James Noonan, PhD
Cards
Appointments
Titles
co-Director of Graduate Studies, Genetics
Contact Info
Appointments
Titles
co-Director of Graduate Studies, Genetics
Contact Info
Appointments
Titles
co-Director of Graduate Studies, Genetics
Contact Info
About
Titles
Albert E. Kent Professor of Genetics and Professor of Neuroscience
co-Director of Graduate Studies, GeneticsBiography
Dr. Noonan received his undergraduate degree in Biology and English Literature (Honors) from Binghamton University in upstate New York. He carried out his graduate work with Dr. Richard Myers in the Department of Genetics, Stanford University, and received his Ph.D. in 2004. He did his postdoctoral work in Dr. Edward Rubin's lab at the Lawrence Berkeley National Laboratory and the U.S. Department of Energy Joint Genome Institute. Dr. Noonan joined the Yale Genetics faculty in September 2007.
Appointments
Genetics
ProfessorPrimaryNeuroscience
ProfessorSecondary
Other Departments & Organizations
- Center for Biomedical Data Science
- Computational Biology and Biomedical Informatics
- Dean's Workshops
- Genetics
- Genomics, Genetics, and Epigenetics
- Kavli Institute for Neuroscience
- Molecular Cell Biology, Genetics and Development
- Neuroscience
- Noonan Lab
- Wu Tsai Institute
- Yale Cancer Center
- Yale Center for Genomic Health
- Yale Combined Program in the Biological and Biomedical Sciences (BBS)
- Yale Stem Cell Center
- Yale Ventures
Education & Training
- Postdoctoral Fellow
- Lawrence Berkeley National Laboratory (2007)
- PhD
- Stanford University (2004)
- BS
- State University of New York at Binghamton (1997)
Research
Overview
Our laboratory has made multiple contributions over the last decade. We were the first to discover that HARs encode transcriptional enhancers with human-specific activity in the developing embryo (Prabhakar et al. 2008). We have since pioneered the development of humanized mouse models to understand how HARs alter developmental gene expression and drive the evolution of novel phenotypes. In a recent study, we found that the HAR HACNS1 upregulates expression of the transcription factor gene Gbx2 in limb bud chondrogenic mesenchyme, suggesting the human-specific gain of function in HACNS1 contributed to changes in skeletal patterning in human limb evolution (Dutrow et al. 2019).
We also developed methods to map and quantify the activity of gene regulatory elements during mammalian organogenesis, and to identify their gene targets (Cotney et al. 2012 and DeMare et al. 2013). Building on this work, we implemented comparative epigenetics approaches to identify uniquely human regulatory innovations by direct analysis of developing human and nonhuman tissues. This work discovered thousands of promoters and enhancers that have gained activity during human limb and neocortical development (Cotney et al. 2013 and Reilly et al. 2015). These studies have also identified biological pathways in limb and cortical development potentially altered by human-specific regulatory changes, providing the basis for understanding their effects using genetic and experimental models. We also leveraged these findings to understand general principles of developmental enhancer evolution and identify specific regulatory innovations contributing to the emergence of the mammalian neocortex (Emera et al. 2016). We also demonstrated that a major autism risk gene, CHD8, directly regulates other autism-associated genes during neurodevelopment, providing an entry point for deciphering gene regulatory networks contributing to autism risk (Cotney et al. 2015).
In the last several years, we have adopted massively parallel screening approaches to characterize gene regulatory functions contributing to the development and evolution of the human brain. We used massively parallel genome editing in human neural stem cells to disrupt thousands of enhancers active during human cortical development and identify enhancers, including HARs, required for neural stem cell self renewal (Geller et al. 2019). This study established a clear biological function for HARs in neurodevelopment. We have also used massively parallel reporter assays in neural stem cells to measure the effect of >32,000 uniquely human sequence changes on enhancer activity (Uebbing and Gockley et al. 2021).
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Steven Reilly, PhD
Curt Scharfe, MD, PhD, FACMG
Timothy Nottoli, PhD
Arya Mani, MD, FACC, FAHA
Sameet Mehta, PhD
Wenzhong Liu
Evolution, Molecular
Gene Regulatory Networks
Genomics
Publications
2024
CpG island turnover events predict evolutionary changes in enhancer activity
Kocher A, Dutrow E, Uebbing S, Yim K, Rosales Larios M, Baumgartner M, Nottoli T, Noonan J. CpG island turnover events predict evolutionary changes in enhancer activity. Genome Biology 2024, 25: 156. PMID: 38872220, PMCID: PMC11170920, DOI: 10.1186/s13059-024-03300-z.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsHuman-gained enhancersCpG islandsFunction of transcriptional enhancersEvolution of biological diversityHuman CpG islandsGene regulatory changesInfluence enhancer activityCpG island contentHistone modification levelsEnhanced activitySpecies-specific activityTrait evolutionNucleotide substitutionsHistone modificationsTranscriptional enhancersMouse orthologEvolutionary changesTurnover eventsModification levelsMammalian speciesMultiple tissuesEmbryonic developmentMouse diencephalonHuman embryonic developmentSpeciesMassively parallel disruption of enhancers active in human neural stem cells
Geller E, Noble M, Morales M, Gockley J, Emera D, Uebbing S, Cotney J, Noonan J. Massively parallel disruption of enhancers active in human neural stem cells. Cell Reports 2024, 43: 113693. PMID: 38271204, PMCID: PMC11078116, DOI: 10.1016/j.celrep.2024.113693.Peer-Reviewed Original ResearchCitationsAltmetricConceptsHuman neural stem cellsNeural stem cellsStem cellsProliferation phenotypeAssociated with neurodevelopmental disordersNeurodevelopmental disordersEnhanced disruptionHuman Accelerated RegionsNeural progenitor proliferationEffects of genetic variationHuman cortical evolutionProgenitor proliferationSelf-renewalNeural progenitorsProgenitor populationsCerebral cortexChromatin interactionsHuman cerebral cortexNeural progenitor populationsGene regulationRegulatory elementsConserved regionGene disruptionGenetic variationRegulatory relationships
2023
A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension
Gunawardhana K, Hong L, Rugira T, Uebbing S, Kucharczak J, Mehta S, Karunamuni D, Cabera-Mendoza B, Gandotra N, Scharfe C, Polimanti R, Noonan J, Mani A. A systems biology approach identifies the role of dysregulated PRDM6 in the development of hypertension. Journal Of Clinical Investigation 2023, 133: e160036. PMID: 36602864, PMCID: PMC9927944, DOI: 10.1172/jci160036.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsDevelopment of hypertensionParallel reporter assaysRenin inhibitor aliskirenNeural crest-derived cellsRenin-producing cellsSystems biology approachRNA-seq analysisCell-specific disruptionCrest-derived cellsSmooth muscle cellsMuscle cell proteinsSystemic hypertensionBlood pressureWT miceAntihypertensive drugsBiology approachSuper enhancersFine mappingWT littermatesThird intronMultiple GWASCollagen depositionMouse aortaReporter assaysFate mapping
2022
Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome
Dutrow EV, Emera D, Yim K, Uebbing S, Kocher AA, Krenzer M, Nottoli T, Burkhardt DB, Krishnaswamy S, Louvi A, Noonan JP. Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome. Nature Communications 2022, 13: 304. PMID: 35027568, PMCID: PMC8758698, DOI: 10.1038/s41467-021-27899-w.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAnimalsBase SequenceCell DifferentiationChondrocytesChondrogenesisEmbryo, MammalianEnhancer Elements, GeneticEpigenesis, GeneticExtremitiesGene Expression ProfilingGene Expression RegulationGene Knock-In TechniquesGenomeHomeodomain ProteinsHomozygoteHumansMesodermMice, Inbred C57BLModels, GeneticPan troglodytesPromoter Regions, GeneticTime FactorsConceptsHuman Accelerated RegionsGene expressionHuman-specific sequence changesDevelopmental gene regulationSingle-cell RNA sequencingGene regulatory functionsHuman evolutionEndogenous gene expressionAlters gene expressionSkeletal patterningMolecular functionsGene regulationChondrogenic mesenchymeMouse genomeRegulatory modificationHomozygous embryosLimb developmentTranscriptional enhancersTranscription factorsRNA sequencingEnhancer activityMouse embryosRegulatory functionsAccelerated regionSequence changes
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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsHuman-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
Origin and evolution of developmental enhancers in the mammalian neocortex
Emera D, Yin J, Reilly SK, Gockley J, Noonan JP. Origin and evolution of developmental enhancers in the mammalian neocortex. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e2617-e2626. PMID: 27114548, PMCID: PMC4868431, DOI: 10.1073/pnas.1603718113.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsRegulatory elementsDe novo birthMammalian stem lineageNovel regulatory sequencesWeak evolutionary constraintsMammalian neocortexBackground genomic sequencesDevelopmental enhancersEvolutionary constraintsMorphological innovationsStem lineageEutherian mammalsGenomic sequencesRegulatory sequencesPhylogenetic originComplex enhancerCell signalingGenomic backgroundMouse corticogenesisCell migrationMammalsMammalian forebrainEnhancerGenesLife cycle
2015
Chromatin Immunoprecipitation with Fixed Animal Tissues and Preparation for High-Throughput Sequencing
Cotney J, Noonan J. Chromatin Immunoprecipitation with Fixed Animal Tissues and Preparation for High-Throughput Sequencing. Cold Spring Harbor Protocols 2015, 2015: pdb.err087585. PMID: 25834253, PMCID: PMC5956515, DOI: 10.1101/pdb.err087585.Peer-Reviewed Original ResearchCitationsAltmetricThe autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment
Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nature Communications 2015, 6: 6404. PMID: 25752243, PMCID: PMC4355952, DOI: 10.1038/ncomms7404.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsASD risk genesRisk genesRegulatory networksAncient gene regulatory networksHuman neural stem cellsLoss of CHD8Specific regulatory networksGene regulatory networksCo-expression networkAutism risk genesEmbryonic mouse cortexChromatin modifiersIdentification of recurrentChromodomain-HelicaseChd8 knockdownNeural stem cellsMouse neurodevelopmentCHD8Human brain developmentFunction mutationsGenesStem cellsHuman neurodevelopmentNovo lossBrain developmentEvolutionary 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsCorrelated 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
2014
Evolution of Gene Regulation in Humans
Reilly S, Noonan J. Evolution of Gene Regulation in Humans. Annual Review Of Genomics And Human Genetics 2014, 17: 1-23. DOI: 10.1146/annurev-genom-090314-045935.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsCitationsConceptsRegulatory functionsGene regulationHuman-specific genetic changesGenetic changesNovel human phenotypeNew regulatory functionInduced pluripotent stem cellsPluripotent stem cellsUnique biological featuresSpecific regulatory changesHomologous humanGenome editingGene expressionHuman phenotypesFinal online publication datePrimate cellsHuman evolutionRegulatory activityStem cellsOnline publication dateExpression levelsNonhuman primate cellsBiological featuresRegulationRegulatory innovation
Academic Achievements and Community Involvement
honor Mallinckrodt Foundation Fellowship
National AwardEdward J. Mallinckrodt FoundationDetails08/01/2008United States
Links & Media
News
- March 02, 2023
James Noonan, Kent Professor of Genetics and Professor of Neuroscience takes a “uniquely human” path to genetics research
- January 10, 2023
A Therapeutic Target for High Blood Pressure Control
- July 21, 2022Source: YaleNews
Noonan appointed Kent Professor of Genetics and Professor of Neuroscience
- June 24, 2022
Evolutionary genetics and ancient DNA expert Diyendo Massilani joins Yale Genetics
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