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Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains
- Source :
- Molecular Neurodegeneration, Vol 16, Iss 1, Pp 1-22 (2021)
- Publication Year :
- 2021
- Publisher :
- BMC, 2021.
-
Abstract
- Abstract 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. Graphical Abstract
Details
- Language :
- English
- ISSN :
- 17501326
- Volume :
- 16
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Molecular Neurodegeneration
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.5f8f0005adc8489a84cea23c2baf2b57
- Document Type :
- article
- Full Text :
- https://doi.org/10.1186/s13024-021-00481-0