355, DOI: 10.1126/science.adq1456.Peer-Reviewed Original ResearchConceptsTranscription factor binding sitesWhole-genome sequencingOpen chromatinMutational processesSomatic mutationsFactor binding sitesSchizophrenia casesSchizophrenia risk genesSomatic mosaicismSomatic variantsRisk genesG mutationGene expressionGermline mutationsBinding sitesGenesMutationsIncreased somatic mutationsChromatinMosaic somatic mutationsPrenatal neurogenesisContext of schizophreniaBrain neuronsSchizophrenia brainVariantsMassively parallel characterization of regulatory elements in the developing human cortex
Deng C, Whalen S, Steyert M, Ziffra R, Przytycki P, Inoue F, Pereira D, Capauto D, Norton S, Vaccarino F, Pollen A, Nowakowski T, Ahituv N, Pollard K, Akbarian S, Abyzov A, Ahituv N, Arasappan D, Almagro Armenteros J, Beliveau B, Bendl J, Berretta S, Bharadwaj R, Bhattacharya A, Bicks L, Brennand K, Capauto D, Champagne F, Chatterjee T, Chatzinakos C, Chen Y, Chen H, Cheng Y, Cheng L, Chess A, Chien J, Chu Z, Clarke D, Clement A, Collado-Torres L, Cooper G, Crawford G, Dai R, Daskalakis N, Davila-Velderrain J, Deep-Soboslay A, Deng C, DiPietro C, Dracheva S, Drusinsky S, Duan Z, Duong D, Dursun C, Eagles N, Edelstein J, Emani P, Fullard J, Galani K, Galeev T, Gandal M, Gaynor S, Gerstein M, Geschwind D, Girdhar K, Goes F, Greenleaf W, Grundman J, Guo H, Guo Q, Gupta C, Hadas Y, Hallmayer J, Han X, Haroutunian V, Hawken N, He C, Henry E, Hicks S, Ho M, Ho L, Hoffman G, Huang Y, Huuki-Myers L, Hwang A, Hyde T, Iatrou A, Inoue F, Jajoo A, Jensen M, Jiang L, Jin P, Jin T, Jops C, Jourdon A, Kawaguchi R, Kellis M, Khullar S, Kleinman J, Kleopoulos S, Kozlenkov A, Kriegstein A, Kundaje A, Kundu S, Lee C, Lee D, Li J, Li M, Lin X, Liu S, Liu J, Liu J, Liu C, Liu S, Lou S, Loupe J, Lu D, Ma S, Ma L, Margolis M, Mariani J, Martinowich K, Maynard K, Mazariegos S, Meng R, Myers R, Micallef C, Mikhailova T, Ming G, Mohammadi S, Monte E, Montgomery K, Moore J, Moran J, Mukamel E, Nairn A, Nemeroff C, Ni P, Norton S, Nowakowski T, Omberg L, Page S, Park S, Patowary A, Pattni R, Pertea G, Peters M, Phalke N, Pinto D, Pjanic M, Pochareddy S, Pollard K, Pollen A, Pratt H, Przytycki P, Purmann C, Qin Z, Qu P, Quintero D, Raj T, Rajagopalan A, Reach S, Reimonn T, Ressler K, Ross D, Roussos P, Rozowsky J, Ruth M, Ruzicka W, Sanders S, Schneider J, Scuderi S, Sebra R, Sestan N, Seyfried N, Shao Z, Shedd N, Shieh A, Shin J, Skarica M, Snijders C, Song H, State M, Stein J, Steyert M, Subburaju S, Sudhof T, Snyder M, Tao R, Therrien K, Tsai L, Urban A, Vaccarino F, van Bakel H, Vo D, Voloudakis G, Wamsley B, Wang T, Wang S, Wang D, Wang Y, Warrell J, Wei Y, Weimer A, Weinberger D, Wen C, Weng Z, Whalen S, White K, Willsey A, Won H, Wong W, Wu H, Wu F, Wuchty S, Wylie D, Xu S, Yap C, Zeng B, Zhang P, Zhang C, Zhang B, Zhang J, Zhang Y, Zhou X, Ziffra R, Zeier Z, Zintel T. Massively parallel characterization of regulatory elements in the developing human cortex. Science 2024, 384: eadh0559. PMID: 38781390, DOI: 10.1126/science.adh0559.Peer-Reviewed Original ResearchConceptsGene regulatory elementsRegulatory elementsRegulation of enhancer activityCharacterization of regulatory elementsCis-regulatory activityNeuronal developmentPrimary cellsEnhanced activityGene regulationHuman neuronal developmentNucleotide changesEnhancer sequencesSequence basisUpstream regulatorComprehensive catalogHuman cellsDeveloping cortexSequenceVariantsOrganoidsCellsCerebral organoidsCortexHuman cortexNucleotideSingle-cell genomics and regulatory networks for 388 human brains
Emani P, Liu J, Clarke D, Jensen M, Warrell J, Gupta C, Meng R, Lee C, Xu S, Dursun C, Lou S, Chen Y, Chu Z, Galeev T, Hwang A, Li Y, Ni P, Zhou X, Bakken T, Bendl J, Bicks L, Chatterjee T, Cheng L, Cheng Y, Dai Y, Duan Z, Flaherty M, Fullard J, Gancz M, Garrido-Martín D, Gaynor-Gillett S, Grundman J, Hawken N, Henry E, Hoffman G, Huang A, Jiang Y, Jin T, Jorstad N, Kawaguchi R, Khullar S, Liu J, Liu J, Liu S, Ma S, Margolis M, Mazariegos S, Moore J, Moran J, Nguyen E, Phalke N, Pjanic M, Pratt H, Quintero D, Rajagopalan A, Riesenmy T, Shedd N, Shi M, Spector M, Terwilliger R, Travaglini K, Wamsley B, Wang G, Xia Y, Xiao S, Yang A, Zheng S, Gandal M, Lee D, Lein E, Roussos P, Sestan N, Weng Z, White K, Won H, Girgenti M, Zhang J, Wang D, Geschwind D, Gerstein M, Akbarian S, Abyzov A, Ahituv N, Arasappan D, Almagro Armenteros J, Beliveau B, Berretta S, Bharadwaj R, Bhattacharya A, Brennand K, Capauto D, Champagne F, Chatzinakos C, Chen H, Cheng L, Chess A, Chien J, Clement A, Collado-Torres L, Cooper G, Crawford G, Dai R, Daskalakis N, Davila-Velderrain J, Deep-Soboslay A, Deng C, DiPietro C, Dracheva S, Drusinsky S, Duong D, Eagles N, Edelstein J, Galani K, Girdhar K, Goes F, Greenleaf W, Guo H, Guo Q, Hadas Y, Hallmayer J, Han X, Haroutunian V, He C, Hicks S, Ho M, Ho L, Huang Y, Huuki-Myers L, Hyde T, Iatrou A, Inoue F, Jajoo A, Jiang L, Jin P, Jops C, Jourdon A, Kellis M, Kleinman J, Kleopoulos S, Kozlenkov A, Kriegstein A, Kundaje A, Kundu S, Li J, Li M, Lin X, Liu S, Liu C, Loupe J, Lu D, Ma L, Mariani J, Martinowich K, Maynard K, Myers R, Micallef C, Mikhailova T, Ming G, Mohammadi S, Monte E, Montgomery K, Mukamel E, Nairn A, Nemeroff C, Norton S, Nowakowski T, Omberg L, Page S, Park S, Patowary A, Pattni R, Pertea G, Peters M, Pinto D, Pochareddy S, Pollard K, Pollen A, Przytycki P, Purmann C, Qin Z, Qu P, Raj T, Reach S, Reimonn T, Ressler K, Ross D, Rozowsky J, Ruth M, Ruzicka W, Sanders S, Schneider J, Scuderi S, Sebra R, Seyfried N, Shao Z, Shieh A, Shin J, Skarica M, Snijders C, Song H, State M, Stein J, Steyert M, Subburaju S, Sudhof T, Snyder M, Tao R, Therrien K, Tsai L, Urban A, Vaccarino F, van Bakel H, Vo D, Voloudakis G, Wang T, Wang S, Wang Y, Wei Y, Weimer A, Weinberger D, Wen C, Whalen S, Willsey A, Wong W, Wu H, Wu F, Wuchty S, Wylie D, Yap C, Zeng B, Zhang P, Zhang C, Zhang B, Zhang Y, Ziffra R, Zeier Z, Zintel T. Single-cell genomics and regulatory networks for 388 human brains. Science 2024, 384: eadi5199. PMID: 38781369, PMCID: PMC11365579, DOI: 10.1126/science.adi5199.Peer-Reviewed Original ResearchConceptsSingle-cell genomicsSingle-cell expression quantitative trait locusExpression quantitative trait lociDrug targetsQuantitative trait lociPopulation-level variationSingle-cell expressionCell typesDisease-risk genesTrait lociGene familyRegulatory networksGene expressionCell-typeMultiomics datasetsSingle-nucleiGenomeGenesCellular changesHeterogeneous tissuesExpressionCellsChromatinLociMultiomics
2023
Multi-omic profiling of the developing human cerebral cortex at the single-cell level
Zhu K, Bendl J, Rahman S, Vicari J, Coleman C, Clarence T, Latouche O, Tsankova N, Li A, Brennand K, Lee D, Yuan G, Fullard J, Roussos P. Multi-omic profiling of the developing human cerebral cortex at the single-cell level. Science Advances 2023, 9: eadg3754. PMID: 37824614, PMCID: PMC10569714, DOI: 10.1126/sciadv.adg3754.Peer-Reviewed Original ResearchConceptsCis-regulatory elementsChromatin accessibilityGene expressionPseudotime trajectory analysisNeuronal lineage commitmentMulti-omics profilingSingle-cell levelSpecific genetic lociDevelopmental time pointsChromatin structureType-specific domainsLineage determinationCellular complexityLineage commitmentNeuropsychiatric traitsComplex regulationGenetic lociSpatiotemporal activityDynamic changesCritical roleExpressionSpatiotemporal alterationsCell compositionCritical stageNeuropsychiatric diseasesLineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome
Rahman S, Dong P, Apontes P, Fernando M, Kosoy R, Townsley K, Girdhar K, Bendl J, Shao Z, Misir R, Tsankova N, Kleopoulos S, Brennand K, Fullard J, Roussos P. Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome. Nucleic Acids Research 2023, 51: 11142-11161. PMID: 37811875, PMCID: PMC10639075, DOI: 10.1093/nar/gkad798.Peer-Reviewed Original ResearchConceptsChromatin interactomeNeural developmentSpecific gene expressionEnhancer-promoter loopsDistinct cell typesGenome compartmentalizationRepressive compartmentGenome architectureFine-scale changesGenome structureChromatin loopsGWAS lociTAD boundariesTranscriptional inactivationActive promotersGene expressionInteractomeGenomeCell typesComplex organDisease mechanismsHuman brainAdult prefrontal cortexAdult human brainNeurodevelopmental processes
2022
Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
Fulton S, Wenderski W, Lepack A, Eagle A, Fanutza T, Bastle R, Ramakrishnan A, Hays E, Neal A, Bendl J, Farrelly L, Al-Kachak A, Lyu Y, Cetin B, Chan J, Tran T, Neve R, Roper R, Brennand K, Roussos P, Schimenti J, Friedman A, Shen L, Blitzer R, Robison A, Crabtree G, Maze I. Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome. Nature Communications 2022, 13: 6384. PMID: 36289231, PMCID: PMC9606253, DOI: 10.1038/s41467-022-34200-0.Peer-Reviewed Original ResearchConceptsGene expressionChromatin accessibilityChromatin effectorsBAF chromatinGenetic basisTrisomic animalsIPS cellsBRWD1Chromosome 21Down syndromeHSA21Ts65Dn mouse modelCommon chromosomal conditionExpressionChromatinNormal neurodevelopmentChromosomal conditionHippocampal LTPMouse modelMistargetingGenesTrisomic miceCognitive deficitsEffectorsSyndromeThe three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease
Bendl J, Hauberg M, Girdhar K, Im E, Vicari J, Rahman S, Fernando M, Townsley K, Dong P, Misir R, Kleopoulos S, Reach S, Apontes P, Zeng B, Zhang W, Voloudakis G, Brennand K, Nixon R, Haroutunian V, Hoffman G, Fullard J, Roussos P. The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease. Nature Neuroscience 2022, 25: 1366-1378. PMID: 36171428, PMCID: PMC9581463, DOI: 10.1038/s41593-022-01166-7.Peer-Reviewed Original ResearchConceptsOpen chromatin regionsCis-regulatory domainsChromatin accessibilitySpecific enhancer-promoter interactionsTranscription factor regulatory networksEnhancer-promoter interactionsATAC-seq librariesChromatin regionsLysosomal genesNonneuronal nucleiRegulatory networksThree-dimensional structureGenomeThree-dimensional landscapeRegulatory effectsAlzheimer's diseaseCommunity-based analysisUSF2GenesDysregulationRepertoireTFAD casesLandscapeDomainChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Farrelly L, Zheng S, Schrode N, Topol A, Bhanu N, Bastle R, Ramakrishnan A, Chan J, Cetin B, Flaherty E, Shen L, Gleason K, Tamminga C, Garcia B, Li H, Brennand K, Maze I. Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia. Nature Communications 2022, 13: 2195. PMID: 35459277, PMCID: PMC9033776, DOI: 10.1038/s41467-022-29922-0.Peer-Reviewed Original ResearchConceptsHistone posttranslational modificationsPosttranslational modificationsUnbiased proteomic approachPluripotent stem cellsPatient-derived neuronsH2A.Z acetylationChromatin profilingHyperacetylated histonesFamily proteinsProteomic approachProtein interactionsHistone acetylationTranscriptional abnormalitiesEpigenetic factorsExtraterminal (BET) proteinsSZ casesRisk variantsHuman neuronsStem cellsAberrant roleProtein inhibitionBona fideTreatment of schizophreniaPostmortem human brainCritical role
2020
A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles
Sey NYA, Hu B, Mah W, Fauni H, McAfee JC, Rajarajan P, Brennand KJ, Akbarian S, Won H. A computational tool (H-MAGMA) for improved prediction of brain-disorder risk genes by incorporating brain chromatin interaction profiles. Nature Neuroscience 2020, 23: 583-593. PMID: 32152537, PMCID: PMC7131892, DOI: 10.1038/s41593-020-0603-0.Peer-Reviewed Original ResearchConceptsChromatin interaction profilesH-MAGMARisk genesMost risk variantsGenome-wide association studiesCell typesGene regulatory relationshipsRelevant target genesCell-type specificitySingle nucleotide polymorphism associationsBrain cell typesDisease-relevant tissuesInteraction profilesGenomic annotationsNearest geneTarget genesRegulatory relationshipsAssociation studiesBiological pathwaysGenesRisk variantsDevelopmental windowBiological mechanismsNeurodegenerative disordersHuman brain tissue
2019
Spatial genome exploration in the context of cognitive and neurological disease
Rajarajan P, Borrman T, Liao W, Espeso-Gil S, Chandrasekaran S, Jiang Y, Weng Z, Brennand KJ, Akbarian S. Spatial genome exploration in the context of cognitive and neurological disease. Current Opinion In Neurobiology 2019, 59: 112-119. PMID: 31255842, PMCID: PMC6889018, DOI: 10.1016/j.conb.2019.05.007.Peer-Reviewed Original ResearchConceptsGenome explorationSpecific gene expression programsImportant regulatory layerTopological chromatin domainsGene expression programsChromosomal contact mapsChromatin domainsGenome organizationExpression programsRegulatory layerTranscriptional regulationChromosomal contactsWidespread remodelingTranscriptomic analysisRepeat sequencesUnexpected linkNeuronal lineageNeural differentiationNon-contiguous sequencesContact mapsAbnormal expansionNeurodegenerative diseasesNew insightsSequenceMouse brain
2017
The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain
Jiang Y, Loh YE, Rajarajan P, Hirayama T, Liao W, Kassim BS, Javidfar B, Hartley BJ, Kleofas L, Park RB, Labonte B, Ho SM, Chandrasekaran S, Do C, Ramirez BR, Peter CJ, C W JT, Safaie BM, Morishita H, Roussos P, Nestler EJ, Schaefer A, Tycko B, Brennand KJ, Yagi T, Shen L, Akbarian S. The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nature Genetics 2017, 49: 1239-1250. PMID: 28671686, PMCID: PMC5560095, DOI: 10.1038/ng.3906.Peer-Reviewed Original Research