2024
Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain
Wen C, Margolis M, Dai R, Zhang P, Przytycki P, Vo D, Bhattacharya A, Matoba N, Tang M, Jiao C, Kim M, Tsai E, Hoh C, Aygün N, Walker R, Chatzinakos C, Clarke D, Pratt H, Peters M, Gerstein M, Daskalakis N, Weng Z, Jaffe A, Kleinman J, Hyde T, Weinberger D, Bray N, Sestan N, Geschwind D, Roeder K, Gusev A, Pasaniuc B, Stein J, Love M, Pollard K, Liu C, Gandal M, Akbarian S, Abyzov A, Ahituv N, Arasappan D, Almagro Armenteros J, Beliveau B, Bendl J, Berretta S, Bharadwaj R, 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, Clement A, Collado-Torres L, Cooper G, Crawford G, 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, Gaynor S, 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, Iatrou A, Inoue F, Jajoo A, Jensen M, Jiang L, Jin P, Jin T, Jops C, Jourdon A, Kawaguchi R, Kellis M, 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 S, Lou S, Loupe J, Lu D, Ma S, Ma L, 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, Phalke N, Pinto D, Pjanic M, Pochareddy S, Pollen A, 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, Seyfried N, Shao Z, Shedd N, Shieh A, Shin J, Skarica M, Snijders C, Song H, State M, Steyert M, Subburaju S, Sudhof T, Snyder M, Tao R, Therrien K, Tsai L, Urban A, Vaccarino F, van Bakel H, Voloudakis G, Wamsley B, Wang T, Wang S, Wang D, Wang Y, Warrell J, Wei Y, Weimer A, 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 C, Zhang B, Zhang J, Zhang Y, Zhou X, Ziffra R, Zeier Z, Zintel T. Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain. Science 2024, 384: eadh0829. PMID: 38781368, DOI: 10.1126/science.adh0829.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesGenome-wide association study lociSplicing quantitative trait lociQuantitative trait lociSplicing regulationCross-ancestryTrait lociAssociation studiesRegulatory elementsCellular contextHuman brainTranscriptome regulationCoexpression networkRisk genesAutism spectrum disorderGenesCellular heterogeneityComprehensive landscapeSpectrum disorderIsoformsSplicingIncreased cellular heterogeneityLociNeuronal maturationRegulationMassively 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 cortexNucleotide
2023
MASSIVELY PARALLEL CHARACTERIZATION OF CONTEXT SPECIFIC REGULATORY RISK ELEMENTS ACROSS PSYCHIATRIC DISORDERS IN HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED GLUTAMATERGIC NEURONS
Townsley K, Sen A, Lee J, Deans P, Jia M, Fernandez-Garcia M, Cartwright S, Cohen S, Goate A, Brennand K, Huckins L. MASSIVELY PARALLEL CHARACTERIZATION OF CONTEXT SPECIFIC REGULATORY RISK ELEMENTS ACROSS PSYCHIATRIC DISORDERS IN HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED GLUTAMATERGIC NEURONS. European Neuropsychopharmacology 2023, 75: s7-s8. DOI: 10.1016/j.euroneuro.2023.08.022.Peer-Reviewed Original ResearchCandidate regulatory sequencesExpression quantitative trait lociRegulatory sequencesTranscriptional activityGWAS statisticsSingle-cell CRISPR screensCell type-specific mannerParallel reporter assaysQuantitative trait lociPutative regulatory elementsHigh-throughput sequencingFine-mapping approachFine-mapping methodsLarge-scale identificationFunctional impactTranscriptomic imputationTrait lociKey genesCRISPR screensLarge-scale screening techniquesRegulatory elementsNeuropsychiatric traitsCausal SNPsReporter assaysCasual variantsActivity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders
Ma Y, Bendl J, Hartley B, Fullard J, Abdelaal R, Ho S, Kosoy R, Gochman P, Rapoport J, Hoffman G, Brennand K, Roussos P. Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders. Biological Psychiatry 2023, 95: 187-198. PMID: 37454787, PMCID: PMC10787819, DOI: 10.1016/j.biopsych.2023.07.003.Peer-Reviewed Original ResearchConceptsTranscriptional programsBrain-related disordersGlutamatergic neuronsGene coexpression network analysisSignificant heritability enrichmentsEnhancer-promoter interactionsCoexpression network analysisDisease-associated genesExpression of genesLarge-scale geneticMultiomics data integrationChromatin accessibilityEpigenomic changesHeritability enrichmentGenetic regulationRegulatory elementsMultiple genesSequence variationGene expressionAxon guidanceGenetic riskPotassium chloride-induced depolarizationActivity-dependent changesDepolarization-induced changesGenes
2020
Massively parallel techniques for cataloguing the regulome of the human brain
Townsley KG, Brennand KJ, Huckins LM. Massively parallel techniques for cataloguing the regulome of the human brain. Nature Neuroscience 2020, 23: 1509-1521. PMID: 33199899, PMCID: PMC8018778, DOI: 10.1038/s41593-020-00740-1.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRegulatory elementsTarget genesParallel reporter assaysPutative regulatory elementsNon-coding regionsDisease-associated lociSpecific expression patternsCandidate risk lociPluripotent stem cellsHigh-throughput assaysRelevant molecular pathwaysTranscriptional responseRegulatory architectureRisk lociExpression patternsReporter assaysComplex brain disordersMolecular pathwaysRegulomeStem cellsRisk architectureGenetic riskGenesLociGenetic diagnosis
2014
A Role for Noncoding Variation in Schizophrenia
Roussos P, Mitchell A, Voloudakis G, Fullard J, Pothula V, Tsang J, Stahl E, Georgakopoulos A, Ruderfer D, Charney A, Okada Y, Siminovitch K, Worthington J, Padyukov L, Klareskog L, Gregersen P, Plenge R, Raychaudhuri S, Fromer M, Purcell S, Brennand K, Robakis N, Schadt E, Akbarian S, Sklar P. A Role for Noncoding Variation in Schizophrenia. Cell Reports 2014, 9: 1417-1429. PMID: 25453756, PMCID: PMC4255904, DOI: 10.1016/j.celrep.2014.10.015.Peer-Reviewed Original ResearchMeSH KeywordsArthritis, RheumatoidCalcium Channels, L-TypeDatabases, GeneticDNA, IntergenicEnhancer Elements, GeneticGene Expression RegulationGenetic LociGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansMolecular Sequence AnnotationOrgan SpecificityPolymorphism, Single NucleotidePromoter Regions, GeneticProtein BindingRisk FactorsSchizophreniaConceptsExpression quantitative trait lociGenome-wide significant lociCommon variant lociQuantitative trait lociPluripotent stem cell-derived neuronsDistal regulatory elementsStem cell-derived neuronsPotential physical interactionsCell-derived neuronsRegulatory element sequencesPotential functional roleGenome architectureChromosomal loopingTranscriptional regulationFunctional annotationTrait lociSignificant lociNoncoding SNPsRegulatory elementsNoncoding variationsRisk lociVariant lociUnknown functionFunctional linkElement sequences