2025
A map of enhancer regions in primary human neural progenitor cells using capture STARR-seq.
Gaynor-Gillett S, Cheng L, Shi M, Liu J, Wang G, Spector M, Guo Q, Qi L, Flaherty M, Wall M, Hwang A, Gu M, Chen Z, Chen Y, Moran J, Zhang J, Lee D, Gerstein M, Geschwind D, White K. A map of enhancer regions in primary human neural progenitor cells using capture STARR-seq. Genome Research 2025, 35: 1887-1901. PMID: 40645663, PMCID: PMC12315878, DOI: 10.1101/gr.279584.124.Peer-Reviewed Original ResearchConceptsGenome-wide association studiesNoncoding regulatory regionEffects of genetic variationHuman neural progenitor cellsDisease-associated pathwaysNeural progenitor cellsEnhanced activityNervous system developmentSTARR-seqAssociation studiesRegulatory networksRegulatory regionsCRISPR deletionGenetic variationActivity enhancementFunctional characterizationProgenitor cellsEnhancer regionExpression analysisEnhancer deletionTarget genesGene expressionGenesDevelopmental timepointsDeletionTUG protein acts through a disordered region to organize the early secretory pathway
Parchure A, Tejada H, Xi Z, Kim Y, Su M, Yan Y, Julca-Zevallos O, Alcázar-Román A, Villemeur M, Liu X, Toomre D, Raote I, Bogan J. TUG protein acts through a disordered region to organize the early secretory pathway. Nature Communications 2025, 16: 5518. PMID: 40593538, PMCID: PMC12218103, DOI: 10.1038/s41467-025-60691-8.Peer-Reviewed Original ResearchConceptsRegulation of GLUT4 traffickingEarly secretory pathwayMembrane trafficking pathwaysSoluble cargo proteinsCentral regulatorN-terminal regionBiomolecular condensates in vitroCondensates in vitroNetwork of tubulesCOPII vesiclesCOPI vesiclesCis-GolgiGolgi morphologyCargo proteinsGLUT4 traffickingSecretory pathwayTrafficking pathwaysIntermediate compartmentDisordered regionsDeletionProteinVesiclesCollagen secretionPathwayGolgiPhenotypic complexities of rare heterozygous neurexin-1 deletions
Fernando M, Fan Y, Zhang Y, Tokolyi A, Murphy A, Kammourh S, Deans P, Ghorbani S, Onatzevitch R, Pero A, Padilla C, Williams S, Flaherty E, Prytkova I, Cao L, Knowles D, Fang G, Slesinger P, Brennand K. Phenotypic complexities of rare heterozygous neurexin-1 deletions. Nature 2025, 642: 710-720. PMID: 40205044, DOI: 10.1038/s41586-025-08864-9.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsCalcium-Binding ProteinsCell Adhesion Molecules, NeuronalDNA Copy Number VariationsFemaleGABAergic NeuronsGene DeletionHeterozygoteHumansInduced Pluripotent Stem CellsLoss of Function MutationMaleMiceNeural Cell Adhesion MoleculesPhenotypeSequence DeletionSynapsesConceptsLoss-of-functionGain-of-functionGain-of-function mechanismCopy number variantsSynaptic activityCell type-specific effectsCell adhesion proteinsPrecision medicineIncreased wild-typeSplicing resultsAlternative splicingIsoform repertoireNRXN1 deletionsAberrant splicingHuman induced pluripotent stem cellsPatient-specific mutationsIncreased synaptic activityDecreased synaptic activityMutant isoformsNRXN1Associated with riskPluripotent stem cellsHeterozygous deletionWild-typeDeletionBorrelia burgdorferi serine protease HtrA is a pleiotropic regulator of stress response, motility, flagellar hemostasis, and infectivity
Zhang K, Sze C, Zhao H, Liu J, Li C. Borrelia burgdorferi serine protease HtrA is a pleiotropic regulator of stress response, motility, flagellar hemostasis, and infectivity. Communications Biology 2025, 8: 341. PMID: 40025221, PMCID: PMC11873206, DOI: 10.1038/s42003-025-07781-x.Peer-Reviewed Original ResearchConceptsBacterial stress responseStress responseRegulators of bacterial stress responseExpression of htrAFamily of serine proteasesSerine protease HtrACryo-electron tomography analysisRegulation of stress responsesLoss-of-function studiesMurine model of Lyme diseaseChemotaxis proteinsHtrA mutantVirulence determinantsDeletion mutantsFollow-up mechanistic studiesProtease HtrAPleiotropic regulatorProtease AEndogenous promoterHtrAPleiotropic rolesSerine proteasesDeletionBacterial locomotionMutants
2024
Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes
Huguet G, Renne T, Poulain C, Dubuc A, Kumar K, Kazem S, Engchuan W, Shanta O, Douard E, Proulx C, Jean-Louis M, Saci Z, Mollon J, Schultz L, Knowles E, Cox S, Porteous D, Davies G, Redmond P, Harris S, Schumann G, Dumas G, Labbe A, Pausova Z, Paus T, Scherer S, Sebat J, Almasy L, Glahn D, Jacquemont S. Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes. Cell Genomics 2024, 4: 100721. PMID: 39667348, PMCID: PMC11701252, DOI: 10.1016/j.xgen.2024.100721.Peer-Reviewed Original ResearchConceptsCopy-number variantsGenome-wide association studiesAssociation studiesCognitive abilitiesBiological processesEffect of gene dosageNeurodevelopmental disordersAssociated with cognitionHigher cognitive performanceGene dosageGene setsAssociated with higher cognitive performanceCognitive performanceGenesCell typesEffect sizeCognitionDeletionDuplicationDisordersNon-brain tissuesMedical comorbiditiesAbilityVariantsBrainMechanistic Investigation of Human DPP9 Deficiency
Xiao T, Brewer J, Zhou L, Han A, Takabe Y, Carlino M, Blackburn H, Flavell R. Mechanistic Investigation of Human DPP9 Deficiency. Blood 2024, 144: 5699-5699. DOI: 10.1182/blood-2024-211123.Peer-Reviewed Original ResearchHuman HSPCsDevelopment of human immune systemHuman NLRP1Loss of hematopoietic cellsHumanized mouse modelHuman hematopoietic stemStem cells in vivoSensors of infectionLaboratory mouse strainsCells in vivoHuman immune systemMouse genomeHematopoietic stemHuman hematopoiesisHematopoietic cellsCellular stressNegative regulatorPancytopeniaProgenitor cellsMouse strainsRegulatory pathwaysMouse modelHSPCsImmune systemDeletionImproved methods for genetic manipulation of the alkaliphile Halalkalibacterium halodurans
Wencker F, Lyon S, Breaker R. Improved methods for genetic manipulation of the alkaliphile Halalkalibacterium halodurans. Frontiers In Microbiology 2024, 15: 1465811. PMID: 39360312, PMCID: PMC11445130, DOI: 10.3389/fmicb.2024.1465811.Peer-Reviewed Original ResearchmiR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression
Fernández-Tussy P, Cardelo M, Zhang H, Sun J, Price N, Boutagy N, Goedeke L, Cadena-Sandoval M, Xirouchaki C, Brown W, Yang X, Pastor-Rojo O, Haeusler R, Bennett A, Tiganis T, Suárez Y, Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression. JCI Insight 2024, 9: e168476. PMID: 39190492, PMCID: PMC11466198, DOI: 10.1172/jci.insight.168476.Peer-Reviewed Original ResearchMiR-33Regulation of biological processesMitochondrial fatty acid oxidationRegulation of lipid metabolismNon-alcoholic fatty liver diseaseDevelopment of effective therapeuticsFatty acid oxidationLipid synthesisProgression of non-alcoholic fatty liver diseaseMitochondrial functionTarget genesBiological processesComplex diseasesNon-alcoholic steatohepatitisLipid accumulationDeletionDevelopment of non-alcoholic fatty liver diseasePathway activationLipid metabolismProgress to non-alcoholic steatohepatitisAcid oxidationHCC progressionEffective therapeuticsTherapeutic targetHepatocellular carcinomaCytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation
LaMoia T, Hubbard B, Guerra M, Nasiri A, Sakuma I, Kahn M, Zhang D, Goodman R, Nathanson M, Sancak Y, Perelis M, Mootha V, Shulman G. Cytosolic calcium regulates hepatic mitochondrial oxidation, intrahepatic lipolysis, and gluconeogenesis via CAMKII activation. Cell Metabolism 2024, 36: 2329-2340.e4. PMID: 39153480, PMCID: PMC11446666, DOI: 10.1016/j.cmet.2024.07.016.Peer-Reviewed Original ResearchGlutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression
Asantewaa G, Tuttle E, Ward N, Kang Y, Kim Y, Kavanagh M, Girnius N, Chen Y, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales T, Taylor K, Alimohammadi F, Duncan R, Sechrist Z, Agostini-Vulaj D, Schafer X, Chang H, Smith Z, O’Connor T, Whelan S, Selfors L, Crowdis J, Gray G, Bronson R, Brenner D, Rufini A, Dirksen R, Hezel A, Huber A, Munger J, Cravatt B, Vasiliou V, Cole C, DeNicola G, Harris I. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression. Nature Communications 2024, 15: 6152. PMID: 39034312, PMCID: PMC11271484, DOI: 10.1038/s41467-024-50454-2.Peer-Reviewed Original ResearchConceptsGlutamate-cysteine ligase catalytic subunitLipid abundanceLipogenic enzyme expressionAbundance in vivoLipid productionCatalytic subunitRepress Nrf2Transcription factorsNrf2 repressionAdult tissuesSynthesis of GSHEnzyme expressionNon-redundantRedox bufferMouse liverLoss of GSHTriglyceride productionIn vivo modelsAbundanceGlutathione synthesisLiver balanceFat storesOxidative stressLipidDeletionMicroglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK
Olveda G, Barasa M, Hill R. Microglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK. Cell Reports 2024, 43: 114385. PMID: 38935500, PMCID: PMC11304498, DOI: 10.1016/j.celrep.2024.114385.Peer-Reviewed Original ResearchA newly identified gene Ahed plays essential roles in murine haematopoiesis
Nakai R, Yokota T, Tokunaga M, Takaishi M, Yokomizo T, Sudo T, Shi H, Yasumizu Y, Okuzaki D, Kokubu C, Tanaka S, Takaoka K, Yamanishi A, Yoshida J, Watanabe H, Kondoh G, Horie K, Hosen N, Sano S, Takeda J. A newly identified gene Ahed plays essential roles in murine haematopoiesis. Nature Communications 2024, 15: 5090. PMID: 38918373, PMCID: PMC11199565, DOI: 10.1038/s41467-024-49252-7.Peer-Reviewed Original ResearchConceptsMutant embryonic stem cellsConditional knockoutUncharacterised genesHaematopoietic cellsNuclear proteinsFunctional genesHaematopoiesis in vivoAssociated with malignancyBiological functionsGenesSomatic mutationsEmbryonic stem cellsHaematopoietic developmentTransplantation experimentsHaematological malignanciesDeletionAdult miceCancer patientsCoordinated actionEmbryonic dayStem cellsHaematopoiesisMurine haematopoiesisCellsMalignancyRegulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease
Huang Y, Wang M, Ni H, Zhang J, Li A, Hu B, Junqueira Alves C, Wahane S, Rios de Anda M, Ho L, Li Y, Kang S, Neff R, Kostic A, Buxbaum J, Crary J, Brennand K, Zhang B, Zou H, Friedel R. Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease. Nature Neuroscience 2024, 27: 1489-1504. PMID: 38802590, PMCID: PMC11346591, DOI: 10.1038/s41593-024-01664-w.Peer-Reviewed Original ResearchPlexin-B1Alzheimer's diseaseGlial netsNetwork hub genesLate-onset ADPlaque-associated astrocytesPathophysiology of Alzheimer's diseaseMouse AD modelPlaque compactionNeuritic dystrophyHub genesGuidance receptorsTranscriptional changesAD modelAmyloid depositsAmyloidReducing neuroinflammationGlial cellsReactive astrocytesReceptor Plexin-B1Net activityGlial processesDeletionGenesCell distanceA comprehensive benchmark of graph-based genetic variant genotyping algorithms on plant genomes for creating an accurate ensemble pipeline
Du Z, He J, Jiao W. A comprehensive benchmark of graph-based genetic variant genotyping algorithms on plant genomes for creating an accurate ensemble pipeline. Genome Biology 2024, 25: 91. PMID: 38589937, PMCID: PMC11003132, DOI: 10.1186/s13059-024-03239-1.Peer-Reviewed Original ResearchConceptsPlant genomesGenotyping methodsComplexity of plant genomesHeterozygous plant genomesGenotypic algorithmsGenotype millionsShort readsGenomic contextGenomic diversitySequencing technologiesHuman genomeGenomeGenetic variantsExcessive repeatsVariant typeGenotypesStructural variationsEnsemble pipelinePlantsConclusionsOur studyVariant genotypesGenotype performanceVariantsDeletionSequenceDivergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse
Smagris E, Shihanian L, Mintah I, Bigdelou P, Livson Y, Brown H, Verweij N, Hunt C, Johnson R, Greer T, Hartford S, Hindy G, Sun L, Nielsen J, Halasz G, Lotta L, Murphy A, Sleeman M, Gusarova V. Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse. PLOS Genetics 2024, 20: e1011179. PMID: 38437227, PMCID: PMC10939284, DOI: 10.1371/journal.pgen.1011179.Peer-Reviewed Original ResearchConceptsAssociation studiesExome-wide association studyHuman genome-wide association studiesGenome-wide association studiesLoss of function variantsFamily enzymesMissense variantsObserved phenotypesFunctional variantsAberrant localizationProtein instabilityAncestry groupsHepatic triglyceride accumulationDivergent rolesLiver phenotypePhysiological functionsTriglyceride accumulationPhenotypeDeletionMouse liverIn vitro studiesHepatic cellsProteinEnzymeKnockout miceNoninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study
Bellair M, Amaral E, Ouren M, Roark C, Kim J, O'Connor A, Soriano A, Schindler M, Wapner R, Stone J, Tavella N, Merriam A, Perley L, Breman A, Beaudet A. Noninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study. Prenatal Diagnosis 2024, 44: 304-316. PMID: 38411249, DOI: 10.1002/pd.6529.Peer-Reviewed Original ResearchConceptsNoninvasive prenatal genetic testingLow-risk pregnanciesConcept clinical studyCopy number analysisPrenatal genetic testingNext-generation sequencingPlacental mosaicismMaternal bloodAneuploidy resultsMeasures of test performanceCK stainingCVS casesClinical studiesGenetic testingNucleated cellsTrophoblastRed cellsNumber analysisPregnancyBloodDeletions/duplicationsAneuploidyDeletionAmniocentesisCellsMitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility
Ergun Y, Imamoglu A, Cozzolino M, Demirkiran C, Basar M, Garg A, Yildirim R, Seli E. Mitochondrial Unfolded Protein Response Gene Clpp Is Required for Oocyte Function and Female Fertility. International Journal Of Molecular Sciences 2024, 25: 1866. PMID: 38339144, PMCID: PMC10855406, DOI: 10.3390/ijms25031866.Peer-Reviewed Original ResearchConceptsCaseinolytic peptidase PMouse modelProtein homeostasisStress responseUnfolded protein stress responseProtein stress responseCumulus/granulosa cellsOocyte competenceOocyte functionGlobal deletionFunctional abnormalitiesGenes clpPMetabolic stress responseFemale subfertilityFemale infertilityOocyte-specificOocytesReproductive functionMtUPRMiceProtein degradationReproductive competenceFemale fertilityDeletionHomeostasisP722: Low-level large deletions in mitochondria genomes: A potential diagnosis of mitochondrial diseases
Yang J, Chen T, Kao E, Dong J, Lattier J, Dai H, Meng L, Xia F, Schmitt E, Peacock S, Craigen W, Rigobello R, Wong L, Eng C, Wang Y. P722: Low-level large deletions in mitochondria genomes: A potential diagnosis of mitochondrial diseases. Genetics In Medicine Open 2024, 2: 101626. DOI: 10.1016/j.gimo.2024.101626.Peer-Reviewed Original Research
2023
CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Hammerschmidt P, Steculorum S, Bandet C, Del Río-Martín A, Steuernagel L, Kohlhaas V, Feldmann M, Varela L, Majcher A, Quatorze Correia M, Klar R, Bauder C, Kaya E, Porniece M, Biglari N, Sieben A, Horvath T, Hornemann T, Brodesser S, Brüning J. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nature Communications 2023, 14: 7824. PMID: 38016943, PMCID: PMC10684560, DOI: 10.1038/s41467-023-42595-7.Peer-Reviewed Original ResearchConceptsMitochondrial stressSpecific ceramide speciesSteroidogenic factor 1Hypothalamic neuronsMitochondrial dynamicsMitochondrial morphologyCeramide synthaseObese miceGlucose homeostasisCeramide speciesCeramide synthesisConditional deletionHypothalamic lipotoxicityCultured hypothalamic neuronsAdverse metabolic effectsFactor 1High-fat dietImpairs glucose homeostasisDiet-induced alterationsCerS6DeletionHomeostasisGlucose toleranceCeramideInsulin sensitivitySis2 regulates yeast replicative lifespan in a dose-dependent manner
Ölmez T, Moreno D, Liu P, Johnson Z, McGinnis M, Tu B, Hochstrasser M, Acar M. Sis2 regulates yeast replicative lifespan in a dose-dependent manner. Nature Communications 2023, 14: 7719. PMID: 38012152, PMCID: PMC10682402, DOI: 10.1038/s41467-023-43233-y.Peer-Reviewed Original ResearchConceptsYeast replicative lifespanReplicative lifespanRNA-seq experimentsCoenzyme A biosynthesis pathwayYeast lifespanYeast strainsStrain librariesLifespan regulationRNA-seqGene networksDose-dependent mannerLifespan extensionTranscriptional increaseYeastLifespan measurementsWild-typeGenesMachinery componentsStrainMicrofluidic platformApplications of microfluidic platformsLifespanDeletionCoenzymePathway
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