Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
Abstract 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. Toward that goal, we conducted ATAC-seq profiling using neuronal nuclear protein (NeuN) sorted-nuclei from 40 frozen brain tissues to determine LOAD-specific changes in chromatin accessibility landscape in a cell-type specific manner. We identified 211 LOAD-specific differential chromatin accessibility sites in neuronal-nuclei, four of which overlapped with LOAD-GWAS regions (±100kb 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. In conclusion, 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. Furthermore, our results convey mechanistic insights into sex differences in LOAD risk and clinicopathology. GRAPHICAL ABSTRACTbiorxiv;2021.04.07.438835v1/UFIG1F1ufig1
Safi Alexias、Yun Young、Gamache Julia、Premasinghe Ivana、Sprague Daniel、Fradin H¨|l¨¨ne、Gordan Raluca、Crawford Gregory E.、Li Jeffrey、Chiba-Falek Ornit、Chipman Danielle、Soldano Karen、Garrett Melanie E.、Song Lingyun、Ashley-Koch Allison E.、Barrera Julio
Center for Genomic and Computational Biology, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical CenterCenter for Genomic and Computational Biology, Duke University Medical CenterCenter for Genomic and Computational Biology, Duke University Medical Center||Department of Biostatistics and Bioinformatics, Duke University Medical Center||Department of Computer Science, Duke UniversityCenter for Genomic and Computational Biology, Duke University Medical Center||Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center||Center for Advanced Genomic Technologies, Duke University Medical CenterCenter for Genomic and Computational Biology, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical CenterDuke Molecular Physiology Institute, Duke University Medical CenterDuke Molecular Physiology Institute, Duke University Medical CenterCenter for Genomic and Computational Biology, Duke University Medical CenterDuke Molecular Physiology Institute, Duke University Medical Center||Department of Medicine, Duke University Medical CenterDivision of Translational Brain Sciences, Department of Neurology, Duke University Medical Center||Center for Genomic and Computational Biology, Duke University Medical Center
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
ATAC-seqchromatin accessibilitynuclei sortinglate-onset Alzheimer’s diseasesnRNA-seqgene dysregulation
Safi Alexias,Yun Young,Gamache Julia,Premasinghe Ivana,Sprague Daniel,Fradin H¨|l¨¨ne,Gordan Raluca,Crawford Gregory E.,Li Jeffrey,Chiba-Falek Ornit,Chipman Danielle,Soldano Karen,Garrett Melanie E.,Song Lingyun,Ashley-Koch Allison E.,Barrera Julio.Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains[EB/OL].(2025-03-28)[2025-07-09].https://www.biorxiv.org/content/10.1101/2021.04.07.438835.点此复制
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