Molecular neurodegeneration · 2021
Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.
Сравнительное исследованиеСтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Barrera Julio, Song Lingyun, Gamache Julia E, Garrett Melanie E, Safi Alexias, Yun Young, Premasinghe Ivana, Sprague Daniel, Chipman Danielle, Li Jeffrey, Fradin Hélène, Soldano Karen, Gordân Raluca, Ashley-Koch Allison E, Crawford Gregory E, Chiba-Falek Ornit
Аннотация
BACKGROUND: In the post-GWAS era, there is an unmet need to decode the underpinning genetic etiologies of late-onset Alzheimer's disease (LOAD) and translate the associations to causation.
METHODS: We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner.
RESULTS: We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets.
CONCLUSIONS: Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.
METHODS: We conducted ATAC-seq profiling using NeuN sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner.
RESULTS: We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100 kb of SNP). While the non-neuronal nuclei did not show LOAD-specific differences, stratification by sex identified 842 LOAD-specific chromatin accessibility sites in females. Seven of these sex-dependent sites in the non-neuronal samples overlapped LOAD-GWAS regions including APOE. LOAD loci were functionally validated using single-nuclei RNA-seq datasets.
CONCLUSIONS: Using brain sorted-nuclei enabled the identification of sex-dependent cell type-specific LOAD alterations in chromatin structure. These findings enhance the interpretation of LOAD-GWAS discoveries, provide potential pathomechanisms, and suggest novel LOAD-loci.
Предметные рубрики MeSH
AgedAged, 80 and overAlzheimer DiseaseBase SequenceBinding SitesCell FractionationCell NucleusChromatinDatasets as TopicFemaleFlow CytometryGene ExpressionGene LibraryGenome-Wide Association StudyHumansMaleMiddle AgedNeurogliaNeuronsSex CharacteristicsSingle-Cell AnalysisTemporal LobeTranscription Factors