Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer's disease brains.
Mol Neurodegener
; 16(1): 58, 2021 08 24.
Article
em En
| MEDLINE
| ID: mdl-34429139
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cromatina
/
Neuroglia
/
Caracteres Sexuais
/
Doença de Alzheimer
Tipo de estudo:
Prognostic_studies
Limite:
Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article