2024
Machine-guided design of cell-type-targeting cis-regulatory elements
Gosai S, Castro R, Fuentes N, Butts J, Mouri K, Alasoadura M, Kales S, Nguyen T, Noche R, Rao A, Joy M, Sabeti P, Reilly S, Tewhey R. Machine-guided design of cell-type-targeting cis-regulatory elements. Nature 2024, 634: 1211-1220. PMID: 39443793, PMCID: PMC11525185, DOI: 10.1038/s41586-024-08070-z.Peer-Reviewed Original ResearchConceptsCis-regulatory elementsCell typesActivation of off-target cellsGene expressionCell type-specific expressionSynthetic cis-regulatory elementsCell-type specificityHuman genomeUnique cell typeTissue identityBiotechnological applicationsTissue specificityIn vitro validationCell linesCre activitySequenceGenesNatural sequenceDevelopmental timeExpressionCellsGenomeTested in vivoMotifOff-target cellsMassively parallel approaches for characterizing noncoding functional variation in human evolution
Rong S, Root E, Reilly S. Massively parallel approaches for characterizing noncoding functional variation in human evolution. Current Opinion In Genetics & Development 2024, 88: 102256. PMID: 39217658, DOI: 10.1016/j.gde.2024.102256.Peer-Reviewed Original ResearchCis-regulatory elementsFunction of cis-regulatory elementsImpact of sequence variantsHigh-throughput approachNoncoding variationGenome functionNoncoding regionsSequence variantsPhenotypic consequencesCRISPR screensGenetic basisGenetic variantsGenetic differencesDiverse phenotypesGene expressionRegulatory functionsHuman evolutionFunctional variationGenomeUnique phenotypePhenotypeRegulatory impactModel systemVariantsGenesMulticenter integrated analysis of noncoding CRISPRi screens
Yao D, Tycko J, Oh J, Bounds L, Gosai S, Lataniotis L, Mackay-Smith A, Doughty B, Gabdank I, Schmidt H, Guerrero-Altamirano T, Siklenka K, Guo K, White A, Youngworth I, Andreeva K, Ren X, Barrera A, Luo Y, Yardımcı G, Tewhey R, Kundaje A, Greenleaf W, Sabeti P, Leslie C, Pritykin Y, Moore J, Beer M, Gersbach C, Reddy T, Shen Y, Engreitz J, Bassik M, Reilly S. Multicenter integrated analysis of noncoding CRISPRi screens. Nature Methods 2024, 21: 723-734. PMID: 38504114, PMCID: PMC11009116, DOI: 10.1038/s41592-024-02216-7.Peer-Reviewed Original ResearchCis-regulatory elementsCRISPR interferenceSingle guide RNADetection of cis-regulatory elementsGuide RNAsCandidate cis-regulatory elementsNoncoding cis-regulatory elementsDNA strand biasGene regulatory landscapeCis-regulatory mechanismsNoncoding genomeNoncoding elementsTranscribed regionsStrand biasHuman cell linesCRISPR screensFunctional characterizationTranscriptional effectsGenomeK562 cellsRegulatory landscapeCell linesConsortium effortCharacterization CenterRNA
2021
Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells
Jagoda E, Xue JR, Reilly SK, Dannemann M, Racimo F, Huerta-Sanchez E, Sankararaman S, Kelso J, Pagani L, Sabeti PC, Capellini TD. Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells. Molecular Biology And Evolution 2021, 39: msab304. PMID: 34662402, PMCID: PMC8760939, DOI: 10.1093/molbev/msab304.Peer-Reviewed Original ResearchConceptsCis-regulatory elementsGene expressionPutative cis-regulatory elementsParallel reporter assaysImmune transcription factorsReporter gene expressionExpression of genesGenic targetsSelective sweepsMPRA dataInnate immune pathwaysPositive selectionTranscription factorsEndogenous sequencesReporter assaysAntiviral defenseDriver variantsGenetic variantsFunctional significanceImmune pathwaysWhite blood cell countGenesModern humansPotential immune responseBlood cell countDirect characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR–FlowFISH
Reilly SK, Gosai SJ, Gutierrez A, Mackay-Smith A, Ulirsch JC, Kanai M, Mouri K, Berenzy D, Kales S, Butler GM, Gladden-Young A, Bhuiyan RM, Stitzel ML, Finucane HK, Sabeti PC, Tewhey R. Direct characterization of cis-regulatory elements and functional dissection of complex genetic associations using HCR–FlowFISH. Nature Genetics 2021, 53: 1166-1176. PMID: 34326544, PMCID: PMC8925018, DOI: 10.1038/s41588-021-00900-4.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingBayes TheoremClustered Regularly Interspaced Short Palindromic RepeatsDelta-5 Fatty Acid DesaturaseDeoxyribonuclease IFatty Acid DesaturasesFlow CytometryGATA1 Transcription FactorHumansIn Situ Hybridization, FluorescenceK562 CellsLIM Domain ProteinsModels, GeneticPolymorphism, Single NucleotideProto-Oncogene ProteinsQuantitative Trait LociRegulatory Sequences, Nucleic AcidRNA, Guide, CRISPR-Cas SystemsConceptsCis-regulatory elementsGenome-wide association signalsGenome functionEpigenetic mappingComplex genetic associationsFunctional dissectionNearest geneGenetic variationAssociation signalsNative transcriptsTarget genesCausal variantsMultiple genesEndogenous functionsReporter assaysGenesCre activitySitu hybridizationGenetic associationFlow cytometryLociTranscriptsHierarchical Bayesian modelReaction fluorescenceHybridization