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 cells
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 countFunctional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation
Khetan S, Kales S, Kursawe R, Jillette A, Ulirsch JC, Reilly SK, Ucar D, Tewhey R, Stitzel ML. Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation. Nature Communications 2021, 12: 5242. PMID: 34475398, PMCID: PMC8413311, DOI: 10.1038/s41467-021-25514-6.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesSingle nucleotide polymorphismsTranscriptional activationEndoplasmic reticulum (ER) stress conditionsTranscriptional stress responseCis-regulatory effectsParallel reporter assaysT2D single nucleotide polymorphismsHigh linkage disequilibriumMultiple single nucleotide polymorphismsT2D genetic riskT2D-associated single nucleotide polymorphismsMIN6 β-cellsChromatin accessibilityCandidate single nucleotide polymorphismsT2D geneticsHuman genomeAssociation signalsRepetitive elementsFunctional characterizationNuclear elementsMolecular mechanismsReporter assaysStress responseAssociation studies
2020
Massively parallel discovery of human-specific substitutions that alter enhancer activity
Uebbing S, Gockley J, Reilly SK, Kocher AA, Geller E, Gandotra N, Scharfe C, Cotney J, Noonan JP. Massively parallel discovery of human-specific substitutions that alter enhancer activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 118: e2007049118. PMID: 33372131, PMCID: PMC7812811, DOI: 10.1073/pnas.2007049118.Peer-Reviewed Original ResearchConceptsHuman-specific substitutionsHuman-gained enhancersGenetic changesEnhancer functionEnhancer activityHuman-specific genetic changesHuman evolutionGene regulatory elementsBackground genetic variationAncestral functionRegulatory evolutionEnhancer assaysGenetic variationRegulatory elementsNeural stem cellsHuman traitsNovel activityNonadditive wayRegulatory activityStem cellsFunctional impactDifferential activityParallel discoveryEnhancerEvolution
2016
Evolution of Gene Regulation in Humans.
Reilly SK, Noonan JP. Evolution of Gene Regulation in Humans. Annual Review Of Genomics And Human Genetics 2016, 17: 45-67. PMID: 27147089, DOI: 10.1146/annurev-genom-090314-045935.Peer-Reviewed Original ResearchConceptsRegulatory functionsGene regulationHuman-specific genetic changesGenetic changesNovel human phenotypeNew regulatory functionInduced pluripotent stem cellsPluripotent stem cellsUnique biological featuresSpecific regulatory changesHomologous humanGenome editingGene expressionHuman phenotypesPrimate cellsHuman evolutionRegulatory activityStem cellsExpression levelsNonhuman primate cellsBiological featuresRegulationRegulatory innovationCellsHumans
2015
Evolutionary changes in promoter and enhancer activity during human corticogenesis
Reilly SK, Yin J, Ayoub AE, Emera D, Leng J, Cotney J, Sarro R, Rakic P, Noonan JP. Evolutionary changes in promoter and enhancer activity during human corticogenesis. Science 2015, 347: 1155-1159. PMID: 25745175, PMCID: PMC4426903, DOI: 10.1126/science.1260943.Peer-Reviewed Original ResearchConceptsCorrelated gene expression patternsSimilar transcription factorsGene expression patternsCommon regulatory mechanismHuman cortical evolutionPotential regulatory changesEvolutionary changeEpigenetic profilingEvolutionary expansionTranscription factorsGenetic mechanismsSite enrichmentEnhancer activityDevelopmental processesExpression patternsHuman corticogenesisRegulatory mechanismsMouse corticogenesisHuman higher cognitionCortical evolutionPromoterCorticogenesisCoordinated patternNeuronal proliferationEnhancer