Timothy Nottoli, PhD
Cards
About
Titles
Senior Research Scientist in Comparative Medicine
Co-director, Yale Genome Editing CenterAppointments
Comparative Medicine
Senior Research ScientistPrimary
Other Departments & Organizations
Education & Training
- PhD
- University of California at Berkeley (1992)
- BA
- University of California at Santa Barbara (1985)
- Fellow
- Yale University
Research
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 ResearchConceptsHuman-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 developmentSpecies
2023
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
Zhao S, Mekbib K, van der Ent M, Allington G, Prendergast A, Chau J, Smith H, Shohfi J, Ocken J, Duran D, Furey C, Hao L, Duy P, Reeves B, Zhang J, Nelson-Williams C, Chen D, Li B, Nottoli T, Bai S, Rolle M, Zeng X, Dong W, Fu P, Wang Y, Mane S, Piwowarczyk P, Fehnel K, See A, Iskandar B, Aagaard-Kienitz B, Moyer Q, Dennis E, Kiziltug E, Kundishora A, DeSpenza T, Greenberg A, Kidanemariam S, Hale A, Johnston J, Jackson E, Storm P, Lang S, Butler W, Carter B, Chapman P, Stapleton C, Patel A, Rodesch G, Smajda S, Berenstein A, Barak T, Erson-Omay E, Zhao H, Moreno-De-Luca A, Proctor M, Smith E, Orbach D, Alper S, Nicoli S, Boggon T, Lifton R, Gunel M, King P, Jin S, Kahle K. Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations. Nature Communications 2023, 14: 7452. PMID: 37978175, PMCID: PMC10656524, DOI: 10.1038/s41467-023-43062-z.Peer-Reviewed Original ResearchConceptsEphrin receptor B4Galen malformationBrain arteriovenous malformationsP120 RasGAPTransmitted variantsArteriovenous malformationsDe novo variantsSingle-cell transcriptomesSignificant burdenCerebrovascular developmentIntegrative genomic analysisEndothelial cellsVenous networkAdditional probandsMalformationsNovo variantsMissense variantsGenomic analysisDevelopmental angiogenesisVascular developmentDamaging variantsVeinRasGAPIntegrated analysisPatientsIsradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities
Stölting G, Dinh H, Volkert M, Hellmig N, Schewe J, Hennicke L, Seidel E, Oberacher H, Zhang J, Lifton R, Urban I, Long M, Rivalan M, Nottoli T, Scholl U. Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities. JCI Insight 2023, 8: e162468. PMID: 37698934, PMCID: PMC10619505, DOI: 10.1172/jci.insight.162468.Peer-Reviewed Original ResearchConceptsPrimary aldosteronismNeurologic abnormalitiesZona glomerulosaIntracellular calciumElevated aldosterone/renin ratioCalcium channel blocker isradipineAldosterone/renin ratioL-type calcium channel Cav1.3Aldosterone-producing lesionsAdrenal aldosterone-producing adenomaHigh-salt dietTonic-clonic seizuresChannel blocker isradipineReduced body weightAldosterone-producing adenomaTherapy of patientsElevated intracellular calciumFunction mutationsDe novo germline mutationsDays of ageIsradipine therapyAldosterone levelsRenin ratioSerum aldosteroneRotarod test
2022
Loss of Serum Glucocorticoid-Inducible Kinase 1 SGK1 Worsens Malabsorption and Diarrhea in Microvillus Inclusion Disease (MVID)
Ahsan K, dos Reis DC, Barbieri A, Sumigray KD, Nottoli T, Salas PJ, Ameen NA. Loss of Serum Glucocorticoid-Inducible Kinase 1 SGK1 Worsens Malabsorption and Diarrhea in Microvillus Inclusion Disease (MVID). Journal Of Clinical Medicine 2022, 11: 4179. PMID: 35887942, PMCID: PMC9319011, DOI: 10.3390/jcm11144179.Peer-Reviewed Original ResearchMicrovillus inclusion diseaseSevere diarrheaInclusion diseaseFluid secretionCystic fibrosis transmembrane conductance regulatorDouble knockout miceMicrovillus inclusionsGlucocorticoid-inducible kinase 1Carbohydrate malabsorptionKnockout miceIntestinal carbohydrateDiarrheaDiarrheal diseaseMalabsorptionMiceVillus enterocytesDiseaseLoss of MYO5BFunction mutationsApical cystic fibrosis transmembrane conductance regulatorFibrosis transmembrane conductance regulatorKinase 1SecretionIntestineTransmembrane conductance regulatorA Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus‐like Disease in Mice
Meas R, Nititham J, Taylor KE, Maher S, Clairmont K, Carufe KEW, Kashgarian M, Nottoli T, Cheong A, Nagel ZD, Gaffney PM, Criswell LA, Sweasy JB. A Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus‐like Disease in Mice. ACR Open Rheumatology 2022, 4: 760-770. PMID: 35708944, PMCID: PMC9469486, DOI: 10.1002/acr2.11471.Peer-Reviewed Original ResearchSystemic lupus erythematosusAntinuclear antibodiesMSH6 variantsLupus erythematosusMSH6 mutationsMouse modelSingle nucleotide polymorphismsDevelopment of SLELevel of ANAInfiltration of CD68Lupus-like diseaseInflammatory lung diseasesLung alveolar spacesRepair genesMismatch repair genesLung diseaseHealthy controlsPeyer's patchesWildtype miceAlveolar spaceCRISPR/Cas9 gene targetingSomatic hypermutation frequenciesAutoimmune phenotypeMiceDifferent mismatch repair genesSerum and Glucocorticoid‐Inducible Kinase 1 (SGK1): An Important Contributor to Diarrhea and Malabsorption in Microvillus Inclusion Disease (MVID)
Ahsan K, dos Reis D, Barbieri A, Sumigray K, Nottoli T, Salas P, Ameen N. Serum and Glucocorticoid‐Inducible Kinase 1 (SGK1): An Important Contributor to Diarrhea and Malabsorption in Microvillus Inclusion Disease (MVID). The FASEB Journal 2022, 36 DOI: 10.1096/fasebj.2022.36.s1.r5730.Peer-Reviewed Original ResearchMicrovillus inclusion diseaseGlucocorticoid-inducible kinase 1Severe diarrheaF miceInclusion diseaseCystic fibrosis transmembrane conductance regulatorFluid secretionWorsening of diarrheaMicrovillus inclusionsPhosphorylation of PDK1Kinase 1Intestinal lysatesSGK1 pathwayCarbohydrate malabsorptionER miceTamoxifen inductionBeta-ENaCDiarrheaDiarrheal diseaseSmall intestineMalabsorptionMiceDCKO miceGlucose lossPhosphorylation of SGK1Modeling 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 ResearchMeSH 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
2021
Mouse Embryonic Fibroblasts Isolated From Nthl1 D227Y Knockin Mice Exhibit Defective DNA Repair and Increased Genome Instability
Marsden CG, Das L, Nottoli TP, Kathe SD, Doublié S, Wallace SS, Sweasy JB. Mouse Embryonic Fibroblasts Isolated From Nthl1 D227Y Knockin Mice Exhibit Defective DNA Repair and Increased Genome Instability. DNA Repair 2021, 109: 103247. PMID: 34826736, PMCID: PMC8787541, DOI: 10.1016/j.dnarep.2021.103247.Peer-Reviewed Original ResearchConceptsGenomic instabilityEmbryonic fibroblastsExogenous DNA damaging agentsBifunctional DNA glycosylaseIncreased genome instabilityGenome editing technologyMurine embryonic fibroblastsDNA damaging agentsMouse embryonic fibroblastsNormal cellular metabolismDefective DNA repairHomozygous stateDNA glycosylase 1Genome instabilityMutant MEFsReplication stressDNA repairCellular phenotypesDNA glycosylaseEditing technologyCellular metabolismDamaging agentsWT proteinOxidative DNA damagePyrimidine lesionsEnhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)
Seidel E, Schewe J, Zhang J, Dinh HA, Forslund SK, Markó L, Hellmig N, Peters J, Muller DN, Lifton RP, Nottoli T, Stölting G, Scholl UI. Enhanced Ca2+ signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+). Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2014876118. PMID: 33879608, PMCID: PMC8092574, DOI: 10.1073/pnas.2014876118.Peer-Reviewed Original ResearchConceptsMild primary aldosteronismHigh-salt dietPrimary aldosteronismAldosterone productionNormal aldosterone productionPeak intracellular calcium concentrationRenin-angiotensin systemSystolic blood pressureEarly-onset hypertensionAdrenal glomerulosa cellsIntracellular calcium concentrationWild-type littermatesElevated intracellular CaCalcium entry pathwayCorresponding knockout miceFunction mutationsFH-IVPlasma aldosteroneRenin ratioBlood pressureChronic settingAdrenal morphologyZona glomerulosaGlomerulosa cellsAdrenal slicesRho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis
Li Q, Gulati A, Lemaire M, Nottoli T, Bale A, Tufro A. Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis. Kidney International 2021, 99: 1102-1117. PMID: 33412162, PMCID: PMC8076076, DOI: 10.1016/j.kint.2020.12.022.Peer-Reviewed Original ResearchConceptsRhoA activityRho-GAP domainActin stress fiber formationCell junction assemblySmall GTPase proteinsNovel candidate genesStress fiber formationBundles actinCytoskeleton regulationGTPase proteinsActomyosin contractilityJunction assemblyMYO9AAutosomal dominant focal segmental glomerulosclerosisCandidate genesGene contributionCytoskeletal apparatusUnconventional myosinNovel componentRhoA geneWhole-exome sequencingGene editingFSGS phenotypeMolecular causesCalmodulin interaction