2023
Lineage 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 processesThe functional and evolutionary impacts of human-specific deletions in conserved elements
Xue J, Mackay-Smith A, Mouri K, Garcia M, Dong M, Akers J, Noble M, Li X, Lindblad-Toh K, Karlsson E, Noonan J, Capellini T, Brennand K, Tewhey R, Sabeti P, Reilly S, Andrews G, Armstrong J, Bianchi M, Birren B, Bredemeyer K, Breit A, Christmas M, Clawson H, Damas J, Di Palma F, Diekhans M, Dong M, Eizirik E, Fan K, Fanter C, Foley N, Forsberg-Nilsson K, Garcia C, Gatesy J, Gazal S, Genereux D, Goodman L, Grimshaw J, Halsey M, Harris A, Hickey G, Hiller M, Hindle A, Hubley R, Hughes G, Johnson J, Juan D, Kaplow I, Karlsson E, Keough K, Kirilenko B, Koepfli K, Korstian J, Kowalczyk A, Kozyrev S, Lawler A, Lawless C, Lehmann T, Levesque D, Lewin H, Li X, Lind A, Lindblad-Toh K, Mackay-Smith A, Marinescu V, Marques-Bonet T, Mason V, Meadows J, Meyer W, Moore J, Moreira L, Moreno-Santillan D, Morrill K, Muntané G, Murphy W, Navarro A, Nweeia M, Ortmann S, Osmanski A, Paten B, Paulat N, Pfenning A, Phan B, Pollard K, Pratt H, Ray D, Reilly S, Rosen J, Ruf I, Ryan L, Ryder O, Sabeti P, Schäffer D, Serres A, Shapiro B, Smit A, Springer M, Srinivasan C, Steiner C, Storer J, Sullivan K, Sullivan P, Sundström E, Supple M, Swofford R, Talbot J, Teeling E, Turner-Maier J, Valenzuela A, Wagner F, Wallerman O, Wang C, Wang J, Weng Z, Wilder A, Wirthlin M, Xue J, Zhang X. The functional and evolutionary impacts of human-specific deletions in conserved elements. Science 2023, 380: eabn2253. PMID: 37104592, PMCID: PMC10202372, DOI: 10.1126/science.abn2253.Peer-Reviewed Original ResearchConceptsHuman-specific deletionHuman phenotypic traitsParallel reporterEvolutionary impactDevelopmental genesPhenotypic traitsEvolutionary mechanismsGenomic sequencesNew traitsTranscriptomic datasetsSequence altersRegulatory functionsCell typesRegulatory activityRich resourceDeletionSynaptic functionTraitsBrain developmentGenesSpeciesReporterHumansSequenceExpression
2021
Applying stem cells and CRISPR engineering to uncover the etiology of schizophrenia
Michael Deans P, Brennand K. Applying stem cells and CRISPR engineering to uncover the etiology of schizophrenia. Current Opinion In Neurobiology 2021, 69: 193-201. PMID: 34010781, PMCID: PMC8387340, DOI: 10.1016/j.conb.2021.04.003.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsCell type-specific fashionStem cell biologyType-specific fashionDisease-associated variantsNeural cell typesCommon genetic variantsMore genesCell biologyCRISPR engineeringGene manipulationGene targetsCRISPR technologyMolecular geneticsInvaluable advancesCell typesHiPSC technologyGenetic variantsStem cellsIndividual variantsEtiology of diseasePolygenic disorderVariantsComplex interactionsRecent advancesEtiology of schizophrenia
2020
Modeling the complex genetic architectures of brain disease
Fernando MB, Ahfeldt T, Brennand KJ. Modeling the complex genetic architectures of brain disease. Nature Genetics 2020, 52: 363-369. PMID: 32203467, PMCID: PMC7909729, DOI: 10.1038/s41588-020-0596-3.Peer-Reviewed Original ResearchConceptsGenetic architectureComplex genetic architectureFunctional validation studiesRelevant disease biologyIntersection of genomicsComplex genetic diseasesCombination of genesPluripotent stem cellsGene perturbationsIsogenic comparisonsMolecular mechanismsPhenotypic drug discoveryCell typesGenetic diseasesFunctional consequencesGenetic backgroundRisk variantsStem cellsCRISPRDisease biologyDrug discoveryRare variantsConfer riskGenetic diagnosisVariants
2019
CRISPR-based functional evaluation of schizophrenia risk variants
Rajarajan P, Flaherty E, Akbarian S, Brennand KJ. CRISPR-based functional evaluation of schizophrenia risk variants. Schizophrenia Research 2019, 217: 26-36. PMID: 31277978, PMCID: PMC6939156, DOI: 10.1016/j.schres.2019.06.017.Peer-Reviewed Original ResearchConceptsSchizophrenia-associated variantsPluripotent stem cellsCRISPR genome engineeringSchizophrenia risk variantsCellular functionsGenome engineeringGenomic studiesSchizophrenia lociList of variantsGene expressionPatient-specific humanGenotype dataRisk variantsStem cellsFunctional impactCommon variantsCRISPRPost-mortem brain tissueRecent findingsVariantsNeuropsychiatric diseasesPoint of convergenceGenetic riskLociSpecific effectsSpatial 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
Common developmental genome deprogramming in schizophrenia — Role of Integrative Nuclear FGFR1 Signaling (INFS)
Narla S, Lee Y, Benson C, Sarder P, Brennand K, Stachowiak E, Stachowiak M. Common developmental genome deprogramming in schizophrenia — Role of Integrative Nuclear FGFR1 Signaling (INFS). Schizophrenia Research 2017, 185: 17-32. PMID: 28094170, PMCID: PMC5507209, DOI: 10.1016/j.schres.2016.12.012.Peer-Reviewed Original ResearchMeSH KeywordsAdultCell DifferentiationCells, CulturedFemaleGene Expression Regulation, DevelopmentalGene Regulatory NetworksGenomeGenomicsHumansInduced Pluripotent Stem CellsMaleMicroRNAsModels, BiologicalMutationReceptor, Fibroblast Growth Factor, Type 1Receptor, Notch1SchizophreniaSignal TransductionTranscriptomeYoung AdultConceptsMRNA networkMajor developmental pathwaysIntegrative nuclear FGFR1MiRNA-mRNA networkHuman gene promotersCommon developmental genomesMiRNA genesMiRNA transcriptomeGene networksUpregulated genesGene promoterNuclear FGFR1Genomic etiologyGene dysregulationDisease ontogenyNuclear formGlobal dysregulationDevelopmental pathwaysGenesNeuron formationDistinct pathwaysConcerted actionPotential therapeutic targetTranscriptomeGenome
2016
Spatial genome organization and cognition
Rajarajan P, Gil S, Brennand K, Akbarian S. Spatial genome organization and cognition. Nature Reviews Neuroscience 2016, 17: 681-691. PMID: 27708356, PMCID: PMC5503467, DOI: 10.1038/nrn.2016.124.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPromoter-enhancer interactionsRegulatory sequencesGene transcription start siteSpatial genome organizationNon-coding DNACis-regulatory sequencesHundreds of kilobasesTranscription start siteCRISPR-Cas systemsChromosomal loopingGenome organizationTranscriptional activatorChromosomal conformationCohesin complexGenetic risk architectureTranscriptional regulationStart siteCandidate genesGene expressionStructural variantsDecoy modelsNeurodevelopmental diseasesCrucial layerEditing techniquesProgenitor cells